Antibiotics in Laboratory Medicine, 6 Ed.

Chapter 14. Extravascular Antimicrobial Distribution and the Respective Blood and Urine Concentrations in Humans

David M. Bamberger, John W. Foxworth, Michael A. Kallenberger, Brian S. Pepito, and Dale N. Gerding

Systemically administered antimicrobials enter the vascular circulation and diffuse or are secreted into a variety of sites in the human body, in widely differing concentrations. The concentration of antimicrobials eventually achieved in a body site is the result of a complex set of factors that includes drug concentration, half-life, protein binding, lipid solubility, ionization, passive diffusion and active transport, extravascular site geometry, and degree of inflammation. Considerable data have been accumulated in the literature about antimicrobial distribution in humans, far more than can be reviewed completely in this chapter. Our purpose is to discuss the principles, models, and methods of assessing antimicrobial distribution in humans and to catalog that distribution in a number of representative extravascular sites.

Parenthetically, the presumed basis for a treatise of this kind, that is, that the extravascular site antimicrobial concentration correlates with the cure of infection at that site, has been demonstrated for some, but by no means all, infection sites. The ultimate cure of an infection entails far more variables than attainment of a specific concentration of an antimicrobial agent at the site of infection. Despite a presumed adequate antimicrobial concentration, the inflammatory milieu at sites of infection may be inhibitory to antimicrobial function (1). Nevertheless, the topic is discussed and the data presented on the assumption that extravascular antimicrobial concentrations within specific sites have at least some importance in the treatment of infection.

Sites of extravascular antimicrobial distribution may be divided into four major categories (2), as shown in Table 14.1. Antibiotic concentrations vary greatly from category to category and from site to site within categories. In general, the highest drug concentrations are found in certain secretory fluids, such as urine or bile, and the lowest in cerebrospinal fluid (CSF) and glandular secretions, such as breast milk and saliva (2).

Fluid-Filled Spaces

These sites provide the most readily interpretable data on extravascular drug distribution. The drug accumulates by means of passive diffusion, specimens rarely are contaminated by blood, and repeated samples can be obtained to profile the drug distribution and determine equilibrium conditions. Sites such as ascitic fluid, joint effusions, pleural effusions, amniotic fluid, pericardial effusions, bursae, blisters, and abscesses are classified in this category. These sites are also characterized by having a relatively small surface area for diffusion, compared with their volume. This results in a slow accumulation of antibiotic with repeated dosing, as well as lower peak and higher trough drug concentrations than those of serum (3,4). In humans, the need to perform an invasive procedure (needle aspiration) to obtain fluid limits the utility of these sites for routine sampling, but cutaneous blister models in humans and tissue cages and semipermeable implanted chambers in animals provide useful models of this type of extravascular site (5–7).

Excretory and Secretory Fluids

These fluids provide the greatest variability in achievable drug concentrations of all extravascular sites. Because many antimicrobials are actively secreted into urine or bile, tremendous concentration of drug is possible. In contrast, many glands and organs appear to pose a substantial barrier to penetration by antimicrobials (e.g., milk and prostatic fluid). Numerous glandular secretions have been studied for antimicrobial penetration, but bile, urine, sputum, and milk are the most frequently examined. Many of these fluids are readily obtained without the aid of invasive techniques (urine, sputum, milk, and saliva) and thus have been repetitively sampled over time to garner data on secretory rates. As with fluid-filled spaces, secretory fluids usually are free of blood contamination and thus provide the opportunity to determine antimicrobial concentrations quite reliably.

Spaces with Diffusion Barriers

Two body sites, the eye and the CSF, have traditionally been treated as unique because of the low concentration of many antimicrobials achieved there. Other secretory organs, such as breast and prostate, also pose barriers to drug penetration but are included under secretory organs. Although referred to as barriers to diffusion, active transport from CSF to blood or removal, by bulk CSF flow, of certain compounds such as penicillins may be a major reason for the low concentrations in CSF (8). Again, these sites provide reliable data about drug penetration because of their usual lack of blood contamination. However, the invasive nature of procedures used to obtain these fluids limits the number of determinations that can be made in patients.

Whole-body Tissues

Concentrations of antimicrobials in whole tissues are frequently difficult to interpret because of contamination of the tissues by blood and body fluids. Tissues have distinct compartments including interstitial fluid and cells, and cells contain various subcellular organelles and cytosol. Antimicrobial concentrations vary among these compartments. Some antimicrobials such as quinolones and macrolides attain high intracellular concentrations, whereas β-lactams and aminoglycosides do not. Further, the site of the infection may vary from being primarily extracellular or intracellular, making the knowledge of total tissue concentrations of questionable value (9). Despite these interpretation difficulties, whole tissue samples are among the specimens most frequently obtained for antimicrobial assay. We have included in this chapter our recommendations for the preparation and assay of whole tissues in order to make these determinations more reliable.

The use of human experimental models for extravascular distribution of antimicrobial agents is a potentially important development because it allows the controlled investigation of complex pharmacokinetic relationships seen in humans as intact individuals (10). The proper use and interpretation of these models can lead to a clearer understanding of the nature of drug distribution to sites outside the extravascular space. The primary experimental models currently under investigation include so-called skin-window techniques (both disk and chamber), skin-blister models (created by suction and irritant cantharides), the implantation of subcutaneous threads, and the use of microdialysis probes inserted into muscle or adipose tissue. The most useful models are likely to be the skin-blister models and microdialysis probes. The use of skin blisters provide sufficient volume of locally produced extravascular fluid to enable enough samples to be taken both for evaluation of the chemical composition of the extravascular fluid and for multiple antimicrobial concentration determinations so that a complete drug area under the curve (AUC) for extravascular fluid can be measured. This complete evaluation makes comparison to intravascular kinetic data more meaningful and valid conclusions more likely. Similarly, the use of microdialysis probes is a minimally invasive technique that provides complete pharmacokinetic data, including AUC data, of non–protein-bound antimicrobial concentrations within the interstial space of a tissue.

Skin-Window Disk

This technique was described by Raeburn (10) as a modification of the skin-window method of Rebuck and Crowley (11). A 25-mm² area of skin is abraded using a 25,000-rpm motorized buffer. The abrasion is done (without bleeding) just prior to measurement of the antibiotic. A sterile paper antibiotic disk (6- or 12-mm diameter) is then applied directly to the abraded area and covered with a sterile glass slide, which is secured in position for a selected period of time (usually 1 hour). New applications are made for each additional 1 hour that tissue fluid is to be sampled. Assays are performed by the bioassay technique using paper disks. The amount of tissue fluid on the disk is quantitated by a comparison of disk weight before and after application. Antibiotic standards for the bioassay should contain the same weight of fluid as the unknown specimen (12), a problem of considerable difficulty because disks increase their absorptive capacity with increasing time in contact with fluid, even up to 24 hours (13). The standards should be prepared in a diluent with a protein content similar to that of the tissue fluid (14). The latter point is particularly important for the assay of highly protein-bound drugs and has not been addressed in published studies with this model (10,12). The method allows for measurement of fluid for a relatively short time period at each site and appears to sample tissue fluid that is absorbed from the denuded dermis by the capillary action of the paper disk. However, the limited amount of fluid obtained makes analysis of its composition difficult.

Skin-Window Chamber

This method, described by Tan et al. (15) and used by Tan and Salstrom (16,17), is also a modification of the Rebuck and Crowley (11) skin-window technique. The dermis is exposed by scraping the epidermis with a scalpel blade and placing a tissue culture chamber, with one glass window removed, over the exposed dermis (18). The chamber is taped in place and filled with 1 mL of sterile saline under slightly negative pressure. During study of a drug, the chamber is periodically emptied and refilled (usually at hourly intervals). The method results in marked dilution of the tissue fluid by saline or buffer. The assumption that equilibration of chamber and tissue fluid occurs within a 1-hour period is likely erroneous, based on the limited diffusing surface area compared with chamber volume. Protein content of the saline fluid is low, as anticipated, and therefore, this method is likely to show an apparent reduced penetration of highly bound drugs, compared with systems containing higher levels of albumin (7).

Skin Blister by Suction

This method is based on work by Kiistala and Mustakallio (19), who demonstrated a noninflammatory separation of the epidermis from the dermis by the application of negative pressure. The method used a Perspex block with eight 8-mm holes drilled in it (17). The block is tightly applied to the skin and 0.3 kg/cm² of pressure is applied to each bore for approximately 2 hours. A block applied to each forearm yields 16 0.15-mL blisters. A different blister is available for evacuation at each sample time. Blisters differ from the skin-window chambers in having fluid with high, rather than low, protein levels. This fluid is produced by the host without the addition of extraneous buffer.

Skin Blister by Cantharides

Cutaneous blisters can also be formed by application of the skin irritant, cantharides, which is prepared from the dried Spanish fly (Cantharis vesicatoria) or blister bug. Cantharidin, the most important active ingredient in Spanish fly, has also been used. Simon and Malerczyk (20) were probably the first to use this method. A plaster of 0.2% cantharides (or cantharidin ointment) is applied to the forearms in a 1-cm²area 8 to 12 hours before study (21). After formation, the blisters are repeatedly sampled with a fine-bore needle and syringe or capillary tube and the integrity of the blister is maintained by spraying the puncture site with a plastic dressing. The total protein and albumin contents of this inflammatory blister model are the highest of the models currently in use (21).

Subcutaneous Threads

Another method for the study of cutaneous antibiotic penetration in humans (22–24) is the subcutaneous thread. An area of the skin is anesthetized locally with lidocaine and multiple umbilical tapes are threaded under the skin with a needle for a distance of 1 to 2 cm. Studies are begun 30 minutes after placement. Tapes are advanced 1 to 2 cm after each time interval to be measured (for long tapes) or removed completely (when multiple short tapes are implanted), and the subcutaneous segment is cut off and assayed. Assay is typically performed by cutting the tape into 1-cm lengths with different concentrations of antibiotic in each piece. Tapes may also be left in place 24 hours prior to antibiotic administration, but this results in a greater inflammatory response (24). The method allows only a limited time for diffusion of tissue fluid at the site when long tapes are continuously advanced, but this problem can be overcome by the implantation of multiple short lengths of umbilical tape. The umbilical tape has a very large surface area exposed for absorption because of the porous cotton weave of the thread. This model poses similar problems for standardization as seen with the paper disk models (13).

Microdialysis Probes

Muller et al. (25) first described the method of measuring antimicrobial concentrations by use of microdialysis probes. Antimicrobial concentrations within the free interstitial fluid of a tissue are measured by insertion of a microdialysis probe into tissue, usually muscle or subcutaneous adipose tissue. The probe has a semipermeable membrane at its tip and is constantly perfused with a physiologic solution at a flow rate of of 1.5 to 2.0 µL/minute. Antimicrobials within the tissue diffuse out of the extravascular fluid into the probe, resulting in a concentration in the perfusion medium. However, the diffusion may be incomplete and depend on flow rates, temperature, membrane surface and porosity, and may not be constant over time (26). Therefore, calibration is required, usually using the retrodialysis method, which assumes that the process of diffusion is equal in both directions. The antimicrobial being studied is added to the perfusion medium and its disappearance rate through the membrane is calculated. In vivo percent recovery is then defined as

100 – [100 • (dialysate concentration out/dialysate concentration in)]

In vivo recovery differs markedly among differing antimicrobials (25). The absolute concentration in the interstitial space is calculated by the following equation:

100 • (concentration in the dialysate/percent in vivo recovery)

Since the semipermeable membrane excludes protein-bound drug, the technique measures free interstitial drug concentrations.

The determination of antimicrobial agent concentrations contained in tissues can be accomplished by methods that are similar to those used for the determination of antibiotics in body fluids (see Chapter 8). The most readily available assay system at the present time is a microbiologic method. This system is based on an indicator organism that is very sensitive to the antibiotic under study and requires no special equipment. It allows for processing of large numbers of samples with minimal expense. An important aspect of this method is preparation of the standard concentration of antibiotic in the same tissue as the unknown sample (14,27). This is necessary so that drug binding to sample constituents is the same in both the unknown sample and the standard curve. Other methods also available for determination of antimicrobial concentrations include (high-pressure) liquid chromatography as well as many specific antibody-based systems such as radioimmunoassay (28) and enzyme immunoassay (29). These other methods, notably liquid chromatography and radioimmunoassay, require extraction of the antimicrobial agent from the specimen prior to assay. Use of these methods necessitates standardization with the tissue and antibiotic under study to ensure that all of the antimicrobial is extracted from the tissue sample or fluid prior to assay.

Microbiologic Assay

Antimicrobials can be determined using the bioassay method with only a limited number of organism species and a few selected media. The agar diffusion bioassay method described by Sabath (30) using Bacillus subtilis American Type Culture Collection strain 6633 is demonstrative of the technique for assay of antimicrobial compounds. The bioassay relies on an antibiotic-sensitive indicator organism seeded into an agar base on to which paper disks containing antibiotic are placed. Tissue homogenates or body fluids may also be placed on the agar in cylinders or in wells that have been cut into the agar. The cylinder and agar-well techniques usually provide increased sensitivity for the bioassay method. The antibiotic in the sample then diffuses into the agar and inhibits growth of the indicator organism. The diameter of the zone of inhibition is proportional to the concentration of antibiotic in the sample. Multiple variables can affect the diameter of the zone of inhibition. These variables include the indicator organism chosen, the agar base used, and the nature of the sample itself. Most of these variables can be eliminated by preparing the samples for the standard curve determination in the same type of tissue homogenate or body fluid as the specimen to be assayed.

Once the indicator organism and specific medium are selected, the microorganism is grown overnight and added to molten agar at 50°C. The microorganisms and agar are thoroughly mixed and this mixture is then poured into flat Petri dishes (15 × 100 mm) on a level surface. Each Petri dish contains a measured volume of 6 mL of the bacteria-seeded agar. The plates are left at room temperature on a level surface to harden and are then stored at 4°C until used. Plates should be stored for a maximum of 14 days under these conditions. The standard line is prepared by adding known concentrations of antibiotic to either tissue fluid or tissue homogenate and subsequently making serial dilutions. Samples of both known and unknown antibiotic-containing fluid are then placed on filter paper disks (usually 20 µL per disk) or pipetted (20 to 200 µL) into cylinders or wells cut in the agar surface. If wells or cylinders are used, the sample should be allowed to diffuse into the agar before movement of the plates to the incubator is attempted. The plates are incubated for 24 hours at 37°C and the diameter of the zone of inhibition is read with calipers to the nearest 0.1 mm. All samples should be assayed in triplicate to ensure an error rate of no more than 10%. The standard line is then plotted on semilogarithmic graph paper and the concentration of antimicrobial in the specimen is read from the standard line.

Occasionally, combinations of antimicrobials can be assayed using this method; however, it is not recommended because the influence of combined agents on indicator microorganisms is often unpredictable. Inactivation of aminoglycosides can be accomplished by lowering the agar pH to 5.5 or less. Also, penicillins or cephalosporins can be inactivated by the addition of β-lactamases to the specimen. When this is done, the same procedure should be performed on all standards to ensure the accuracy of the results.

Liquid Chromatography

Liquid chromatography for the measurement of antimicrobial agent concentrations is a specific method for assay of these drugs. The technique measures drugs in a liquid mobile phase by separating them from interferences on a column under high pressure and then using light absorption for agent detection. The technique is able to separate antimicrobials from other compounds in the sample as well as from both serum and tissue interferences. The method has been reviewed by Yoshikawa et al. (31). Extraction of antimicrobial compounds from the specimen is critical for this assay method. Because of the high protein content in most specimens, direct injection onto the liquid chromatography column is not recommended because the proteins plug the column, thus diminishing its efficiency and useful lifetime. Deproteination of samples can be accomplished by use of organic solvents or acids. Methanol, acetonitrile, and trichloroacetic acid are commonly used for this purpose.

After mixing the specimen with these agents, it is necessary to sediment the protein by centrifugation of the specimen and then inject the supernatant into the chromatographic equipment. Extraction has also been performed by adsorption of the specimen with silica gel and by ion-exchange chromatography for aminoglycosides. We have described a method using ion-exchange chromatography for extraction of penicillins and cephalosporins as well (32–34). Liquid chromatography has the advantage of specifically identifying the compounds under study by their pattern of retention on the chromatographic column. The disadvantages are that the extraction procedures and chromatography time required limit the number of specimens that can be assayed in one 24-hour period. The applicability of liquid chromatography for separation of antimicrobial drugs either singly or in combination is extensive. Once extraction techniques and detection methods have been standardized, this method can quantitate virtually any agent. Liquid chromatography is also very precise and highly reproducible, with coefficients of variation usually less than 5%. The sensitivity of liquid chromatography is similar to that of microbiologic assays and is satisfactory for both clinical and research use. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) has the advantages of high sensitivity and specificity with short analysis time, which is advantageous in analysis of unstable drugs (35).

Antibody Methods

These methods of antimicrobial assay are based on the availability of specific antibody that binds the drug. The amount of drug bound is then measured either by radioactivity or by the availability for enzymatic reaction (28,29). Antimicrobial detection with radioimmunoassay is generally available for the aminoglycosides. The assays are rapid and specific and are as sensitive as microbiologic assays. The radioimmunoassay requires an extraction step; however, the enzyme immunoassay techniques are very rapid and have the advantage of not requiring an extraction. Their usefulness is limited by the availability of specific antisera and thus far, they have been applied to assays of aminoglycosides, vancomycin, and chloramphenicol. The antibody-based methods have been used little for antimicrobial assays of tissue homogenates and therefore require considerable standardization before being applied to assays of drugs in tissues.

The accurate determination and interpretation of antimicrobial assay results from extravascular sites are difficult and often confusing. The tables presented in this chapter illustrate the need for careful sample preparation and standardization in order to avoid conflicting results and possible misinterpretation of data.

Sampling of whole tissues for antibiotic assays in excised tissue should be performed in a carefully controlled manner. The area to be sampled should be identified at operation and easily visible. If possible, the arterial supply should be transiently clamped to allow blood to flow out of the prospective sample area. The specimen is then surgically removed and freed of adherent blood by gentle pressure with sterile gauze. Tissue samples should then be either immediately processed or stored at −70°C until antibiotic assay can be performed. Tissue fluid can be obtained from the tissue sample by homogenization in a phosphate-buffered saline solution at neutral pH. It is usually necessary to dilute the specimen with three volumes of buffer for every one volume of sampled tissue. The homogenization should be done in a hand-homogenizer so that temperature in the specimen is not elevated, which may destroy some drugs. The resulting homogenate can then be assayed directly for antibiotic content as well as for markers of various tissue compartments and blood. The homogenate can also be centrifuged and the supernatant assayed. We suggest preparation of antibiotic solutions for the standard line at the same time as preparation of the unknown sample so that the standards and the unknown are exposed to the tissue for the same amount of time under the same conditions (27).

Rauws and Van Klingeren (36) and Bergan (37) have discussed the difficulty in interpretation of antimicrobial tissue concentrations obtained from homogenized whole tissues. The final amount of detected drug is the sum of the concentrations of the individual components of the tissue as given by:

C_T = C_p f_b(1 − Ht) + C_e f_b(Ht) + C_i f_i + C_c f_c + C_s f_s

where C is the concentration in whole tissue (C_T), plasma (C_p), erythrocytes (C_e), interstitial fluid (C_i), tissue cells (C_c), and specialized tissue components (C_s) such as secretory fluids, and f is the fraction of the homogenate contributed by blood (f_b), interstitial fluid (f_i), tissue cells (f_c), and specialized tissue components (f_s). Ht is the hematocrit level, a critical determination for most studies. The sum of the homogenate fractions is equal to 1, that is, f_b + f_i + f_c + f_s = 1. Because the contribution of antimicrobial agent in blood is one of the most important potential inaccuracies in the assay of tissue homogenates, correction for blood contamination is essential. We have indicated in the tables whenever this has been done. The formula of Plaue et al. (38) can be used for this correction. Their formula simply states that extravascular concentration = (tissue concentration − serum concentration)/(tissue water volume − blood volume).

Blood contamination can be estimated most simply by measurement of the hemoglobin content of the tissue homogenate and comparison of this with the hemoglobin content of the subject’s circulating blood. If estimation of blood contamination is not possible, the significance of this factor can be minimized by obtaining the extravascular fluid or tissue sample at a time when the intravascular antibiotic concentration is expected to be low or at least lower than that in the extravascular site under study. Rinsing the specimen to remove blood should also be avoided because most antimicrobials at the low concentrations found in vivo are readily water-soluble and easily washed out. If desired, the extracellular or interstitial fluid in tissue can also be measured with high-molecular-weight dextran, sodium bromide, or sodium thiocyanate, which is excluded from intact cells (e.g., kidney, gallbladder, and prostate). Corrections for antibiotic concentrations of the secretory product also need to be considered because these fluids often contain high concentrations of antimicrobial agent and significantly contaminate tissue specimens. Most published work on tissue distribution of antibiotics fails to make even simple adjustments for blood contamination, making interpretation difficult or impossible.

Finally, because various body tissues bind antimicrobial agents with different capacities (39) and tissue fluid–antibiotic concentration is a combination of bound and unbound drug (40), it is necessary to know the protein binding of an antibiotic to both the tissue or body fluid and plasma or serum in order to interpret correctly the significance of the tissue concentration. Methods for measurement of protein binding to serum, tissues, and body fluids have been published (39,41,42) and measurements should be performed to optimally interpret extravascular fluid and tissue antimicrobial concentrations.

The proper interpretation of an extravascular antimicrobial concentration depends on a series of factors that are often overlooked or ignored (Table 14.2). These factors (with the possible exception of protein concentration) are independent of permeability barriers or effects of inflammation that may influence the amount of antimicrobial that reaches a given site. They also do not take into account the antimicrobial susceptibility of pathogens likely to be found within a given extravascular site. Such comparisons require a higher level of cognition and are left to readers who may wish to correlate minimal inhibitory concentrations for specific organisms found elsewhere in this text with extravascular site drug concentrations found at the end of this chapter (43). Readers who make such an effort are cautioned that expectations of clinical cure or failure should not be made with a high degree of confidence until more clinical studies on this subject are available (44,45).

Administration Method

The method used to administer an antimicrobial can result in marked differences in serum concentration. High concentrations in serum result rapidly from bolus injections and influence the rate at which antimicrobials enter an extravascular site (46,47). Similarly, intermittent administration results in more rapid attainment of high extravascular levels than does constant intravenous infusion (48,49). Furthermore, extravascular drug concentrations are frequently compared with peak serum concentrations. Rapid intravenous infusions can result in very high serum peaks that, when compared with extravascular concentrations, may give the erroneous perception of poor extravascular drug penetration.

Single or Multiple Dosages

The concentration of antimicrobial at an extravascular site is influenced by the number of doses administered, particularly if the administration frequency is short relative to the serum half-life of the drug (50). Multiple doses may result in considerably higher extravascular antibiotic concentrations than do single doses (51), as a drug accumulates over multiple half-lives depending on the dosing interval. This gradient may be reduced if a loading dose is administered, but the level achieved by a loading dose may not equal the result of the multiple half-lives of accumulation required to reach steady-state condition.

Specimen Handling

Different methods of processing and assaying specimens may lead to confusion in interpretation of extravascular levels, particularly in whole tissues. As previously discussed, the method used to remove blood from tissues, the assay method and standards, and blood contamination corrections are all important to the interpretation of extravascular antibiotic concentrations. Comparison of studies that use dissimilar handling methods is extremely difficult.

Extravascular Protein Content

Antibiotics often bind to proteins (usually albumin) at the extravascular site as well as in serum. For highly bound antimicrobials, the amount of drug that accumulates in an extravascular space depends on the protein content of the space. A site with high albumin content binds a substantial amount of a highly bound antibiotic, and the total (free plus protein-bound) antibiotic concentration in the site is greater at equilibrium than it would be for a site with low albumin content (7,40). In contrast, a site that contains little albumin may have a low total antibiotic concentration, but most of the antibiotic present is free (unbound) drug.

Site Geometry

The amount of antibiotic in a fluid-filled space largely depends on diffusion and, in turn, on the surface area available for diffusion compared with the volume of the space, the so-called surface area to volume (SA/V) ratio. It has been shown in experimental models that spaces with high SA/V ratios show fluctuations of antibiotic concentrations that parallel serum fluctuations, while spaces with low SA/V ratios show a damped response with lower peaks and higher troughs than in serum (52). Animal models that use tissue cages and chambers as extravascular sites and human blister models of extravascular distribution are subject to variation in drug penetration because of differences in SA/V ratios (52). This simple ratio of SA/V is the major determinant of peak and trough drug levels in large-volume, fluid-filled spaces that fill mainly by passive diffusion. Experimental data for ascites in dogs clearly support this concept (53).

Method of Serum and Site Comparison

The method used to compare serum and extravascular site antibiotic concentrations can markedly influence the perception of how well a drug enters an extravascular site. Most antimicrobials are administered intermittently, yielding a rapid rise in serum concentration followed by a logarithmic decay in serum levels. Extravascular site concentrations follow a similar pattern but peak levels are usually lower and occur later than in serum, while trough levels are higher than those in serum (Fig. 14.1). Comparisons of serum and site concentrations are usually done in one of three ways: peak-to-peak comparison, simultaneous-time comparison, or AUC-to-AUC comparison. Peak-to-peak comparisons are difficult to obtain clinically because large numbers of specimens are required to ensure that the peak is obtained. In addition, serum peaks may be very high following rapid intravenous infusion, resulting in an inappropriately low ratio of site-to-serum concentrations. Simultaneous-time determinations are most often employed clinically because it is simpler to obtain a serum specimen at the same time that the site is sampled. Because serum levels are falling at the same time that site levels are rising, the perceived penetration of an antibiotic into an extravascular site may be low if specimens are taken shortly after administration (high serum level and low site level) but appear much higher if sampling is delayed until serum levels have fallen and site levels have risen. Perhaps the best way to compare serum and site antibiotic penetration is by means of AUC data. These studies also require multiple serum and site samples and thus are difficult to perform in certain sites in humans. They are best done following multiple antimicrobial doses to allow equilibrium to occur.

General Comments

Tables 14.3 to 14.20 have been prepared from published literature for reference purposes to illustrate the concentrations of antimicrobials found in a variety of human extravascular sites. Sites have been selected to be representative of each of the categories listed in Table 14.1. Thus, the sites include fluid-filled spaces such as ascites, pleural effusions, joint fluids, and cutaneous blisters (as well as cutaneous chambers, disks, and threads); secretory fluids such as bile, sputum, breast milk, middle ear fluid, and prostate and sinus secretions; barrier spaces such as aqueous humor and CSF; and the whole-body tissues bone, skeletal muscle, cardiac tissue, gallbladder, lung, and prostate.

Requirements for inclusion of a reference in the tables were that the article supply information about drug dosage; number of doses; concentrations of drug both at the site and in serum; timing of both the site and serum specimens; and, if possible, the range or standard error or standard deviation of the data. Only articles with data from at least three subjects were included. Data from articles were frequently reorganized to include only information for specific sampling times in order to make interpretation easier. Extrapolation of graphical data was occasionally required. Many articles contained far more data than could be included in these concise tables. In such cases, data from specific sampling times (e.g., 1, 2, or 3 hours) were arbitrarily selected to obtain simultaneous-time data for the tables. Certain antimicrobials have been studied numerous times at certain body sites. In these instances, no attempt was made to include every reference in the tables. Rather, emphasis was placed on inclusion of data about as many different drugs as possible.

Antimicrobials are grouped into aminoglycosides, cephalosporins and related β-lactams, penicillins, quinolones, tetracyclines, and other antimicrobials. Included under cephalosporins are cephamycins and related β-lactams such as moxalactam, monobactams, and carbapenems. All antimicrobials are listed alphabetically within categories. Method of administration, dose (in grams), and whether single or multiple doses were given are listed after the drug name. The number of subjects studied to obtain the data in the table is given in the column headed n. Serum half-life, if not supplied in the references, was obtained from standard tables (54). The remainder of the table gives the serum concentration (micrograms per milliliter or units per milliliter for penicillin) and time obtained, followed by the site concentration (micrograms per milliliter or micrograms per gram of tissue) and time obtained. The ratio of site concentration to serum concentration is given as a percentage. The “Notes” column includes special information about whether the site was infected or uninfected (if the information is known), whether site assays were corrected for blood contamination (a rarity), and any special information needed to interpret a given study. Specific comments regarding each table are included in the following sections.

Ascites

There are only limited data on antibiotic penetration into ascitic fluid. Data in Table 14.3 are limited to patients from whom ascitic fluid could be aspirated. Only studies that included fluid obtained by aspiration are included. Studies that obtained fluid by placing a paper disk under a loop of bowel at surgery or that measured peritoneal fluid samples from peritoneal drains after abdominal surgery or from patients undergoing peritoneal dialysis were not included. In the majority of studies, antibiotics penetrated into ascitic fluid well, although there was a lag in the ascitic fluid values compared with the serum values in the first few hours after the initial dose. AUC ratios of ascites to serum for several antimicrobial agents of different classes ranged from 30% to greater than 100% (55–61).

Pleural Fluid

The antibiotic levels in pleural fluid are listed as infected (i.e., empyema) or uninfected (Table 14.4). The uninfected groups consist of patients with congestive heart failure and malignant or parapneumonic effusions; some also included cases of nonpyogenic infection such as tuberculosis. When specified, most samples were collected by chest tube drainage. Few studies provided data on antibiotic penetration into pleural empyemas. It is notable that the aminoglycosides penetrated poorly into empyema fluid, compared with uninfected pleural fluid, as shown by the study of Thys et al. (62). The quinolones demonstrated good pleural fluid penetration, which appeared to be enhanced by the presence of empyema. Aztreonam also demonstrated excellent penetration into the pleural fluid.

Joint Fluid

In compiling this table of antimicrobial penetration into joint fluid spaces (Table 14.5), single-patient studies were combined when possible to give a better overall reflection of the penetration of individual agents. No attempt at correction for blood contamination was made, and only rarely was there an attempt made to correlate protein content or antimicrobial/tissue fluid protein binding with drug penetration (24). The reported fluid-to-serum antimicrobial concentration ratios are quite high for this group of studies, which is primarily due to the high protein content of the extravascular fluid plus the fact that many of these studies were performed after multiple systemic doses of the antimicrobial agent had been administered. Data from single infected patients treated with cephapirin (63) have not been included in Table 14.5.

Cutaneous Blister/Disks/Threads/Microdialysis Samples of Interstitial Fluid

Table 14.6 contains a summary of reports of antimicrobial distribution based on models in humans. All sites were done in uninfected patients except the studies done by Tegeder et al. (64) of imipenem. None of the studies have made any attempt to correct for blood contamination other than avoiding gross blood. Data are also available for penicillin (23) and pivampicillin (23) but are not included in Table 14.6because fewer than three subjects were studied. While only a limited number of multiple-dose studies have been done, even the single-dose studies often demonstrate high ratios of drug concentration in the extravascular site to that in serum, reflecting the small size of the extravascular space under study. One study attempted to correlate protein concentration to drug penetration and found a significant correlation at r = 0.97 (22). There was considerable variability in the ratio of extravascular to intravascular antimicrobial concentrations, reflected by ratios as low as 3% for nafcillin in the skin-window model (15) to 238% for FCE22101 in a cantharides blister study (65). Many articles supply data that can provide an AUC for the agent under study in both the intravascular and extravascular spaces. This is a notable achievement in the study of extravascular drug penetration, although more multiple-dose studies are needed as well as more attention to antimicrobial binding at extravascular sites.

Bile

Specimens of bile obtained by three methods are included in Table 14.7: aspirations of gallbladder or common duct bile at surgery, external bile drainage from T-tubes, or bile obtained by endoscopic retrograde cholangiopancreatography. Studies in which bile was obtained by duodenal aspiration were not included because of unknown specimen dilution by gastrointestinal fluids. Several studies in Table 14.7 confirm the observation that bile concentrations are lower or absent in the presence of cystic duct obstruction (66) or common bile duct obstruction (67–69). In general, T-tube and common duct bile levels seem to be somewhat higher than gallbladder bile levels (70–74) when comparably timed specimens are obtained. This may be related to partial obstruction of the cystic duct. Multiple antibiotic doses also result in higher bile levels than do single doses (74–76).

Ratios of site-to-serum levels are extremely variable, ranging from zero in the presence of obstruction to 18,400% for rifampin (77), with numerous examples of ratios greater than 100%. After relief of biliary obstruction, the excretion of antibiotics (aztreonam, piperacillin, and cefamandole) remains depressed for a prolonged period of time, which may exceed 28 days (67,78). Data on ratios of AUC in bile to AUC in serum were available for a limited number of drugs, and they also showed wide variation: 19% for cephacetrile (79); 38% to 44% for amoxicillin, penicillin G, and oral ampicillin (71,72); 46% for ceftazidime (80); 65% for amikacin (75); 96% for intravenous ampicillin (72); 100% for cefuroxime (81); and 2,089% for mezlocillin (82).

Although biliary penetration is often touted as advantageous in the therapy of biliary tract infection, it is not at all clear that this is an important treatment variable in view of the poor penetration in the presence of obstruction. Keighley et al. (83) have shown that biliary antibiotic concentrations have no influence on rates of bacteremia and wound infection associated with biliary tract surgery. Smith and LeFrock (84), Nagar and Berger (85), and Dooley et al. (86) have extensively reviewed biliary antibiotic penetration and clinical use in biliary infection.

Sputum

Both sputum and bronchial secretion specimens are included in Table 14.8. Bronchial secretions were obtained via bronchoscopy or by suction aspiration from patients with endotracheal tubes or tracheostomies. Some articles provide data on antimicrobial concentrations in epithelial lining fluid in the lung, which is indicated in Table 14.8 (87). Most subjects had chronic bronchitis, but some studies were done with children with cystic fibrosis, and occasionally patients had pneumonia. Nearly all studies were done with infected patients. Some studies suggest higher sputum antibiotic levels with the use of mucolytic agents (88–90). Ratios of sputum-to-serum concentrations are low for most drugs. Data on AUC ratios were limited but showed ratios of 2.7% and 4.5% for cefotaxime (91), 14% for cefuroxime (92), 106% for ciprofloxacin (93), and 19% for netilmicin by both intermittent and continuous intravenous infusions. Sputum concentrations of the cefotaxime metabolite desacetyl-cefotaxime are much higher than those of the parent drug (94).

Some studies have shown a relationship between clinical infection cure and antibiotic concentration in sputum (89,95) and have shown that the antibiotic concentration increases with the degree of sputum purulence for at least some antibiotics (96). Reviews of this topic have differed on the importance of sputum antibiotic concentrations to the cure of infection, with Lambert (97) taking a somewhat skeptical view, while Pennington (98) has taken a supportive stand with which Smith and LeFrock (99) have concurred. Readers are also directed to an excellent study by Wong et al. (100), which could not be included in Table 14.8 because of the graphical presentation of the data. Hitt and Gerding (43) have compiled ratios of sputum antimicrobial levels to the minimal inhibitory concentration for 90% of common bacterial pathogens that cause bronchitis and pneumonia. These ratios may prove predictive of clinical outcome, but good clinical correlation is lacking.

Breast Milk

The studies of breast milk (Table 14.9) were performed in lactating mothers who were normal volunteers or were being treated for nonbreast infections. The results show that the secretion of most antibiotics into breast milk is insignificant. However, a few agents, notably metronidazole, chloramphenicol, tetracycline, and lincomycin, were found in milk at levels approaching the serum levels. Giamarellou et al. (101) reported a study showing that quinolones (ciprofloxacin, ofloxacin, and pefloxacin) also have excellent penetration into breast milk, posing a possible risk to newborn infants. In a single study addressing milk penetration during puerperal mastitis, concentrations of phenoxymethyl-penicillin were higher in the milk from the mastitic breasts than in the nonmastitic breasts, but serum concentrations were not determined for the patients with mastitis (102). Even though only small quantities of most antibiotics reach the breast milk, the potential still exists for allergy or toxicity in the infant.

Middle Ear Fluid

Antibiotic levels were assayed in middle ear fluid from patients categorized as infected (acute otitis media) or uninfected (serous otitis or otitis media with effusion) (Table 14.10). The middle ear fluid samples were usually removed by needle aspiration. Pediatric subjects were studied most often. Most antibiotics penetrated significantly into the middle ear fluid. In the few cases where direct comparison was possible, the presence of acute infection appeared to enhance antibiotic penetration into the middle ear fluid.

Sinus Secretions

The sinus secretion studies were done primarily in patients with either acute or chronic maxillary sinusitis. None of the studies corrected for blood contamination, but this was likely minimal. On the basis of the data presented in Table 14.11, tetracyclines, erythromycin, and trimethoprim seemed to achieve better penetration than the β-lactams. There may be an inverse correlation between degree of purulence and amount of antibiotic penetration (103,104). One clinical correlation showed that an antibiotic concentration higher than the minimal inhibitory concentration of the pathogen was associated with clearance of the bacteria (105).

Prostatic Secretions

There are only a limited number of human studies detailing antibiotic concentrations in human prostatic secretions (Table 14.12). Winningham et al. (106) have determined in a dog model, in which urinary contamination has been excluded, that the major factors controlling antibiotic penetration into the prostatic fluid are the degree of lipid solubility, the pK_a, and the amount of protein binding. Using the dog model, Madsen et al. (107), Meares (108,109), and Gasser et al. (110) have determined that only trimethoprim, erythromycin, rosamicin, oleandomycin, clindamycin, enoxacin, and fleroxacin concentrate into prostatic fluid. The dog model may not necessarily reflect the situation in humans, however, because prostatic secretions in humans with prostatitis are more alkaline than the secretion found in normal dogs (59,111). One study suggested that prostatic fluid concentrations of cephalosporins are increased in patients with acute prostatitis, compared with uninfected controls (112). The higher pH found in humans may favor the penetration of some quinolones that are zwitterions (110). The degree of antibiotic penetration into prostatic fluid may be more important than prostatic tissue concentration because bacteria that cause chronic bacterial prostatitis reside within the prostatic fluid, and the prostatic epithelium acts as a barrier to the passage of most antibiotics into the fluid (113). When prostatic fluid drug levels in normal patients were compared with levels in a patient with ureterosigmoidostomy, it was found that the drug concentrations of nitrofurantoin and ampicillin found in normal patients were almost entirely due to urinary contamination (114,115). One group measured iohexol in the prostatic fluid after intravenous injection to exclude urinary contamination (116–118). Clinical data have revealed that trimethoprim is only partially effective in the treatment of chronic bacterial prostatitis. Quinolones may be of some benefit in the treatment of chronic bacterial prostatitis, but long-term follow-up has often been inadequate (119).

Cerebrospinal Fluid

Table 14.13 lists antimicrobial studies investigating the penetration of various agents into human CSF. There have been several reviews on the same topic that also dealt with the kinetics of central nervous system handling of drugs (120,121). There was no correction for blood contamination in these studies, and the results demonstrated considerable variability in the ratios of antimicrobial concentrations in CSF and serum. Many studies, typified by that of Mullaney and John (122), provide useful information on CSF levels of drugs such as cefotaxime, but make evaluation of drug penetration impossible by not presenting data on concentrations in serum. Similarly, data for ampicillin (123), nafcillin (124), and rifampin (125) are available but include small numbers of patients or lack actual drug levels. The CSF-to-serum ratio ranged from 0% for rifampin in uninfected controls (126) and 0% for low-dose oxytetracycline (127) to 199% for amoxicillin when measured 4 hours after a single intravenous dose (128). In general, because samples were taken at longer time intervals following the systemic drug administration, serum levels were lower in relation to CSF concentrations and the CSF-to-serum ratios increased. Data for several antimicrobials are included in detail to illustrate changes in CSF concentrations with time after administration, duration of meningitis, and multiple dosing (128–130).

Aqueous Humor

In almost all studies, the antibiotic levels in aqueous humor were measured in uninfected patients undergoing cataract surgery (Table 14.14). Under those conditions, most antibiotics penetrated poorly into the aqueous humor when given systemically, resulting in levels that are inadequate for treating endophthalmitis. Data are limited on penetration of antibiotics into infected eyes. One study examined doxycycline levels in acutely inflamed eyes and found levels similar to those in uninflamed eyes (131). Animal studies of bacterial endopthalmitis have shown enhanced penetration into the aqueous and vitreous humors of infected eyes with some antibiotics (132,133).

Skeletal Muscle

The majority of studies measuring antibiotic concentrations in skeletal muscle were done on uninfected normal muscle obtained during surgical procedures (Table 14.15). One study measured drug concentrations in the muscle of a decubitus ulcer (134). The higher concentrations observed for clindamycin and ciprofloxacin (compared with β-lactams) probably reflect the higher intracellular concentrations of lincosamides and quinolones (135). Newer studies have used microdialysis techniques, which distinguishes whole tissue from interstitial fluid concentrations within muscle (136,137).

Bone

A multitude of studies on antibiotic penetration into bone have been published (Table 14.16). Most of the studies were performed on uninfected bone, following antibiotics given prophylactically to patients prior to orthopedic procedures. There is a wide variance in technique, making the results conflicting and difficult to interpret. The majority of studies reported techniques that cut or crushed the bone, suspended the material in a buffer for a variable amount of time, and then measured the antibiotic extracted into the buffer, using a microbiologic assay. Newer studies used microdialysis techniques measuring interstitial fluid concentrations within bone. Many investigators washed or rinsed the bone to remove blood after removing the sample. It is unknown whether this could also remove some of the antibiotic.

The buffer/bone mixture is usually shaken at 4°C to 6°C for 1 to 24 hours. An 8-hour shake/elution technique has resulted in 79.9% recovery of cefazolin and 77% recovery of cephradine, but only 10.8% recovery of cephalothin (138). Schurman et al. (139) found that when the extraction procedure was performed for more than 3 to 5 hours, the recovery of cephalothin, but not cefamandole, declined by 67% at 24 hours. Rosdahl et al. (140) added several antibiotics to cancellous and cortical bone specimens and then homogenized the specimens before microbiologic assay. Recovery of the antibiotic ranged from 4% to 100%. The fall in antibiotic concentration was primarily due to the instability of the antibiotics during the homogenization procedures and was not due to binding of the antibiotic to bone. Adam et al. (141) found that neither ticarcillin nor clavulanate was adsorbed to inorganic bone; however, Wittmann and Kotthaus (142) found that the hydroxyapatite portion of bone acts as a depot carrier for several quinolone antibiotics. Other investigators have found that the quinolones bind to bone samples (143) and require several extraction steps for full extraction of the antibiotic from the bone (142).

Numerous studies noted differences between cortical and cancellous bone antibiotic concentrations, with the cortical bone usually having lower drug levels. This may reflect the fact that many antibiotics do not bind to inorganic bone, or it may be due to a difference in the blood supply. Fitzgerald (144), using data compiled from animal models, concluded that there is no anatomic or physiologic barrier preventing antibiotic diffusion into bone. He concluded that, at least in the case of β-lactams and aminoglycosides, the osseous interstitial fluid concentration of an antibiotic was a reflection of the serum concentration. This agrees with the results of Williams et al. (145), who thought that, although the relationship was not clear-cut, antibiotics with high serum levels and long half-lives usually had higher bone concentrations. Hughes and Anderson (146) thought that the capillary blood supply to the bone was of critical importance in delivering the antibiotic to the bone. In one study in which necrotic bone was sampled, cefamandole concentration was usually not detectable (147). We are not aware of any conclusive studies that attempt to correlate clinical outcome with the degree of antibiotic bone penetration, either in treating osteomyelitis or in preventing postoperative infection.

Cardiac Tissue

Antibiotic levels in cardiac tissue were measured in atrial appendage, valve, or heart muscle (Table 14.17). Virtually all studies were done in uninfected hearts. Study patients received a dose of antibiotic prior to undergoing valve replacements, coronary artery bypass grafting, or repair of congenital heart abnormalities. The cephalosporins were most widely studied and showed moderate penetration into cardiac tissue, with cephalothin and cefonicid having the lowest site-to-serum ratios. Particularly high penetration into cardiac tissue was noted for clindamycin, teicoplanin, and the quinolones. Readers are cautioned to note that cardiac penetration may not correlate with the efficacy of an antibiotic in preventing infection in patients undergoing cardiac surgery.

Gallbladder

Studies of antibiotic concentration in gallbladder tissue (Table 14.18) are difficult to interpret because specimens may be contaminated by bile as well as blood. Only one study cited in Table 14.18 corrected assay results for blood contamination (148). One study failed to show any difference in gallbladder levels of ceforanide when the cystic duct was obstructed or unobstructed (149). Other studies, however, revealed higher gallbladder levels of clindamycin when the common duct was patent than when it was obstructed (68) and higher levels when the gallbladder functioned than when it did not (150).

Lung Tissue

Antimicrobial concentrations in lung tissue (Table 14.19) have been measured almost exclusively following pulmonary resection of lung cancers. An exception involved a unique method of positron emission labeling of erythromycin followed by scanning of the lungs, while increasing numbers of samples of pulmonary tissue were obtained by transbronchial biopsy (151). Correction for blood contamination of specimens was done in only a few studies (151–155). The antimicrobial concentrations achieved in lung tissue were considerably higher than those in sputum (Table 14.8), but far fewer studies of lung tissue have been performed. Several drugs, such as ciprofloxacin (156), erythromycin (157), cefotaxime (158), and trimethoprim (159), showed much higher levels in lung than in blood. These studies were usually done 3 to 15 hours after the last doses of drug, at a time of relatively low serum levels, but nonetheless, they showed considerably more activity in lung tissue than in serum. Many of these agents (ciprofloxacin, erythromycin, and rifampin) are concentrated within cells, which may explain their high tissue levels. A few investigators have examined the concentrations of drug in infected or inflamed lung tissue (151,159–161). These levels were not substantially different from those in normal lung tissue from the same individuals. We are unaware of good correlation between lung antimicrobial concentrations and clinical therapeutic or prophylactic efficacy in humans. Therefore, clinical inferences from these data should be made with caution.

Prostatic Tissue

Numerous studies have measured antimicrobial concentrations in human prostatic tissue (Table 14.20). Most of the studies were performed with patients without infection, undergoing transurethral or suprapubic prostatectomy. Techniques for tissue preparation were variable. As is the case with prostatic secretions, the prostatic tissue concentrations observed in most of these studies may be due to urinary contamination and therefore must be interpreted with caution (107,162).

Interpretation of antimicrobial serum or plasma concentration data requires a basic understanding of the principles that govern pharmacokinetics: absorption, distribution, metabolism, and excretion of drug. In addition, method of administration, number of dosage administrations prior to sample collection, and timing of the sample collection with respect to the previous dose are equally important factors to consider when comparing data (163–165). Figure 14.2 depicts theoretical serum concentration data, using a two-compartment open simulation model, following a single 1-g dose of an antimicrobial by four different methods: intravenous bolus (1-minute infusion), 30-minute intravenous infusion, oral, and intramuscular administration. The apparent volume of distribution, bioavailability (100%), rate of elimination, and transfer rate constants between the central and peripheral compartments were all held constant in order to show just how different theoretical concentration-time curves may look when only one of these variables (administration) is altered.

Absorption

Absorption is the process by which antibiotic transfers from the site of administration (such as intravenous, intramuscular, oral, and topical) into the general circulation (central compartment) of the body, and it ranges from 0% to 100%. Percentage bioavailability (Table 14.21) is simply 100 times the ratio of the amount of active antibiotic (A) reaching the general circulation to the amount administered (dose).

Percentage bioavailability = 100 × A/dose

For most antimicrobials administered intravenously or intramuscularly, percentage bioavailability is 100%. However, some, such as chloramphenicol succinate, are in an inactive form when given parenterally and the actual percentage bioavailability may be less than 100% because of partial conversion. Absorption from oral administration is less than 100% for most antimicrobials; therefore, the area under the serum concentration–time curve following oral administration is less than that following parenteral administration, with all other variables held constant. Percentage bioavailability refers only to the extent of absorption; it gives no indication of how rapidly the antimicrobial is absorbed and does not account for protein binding.

Rate of Administration

Difficulty in interpreting differences in concentration with various routes of administration is often attributed to the respective rates of antimicrobial administration. Generally, intravenous administration is achieved through a zero-order process (constant rate of administration over time) and intramuscular and oral administrations are thought to follow a first-order process (Fick’s law of passive diffusion). Intramuscular and oral absorption rates are also influenced by a number of local factors, such as pH, gastrointestinal motility, dosage form, food, and muscle perfusion, to mention a few; each of which may be significant. As a result, peak serum concentration following intramuscular or oral administration tends to be lower and less predictable than that after intravenous administration. Again, the simulations in Figure 14.2, in which the oral and intramuscular half-life of drug absorption (T_1/2a) was held constant (1 hour) and the intravenous rates differ, show the effects observed by simply changing the rate of antibiotic administration.

Distribution

Once the antibiotic reaches the general circulation (central compartment), the antibiotic begins to diffuse into other body spaces and tissues (peripheral compartments) not at equilibrium with the central compartment (Fig. 14.1). This process is often referred to as distribution, and the time period during which this is most evident on the serum concentration–time curve is often referred to as the distribution phase or α-phase. Although distribution takes place following all forms of antimicrobial administration, the distribution phase is most apparent immediately following intravenous bolus or short infusion, which makes timing of sample collection most critical for concentration comparisons. The distribution phase of the serum concentration–time curve is generally short-lived (less than 1 hour); however, minor differences in the time of serum sample collection during the distribution phase may result in major differences in antimicrobial concentrations and therefore interpretation. Because of the difficulty in timing and collecting samples in and around the distribution phase of the curve, peak serum concentration data reported in the literature are often conflicting and misleading. The distribution phase for most antibiotics is of brief duration and is difficult to characterize. In order to avoid confusion and subsequent misinterpretation, many authors choose not to sample during the distribution phase but rather report the time at which serum samples for determination of antibiotic concentration were obtained following antibiotic administration. Data on achievable serum concentrations in Table 14.21 are presented with the time at which samples were obtained. In general, intravenous administration results in serum concentrations that are greater than those following oral or intramuscular administration and are most vulnerable to misinterpretation due to the distribution phase.

Elimination

Elimination is the loss of active antibiotic from the body and is due to excretion and/or metabolism. Excretion is the loss of unchanged antibiotic, and metabolism is the loss due to conversion of the antibiotic to another chemical compound (metabolite). Metabolites may or may not have antimicrobial activity. For most antibiotics, elimination is a first-order process, which simply means that serum concentration declines exponentially with time:

C_t = C × e^−k_el × t

where C is serum concentration, C_t is the serum concentration at some time t after C was determined, and k_ef is an elimination rate constant. With first-order elimination, the time for the serum concentration to decline by one-half (half-life) is constant:

t_1/2 = (ln2)/k_el

where t_1/2 is the serum half-life and k_ef is the elimination rate constant. Knowing the serum half-life, one can then estimate the fraction of the dose that remains in the body at any time after the dose was given:

Fraction remaining = e^−0.693n

where n is the number of half-lives that have elapsed since the dose was administered.

Renal Excretion

Most antimicrobials are eliminated in the urine, either unchanged or as metabolites. The data on achievable urinary concentration are often difficult to interpret. Urinary concentrations are constantly changing as a function of changing serum concentration and urine volume. The fraction of drug in general circulation that is excreted unchanged in the urine, fe, is a pharmacokinetic parameter that describes the contribution of urinary elimination to the overall elimination of antibiotic from the body.

fe = total drug excreted unchanged/total dose

The percentage of antibiotic excreted unchanged (fe 100) is high for antibiotics with renal excretion as the sole or primary route of elimination and low for antibiotics that are not readily excreted in the urine or that undergo significant metabolism. Determination of fe requires both an assay that is specific for the parent compound and a sampling time sufficiently long to ensure complete urinary excretion (at least five times the half-life).

Appendix 14.1 shows urinary excretion, metabolites, and reported urine levels for some selected antimicrobial agents.

   

Disease and Other Factors

A number of diseases are known to influence the absorption, distribution, and elimination of antimicrobials. Absorption may be enhanced or impaired by a number of factors. Gastrointestinal surgery, achlorhydria, malabsorption syndrome, stress, formulation differences, other drugs, and food are some of the more common conditions or factors that may alter drug absorption. Similarly, a number of conditions are associated with altered elimination. The two most readily identifiable conditions are decreased kidney function (renal excretion) and decreased hepatic function (metabolism). Each may be due to intrinsic loss of functional tissue alone or may be due to other causes such as decreased cardiac output, which may result in decreased blood flow to the kidney or liver (163–165). Severe peripheral vascular disease has been demonstrated to diminish the skeletal muscle concentration of gentamicin after a single intravenous dose (166). Data from human subjects with underlying conditions or disease states or from persons taking any other medications must be interpreted with caution.

Studies have used the microdialysis method to compare the tissue pharmacokinetics of antimicrobials in healthy individuals with those of critically ill with sepsis. Joukhadar et al. (167) found that the AUC in serum of piperacillin to be marginally reduced in critically ill patients with sepsis compared with healthy controls. However, the interstitial muscle and subcutaneous skin concentrations of piperacillin were markedly reduced in critically ill patients compared with that of healthy controls, with maximal antimicrobials in tissues in critically ill patients only about 10% of those in healthy controls. Tegeder et al. (63) found the AUC of imipenem in serum to be similar in critically ill patients compared with that of healthy controls, but the AUC in interstitial fluid of muscle and subcutaneous tissue of skin were markedly lower in critically ill patients than in healthy controls. Further, the C_max exceeded the usual minimum inhibitory concentration cutoff of 4 µg/mL in only one of four patients after administration of appropriate doses based on renal function. Studies performed with linezolid revealed a higher volume of distribution and increased clearance rates in septic patients, with a high degree of patient variability, and suggested that critically ill patients may need more frequent dosing (168).

The data in Table 14.21 have been extracted from published scientific literature and the respective manufacturer’s published product information. All data are listed either as a mean value or as a range of values. The purpose of Table 14.21 is to serve as a general reference for the comparative evaluation of the basic pharmacokinetics of antimicrobials. Except where noted, listed serum concentrations and the sampling times, percentage renally excreted, and bioavailability are from single-dose studies. Elimination half-life data are broken into two categories: those from young healthy adults (normal) and those from persons with end-stage renal disease. As previously mentioned, most antimicrobials are eliminated to varying degrees by glomerular filtration or tubular secretion. Percentage renal excretion is that percentage of a single dose that has been reported to be recovered in the urine as the active parent compound. Some antimicrobials have metabolites with significant antimicrobial activity and are noted.

The major considerations in quality control of antimicrobial determinations in extravascular sites are proper specimen processing and adequate controls for assay procedures. Blood and body fluid contamination (particularly urine and bile) are the most serious concerns in specimen processing, but care must also be given to possible drug inactivation due to prolonged vigorous specimen preparations such as are often used in assays of bone. These issues have been discussed earlier in the chapter and recommendations were made for optimal handling of specimens.

Problems in quality control of assays center primarily on the use of proper diluents in the preparation of standard curves for biologic assays. Again, these principles have been thoroughly discussed earlier in the chapter.

Finally, of major concern is the proper interpretation of extravascular antimicrobial concentrations with regard to any clinical application of this information. Clinical correlations of infection cure as a function of local antimicrobial concentration are still imperfect and probably will remain so until more definitive information becomes available.

This chapter was based extensively on the work of Drs. Lance Peterson, Carolyn Hughes, Tom Larson, Darcie Bridwell, and Christopher Shain from previous editions of this text. Michelle Beattie and Susan Sanders have provided valued assistance in the literature search.

  1.  Bamberger DM, Herndon BL, Suvarna PR. The effect of zinc on microbial growth and bacterial killing by cefazolin a Staphylococcus aureus abscess milieu. J Infect Dis 1993;168:893–896.

  2.  Gerding DN, Peterson LR. Comparative tissue and extravascular fluid concentrations of ceftizoxime. J Antimicrob Chemother 1982;10(Suppl C):105–116.

  3.  Gerding DN, Peterson LR, Legler DC, et al. Ascitic fluid cephalosporin concentrations: influence of protein binding and serum pharmacokinetics. Antimicrob Agents Chemother 1978;14:234–239.

  4.  Gerding DN, Peterson LR, Salomonson JK, et al. Prediction of the concentration of penicillins in ascitic fluid from serum kinetics and protein binding of the antibiotics in serum and ascitic fluid of dogs. J Infect Dis 1978;138:166–173.

  5.  Chisholm GD, Waterworth PM, Calnan JS, et al. Concentration of antibacterial agents in interstitial tissue fluid. Br Med J 1973;1:569–573.

  6.  Gerding DN, Hall WH, Schierl EA, et al. Cephalosporin and aminoglycoside concentrations in peritoneal capsular fluid in rabbits. Antimicrob Agents Chemother 1976;10:902–911.

  7.  Peterson LR, Gerding DN. Prediction of cefazolin penetration into high- and low-protein-containing extravascular fluid: new method for performing simultaneous studies. Antimicrob Agents Chemother 1978;14:533–538.

  8.  Dixon RL, Owens ES, Rall DP. Evidence of active transport of benzyl-¹⁴C-penicillin from cerebrospinal fluid to blood. J Pharm Sci 1969;58:1106–1109.

  9.  Mouton JW, Theuretzbacher U, Craig WA, et al. Tissue concentrations: do we ever learn? J Antimicrob Chemother 2008;61:235–237.

 10.  Raeburn JA. A review of experimental models for studying the tissue penetration of antibiotics in man. Scand J Infect Dis 1978;14(Suppl):225–227.

 11.  Rebuck JW, Crowley JH. A method of studying leukocytic functions in vivo. Ann NY Acad Sci 1955;59:757–805.

 12.  Gillett AP, Wise R. Penetration of four cephalosporins into tissue fluid in man. Lancet 1978;1:962–964.

 13.  Peterson LR, Van Etta LL, Gerding DN. Interstitial concentration of antibiotics. J Antimicrob Chemother 1981;8:425.

 14.  Peterson LR, Schierl EA, Hall WH. Effect of protein concentration and binding on antibiotic assays. Antimicrob Agents Chemother 1975;7:540–542.

 15.  Tan JS, Trott A, Phair JP, et al. A method for measurement of antibiotics in human interstitial fluid. J Infect Dis 1972;126:492–497.

 16.  Tan JS, Salstrom SJ. Levels of carbenicillin, ticarcillin, cephalothin, cefazolin, cefamandole, gentamicin, tobramycin and amikacin in human serum and interstitial fluid. Antimicrob Agents Chemother 1977;11:698–700.

 17.  Tan JS, Salstrom SJ. Bacampicillin, ampicillin, cephalothin and cephapirin levels in human blood and interstitial fluid. Antimicrob Agents Chemother 1979;15:510–512.

 18.  Tan JS, Salstrom S, Signs SA, et al. Pharmacokinetics of intravenous cefmetazole with emphasis on comparison between predicted theoretical levels in tissue and actual skin window fluid levels. Antimicrob Agents Chemother 1989;33:924–927.

 19.  Kiistala V, Mustakallio KK. Dermo-epidermal separation with suction: electron microscopic and histochemical study of initial events of blistering of human skin. J Invest Dermatol 1967;48:466–467.

 20.  Simon VC, Malerczyk V. Serum and skin blister levels of cefadroxil in comparison to cephalexin. In: Program and abstracts of the 18th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1978. Abstract 225.

 21.  Wise R, Dyhs A, Hegarty A, et al. Pharmacokinetics and tissue penetration of aztreonam. Antimicrob Agents Chemother 1982;22:969–971.

 22.  Hoffstedt B, Walder M. Influence of serum protein binding and mode of administration on penetration of five cephalosporins into subcutaneous tissue fluid in humans. Antimicrob Agents Chemother 1981;20:783–786.

 23.  Hoffstedt B, Walder M. Penetration of ampicillin, doxycycline and gentamicin into interstitial fluid in rabbits and of penicillin V and pivampicillin in humans measured with subcutaneously implanted cotton threads. Infection 1981;9:7–11.

 24.  Howell A, Sutherland R, Rolinson GN. Effect of protein binding on levels of ampicillin and cloxacillin in synovial fluid. Clin Pharmacol Ther 1972;13:724–732.

 25.  Muller M, Haag O, Burgdorff T, et al. Characterization of peripheral-compartment kinetics of antibiotics by in vivo microdialysis in humans. Antimicrob Agents Chemother 1996;40:2703–2709.

 26.  Muller M, Rohde B, Kovar A, et al. Relationship between serum and free interstitial concentrations of cefodizime and cefpirome in muscle and subcutaneous adipose tissue of healthy volunteers measured by microdialysis. J Clin Pharmacol 1997;37:1108–1113.

 27.  Kaplan JM, McCracken GH, Snyder E. Influence of methodology upon apparent concentrations of antibiotics in tissues. Antimicrob Agents Chemother 1973;3:143–146.

 28.  Parker CW. Radioimmunoassay. Annu Rev Pharmacol Toxicol 1981;21:113–132.

 29.  Voller A, Bidwell DE, Bartlett A. Enzyme immunoassays in diagnostic medicine. Bull World Health Organ 1976;53:55–65.

 30.  Sabath LD. The assay of antimicrobial compounds. Hum Pathol 1976;7:287–295.

 31.  Yoshikawa TT, Maitra SK, Schotz MC, et al. High-pressure liquid chromatography for quantitation of antimicrobial agents. Rev Infect Dis 1980;2:169–181.

 32.  Fasching CE, Peterson LR. Anion-exchange extraction of cephapirin, cefotaxime, and cefoxitin from serum for liquid chromatography. Antimicrob Agents Chemother 1982;21:628–633.

 33.  Fasching CE, Peterson LR. High-pressure liquid chromatographic assay of azlocillin and mezlocillin with an anion-exchange extraction technique. J Liq Chromatogr 1983;6:2513–2520.

 34.  Fasching CE, Peterson LR, Bettin KM, et al. High-pressure liquid chromatographic assay of ceftizoxime with an anion-exchange extraction technique. Antimicrob Agents Chemother 1982;22:336–337.

 35.  Landersdorfer DB, Bulitta JB, Kinzig M, et al. Penetration of antibacterials into bone pharmacokinetic, pharmacodynamic and bioanalytical considerations. Clin Pharmacokinet 2009;48:89–124.

 36.  Rauws AG, Van Klingeren B. Estimation of antibiotic levels of interstitial fluid from whole tissue levels. Scand J Infect Dis 1978;14(Suppl):186–188.

 37.  Bergan T. Pharmacokinetics of tissue penetration of antibiotics. Rev Infect Dis 1981;3:45–66.

 38.  Plaue VR, Bethke RO, Fabricius K, et al. Kritische Untersuchungen zur Methodik von Antibiotikaspiegelbestimmungen in Menschlichen Geweben. Arzneimittelforschung 1980;30:1–5.

 39.  Kunin CM. Binding of antibiotics to tissue homogenates. J Infect Dis 1970;121:55–64.

 40.  Peterson LR, Gerding DN. Influence of protein binding of antibiotics on serum pharmacokinetics and extravascular penetration: clinically useful concepts. Rev Infect Dis 1980;2:340–348.

 41.  Peterson LR, Gerding DN, Zinneman HH, et al. Evaluation of three newer methods for investigating protein interactions of penicillin G. Antimicrob Agents Chemother 1977;11:993–998.

 42.  Peterson LR, Hall WH, Zinneman HH, et al. Standardization of a preparative ultracentrifuge method for quantitative determination of protein binding of seven antibiotics. J Infect Dis 1977;136:778–783.

 43.  Hitt JA, Gerding DN. Sputum antimicrobial levels and clinical outcome in bronchitis. Semin Respir Infect 1991;6:122–128.

 44.  Diaz Gomez ML, Rebora Guiterrez R, Galindo Hernandez E, et al. Cefadroxil, serum, and pleural fluid levels. In: Program and abstracts of the 18th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1978. Abstract 223.

 45.  Hall WH, Gerding DN, Schierl EA. Penetration of tobramycin into infected extravascular fluids and its therapeutic effectiveness. J Infect Dis 1977;135:957–961.

 46.  Kozak AJ, Gerding DN, Peterson LR, et al. Gentamicin intravenous infusion rate: effect on interstitial fluid concentration. Antimicrob Agents Chemother 1977;12:606–608.

 47.  Thys J, Klastersky J, Mombelli G. Peak or sustained antibiotic serum levels for optimal tissue penetration. J Antimicrob Chemother 1981;8(Suppl C):29–36.

 48.  Peterson LR, Gerding DN, Fasching CE. Effects of method of antibiotic administration on extravascular penetration: crossover study of cefazolin given by intermittent injection or constant infusion. J Antimicrob Chemother 1981;7:71–79.

 49.  Van Etta LL, Kravitz GR, Russ TE, et al. Effect of method of administration on extravascular penetration of four antibiotics. Antimicrob Agents Chemother 1982;21:873–880.

 50.  Cronberg S. A simple mathematical model of diffusion of drug into an infection site. Scand J Infect Dis 1978;14(Suppl):100–104.

 51.  Gerding DN, Van Etta LL, Peterson LR. Role of serum protein binding and multiple antibiotic doses in the extravascular distribution of ceftizoxime and cefotaxime. Antimicrob Agents Chemother 1982;22:844–847.

 52.  Van Etta LL, Peterson LR, Fasching CE, et al. The effect of the ratio of surface area to volume on the penetration of antibiotics into extravascular spaces in an in vitro model. J Infect Dis 1982;146:423–428.

 53.  Gerding DN, Kromhout JP, Sullivan JJ, et al. Antibiotic penetrance of ascitic fluid in dogs. Antimicrob Agents Chemother 1976;10:850–855.

 54.  Gerding DN. Principles of antimicrobial therapy. In: Soule BM, ed. The APIC curriculum for infection control practice. Dubuque, IA: Kendall/Hunt Publishing Co, 1983:508–509.

 55.  Benoni G, Arosio E, Raimondi MG, et al. Pharmacokinetics of ceftazidime and ceftriaxone and their penetration into the ascitic fluid. J Antimicrob Chemother 1985;16:267–273.

 56.  el Touny M, el Guinaidy M, Abdel Bary M, et al. Pharmacokinetics of cefodizime in patients with liver cirrhosis and ascites. Chemotherapy 1992;38:201–205.

 57.  Grange JD, Gouyette A, Gutmann L, et al. Pharmacokinetics of amoxycillin/clavulanic acid in serum and ascitic fluid in cirrhotic patients. J Antimicrob Chemother 1989;23:605–611.

 58.  Hary L, Smail A, Ducroix JP, et al. Pharmacokinetics and ascitic fluid penetration of piperacillin in cirrhosis. Fundam Clin Pharmacol 1991;5:789–795.

 59.  Pfau A, Perlberg S, Shapira A. The pH of the prostatic fluid in health and disease: implications of treatment in chronic bacterial prostatitis. J Urol 1978;119:384–387.

 60.  Silvain C, Bouquet S, Breux JP, et al. Oral pharmacokinetics and ascitic fluid penetration of ofloxacin in cirrhosis. Eur J Clin Pharmacol 1989;37:261–265.

 61.  Van Gossum A, Quenon M, Van Gossum M, et al. Penetration of cefoperazone into ascites. Eur J Clin Pharmacol 1989;37:577–580.

 62.  Thys JP, Vanderhoeft P, Herchuelz A, et al. Penetration of aminoglycosides in uninfected pleural exudates and in pleural empyemas. Chest 1988;93:530–532.

 63.  Schurman OJ, Burton DS, Kajiyama G, et al. Sodium cephapirin disposition and distribution into human bone. Curr Ther Res 1976;20:194–203.

 64.  Tegeder I, Schmidtko A, Brautigam L, et al. Tissue distribution of imipenem in critically ill patients. Clin Pharmacol Ther 2002;71:325–333.

 65.  Webberly JM, Wise R, Andrews JM, et al. The pharmacokinetics and tissue penetration of FCE22101 following intravenous and oral administration. J Antimicrob Chemother 1988;21:445–450.

 66.  Nielson MW, Justesen T. Excretion of metronidazole in human bile. Scand J Gastroenterol 1977;12:1003–1008.

 67.  Blenkharn JI, Habib N, Mok D, et al. Decreased biliary excretion of piperacillin after percutaneous relief of extrahepatic obstructive jaundice. Antimicrob Agents Chemother 1985;28:778–780.

 68.  Brown RB, Martyak SN, Barza M, et al. Penetration of clindamycin phosphate into the abnormal human biliary tract. Ann Intern Med 1976;84:168–170.

 69.  Granai F, Smart HL, Triger DR. A study of the penetration of meropenem into bile using endoscopic retrograde cholangiography. J Antimicrob Chemother 1992;29:711–718.

 70.  Brogard JM, Blickle JF, Dorner M, et al. Biliary pharmacokinetic profile of piperacillin: experimental data and evaluation in man. Int J Clin Pharmacol 1990;28:462–470.

 71.  Brogard JM, Pinget M, Doffoel M, et al. Evaluation of the biliary excretion of penicillin G. Chemotherapy 1979;25:129–139.

 72.  Brogard JM, Pinget M, Meyer C, et al. Biliary excretion of ampicillin: experimental and clinical study. Chemotherapy 1977;23:213–226.

 73.  Mendelson J, Portnoy J, Sigman H. Pharmacology of gentamicin in the biliary tract of humans. Antimicrob Agents Chemother 1973;4:538–541.

 74.  Mendelson J, Portnoy J, Sigman H, et al. Pharmacology of cephalothin in the biliary tract of humans. Antimicrob Agents Chemother 1974;6:659–665.

 75.  Bermudez RH, Lugo A, Ramirez-Ronda CH, et al. Amikacin sulfate levels in human serum and bile. Antimicrob Agents Chemother 1981;19:352–354.

 76.  Moorthi K, Wiederholt K. Is the administration of doxycycline still indicated in bacterial infections of the gallbladder and the bile ducts? Eur J Clin Pharmacol 1981;20:35–38.

 77.  Binda GE, Domenichini E, Gottardi A, et al. Rifampicin, a general review. Arzneimittelforschung 1971;21:1942–1953.

 78.  Levi JU, Martinez OV, Malinin TI, et al. Decreased biliary excretion of cefamandole after percutaneous biliary decompression in patient with total common bile duct obstruction. Antimicrob Agents Chemother 1984;26:944–946.

 79.  Brogard JM, Haegele P, Dorner M, et al. Biliary excretion of a new semisynthetic cephalosporin, cephacetrile. Antimicrob Agents Chemother 1973;3:19–23.

 80.  Bouza E, Hellin T, Rodriquez-Creixems M, et al. Comparison of ceftazidime concentrations in bile and serum. Antimicrob Agents Chemother 1983;24:104–106.

 81.  Brogard JM, Kopferschmitt J, Pinget M, et al. Cefuroxime concentrations in serum, urine, and bile: pharmacokinetic profile. Proc R Soc Med 1977;70(Suppl 9):42–50.

 82.  Brogard JM, Kopferschmitt J, Arnaud JP, et al. Biliary elimination of mezlocillin: an experimental and clinical study. Antimicrob Agents Chemother 1980;18:69–76.

 83.  Keighley MRB, Drysdale RB, Quoraishi AH, et al. Antibiotics in biliary disease: the relative importance of antibiotic concentrations in bile and serum. Gut 1976;17:495–500.

 84.  Smith BR, LeFrock J. Biliary tree penetration of parenteral antibiotics. Infect Surg 1983;2:110–121.

 85.  Nagar H, Berger SA. The excretion of antibiotics by the biliary tract. Surg Gynecol Obstet 1984;158:601–607.

 86.  Dooley JS, Hamilton-Miller JM, Brumfitt W, et al. Antibiotics in the treatment of biliary infection. Gut 1984;25:988–998.

 87.  Honeybourne D, Baldwin DR. The site concentrations of antimicrobial agents in the lung. J Antimicrob Chemother 1992;30:249–260.

 88.  Bergogne-Berezin E, Berthelot G, Kafe H, et al. Influence of a fluidifying agent (bromhexine) on the penetration of antibiotics into respiratory secretions. Int J Clin Pharmacol Res 1985;5:341–344.

 89.  Braga PC, Scaglione F, Scarpazza G, et al. Comparison between penetration of amoxicillin combined with carbocysteine and amoxicillin alone in pathological bronchial secretions and pulmonary tissue. Int J Clin Pharmacol Res 1985;5:331–340.

 90.  Ricevuti G, Mazzone A, Vecilli E, et al. Influence of erdosteine, a mucolytic agent, on amoxycillin penetration into sputum in patients with an infective exacerbation of chronic bronchitis. Thorax 1988;43:585–590.

 91.  Maesen FPV, Davies BI, Drenth BMH, et al. Treatment of acute exacerbations of chronic bronchitis with cefotaxime: a controlled clinical trial. J Antimicrob Chemother 1980;6(Suppl A):187–192.

 92.  Bergogne-Berezin E, Even P, Berthelot G, et al. Cefuroxime: pharmacokinetic study in bronchial secretions. Proc R Soc Med 1977;70(Suppl 9):34–37.

 93.  Kontou P, Chatzika K, Pitsiou G, et al. Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions of mechanically ventilated patients with chronic pulmonary disease. Antimicrob Agents Chemother 2011;55(9):4149–4153.

 94.  Fick RB Jr, Alexander MR, Prince RA, et al. Penetration of cefotaxime into respiratory secretions. Antimicrob Agents Chemother 1987;31:815–817.

 95.  May JR, Delves DM. Treatment of chronic bronchitis with ampicillin: some pharmacological observations. Lancet 1965;1:929–933.

 96.  Klastersky J, Thys JP, Mombelli G. Comparative studies of intermittent and continuous administration of aminoglycosides in the treatment of bronchopulmonary infections due to Gram-negative bacteria. Rev Infect Dis 1981;3:74–83.

 97.  Lambert HP. Clinical significance of tissue penetration of antibiotics in the respiratory tract. Scand J Infect Dis 1978;14(Suppl):262–266.

 98.  Pennington JE. Penetration of antibiotics into respiratory secretions. Rev Infect Dis 1981;3:67–73.

 99.  Smith BR, LeFrock JL. Bronchial tree penetration of antibiotics. Chest 1983;83:904–908.

100.  Wong GA, Pierce TH, Goldstein E, et al. Penetration of antimicrobial agents into bronchial secretions. Am J Med 1975;59:219–223.

101.  Giamarellou H, Kolokythas E, Petrikkos G, et al. Pharmacokinetics of three newer quinolones in pregnant and lactating women. Am J Med 1989;87(Suppl 5A):49S–51S.

102.  Matsuda S. Transfer of antibiotics into maternal milk. Biol Res Pregnancy 1984;2:57–60.

103.  Gullers K, Lundberg C, Malmborg A-S. Penicillin in paranasal sinus secretions. Chemotherapy 1969;14:303–307.

104.  Lundberg C, Malmborg A-S. Concentration of penicillin V and tetracycline in maxillary sinus secretion after repeated doses. Scand J Infect Dis 1973;5:123–133.

105.  Eneroth C-M, Lundberg C. The antibacterial effect of antibiotics in treatment of maxillary sinusitis. Acta Otolaryngol 1976;81:475–483.

106.  Winningham DG, Nemoy MJ, Stamey TA. Diffusion of antibiotics from plasma into prostatic fluid. Nature 1968;219:139–143.

107.  Madsen PO, Kjaer TB, Baumueller A, et al. Antimicrobial agents in prostatic fluid and tissue. Infection 1976;4(Suppl 2):154–159.

108.  Meares EM Jr. Long-term therapy of chronic bacterial prostatitis with trimethoprim-sulfamethoxazole. Can Med Assoc J 1975;112:22S–25S.

109.  Meares EM Jr. Prostatitis: review of pharmacokinetics and therapy. Rev Infect Dis 1982;4:475–483.

110.  Gasser TC, Graversen PH, Madsen PO. Fleroxacin (Ro 23–6240) distribution in canine prostatic tissue and fluids. Antimicrob Agents Chemother 1987;31:1010–1013.

111.  Barza M, Cuchural G. The penetration of antibiotics into the prostate in chronic bacterial prostatitis. Eur J Clin Microbiol 1984;3:503–505.

112.  Katoh N, Ono Y, Ohshima S, et al. Diffusion of cefmenoxime and latamoxef into prostatic fluid in the patients with acute bacterial prostatitis. Urol Int 1992;48:191–194.

113.  Stamey TA, Meares EM Jr, Winningham DG. Chronic bacterial prostatitis and the diffusion of drugs into prostatic fluid. J Urol 1970;103:187–194.

114.  Madsen PO, Wolf H, Barquin OP, Rhodes P. The nitrofurantoin concentration in prostatic fluid of humans and dogs. J Urol 1968;100:54–56.

115.  Wolf H, Madsen PO, Rhodes P. The ampicillin concentration in prostatic tissue and prostatic fluid. Urol Int 1967;22:453–460.

116.  Naber KG. The role of quinolones in the treatment of chronic bacterial prostatitis. Infection 1991;19(Suppl 3):S170–S177.

117.  Naber KG, Kinzig M, Adam D, et al. Concentrations of cefpodoxime in plasma, ejaculate and in prostatic fluid and adenoma tissue. Infection 1991;19:30–35.

118.  Naber KG, Kinzig M, Adam D, et al. Penetration of ofloxacin into prostatic fluid, ejaculate and seminal fluid. Infection 1993;21:98–100.

119.  Naber KG. Use of quinolones in urinary tract infections and prostatitis. Rev Infect Dis 1989;11(Suppl 5):S1321–S1337.

120.  Barling RWA, Selkon JB. The penetration of antibiotics into cerebrospinal fluid and brain tissue. J Antimicrob Chemother 1978;4:203–227.

121.  Norrby R. A review of the penetration of antibiotics into CSF and its clinical significance. Scand J Infect Dis 1978;14(Suppl):296–309.

122.  Mullaney DT, John JF. Cefotaxime therapy. Arch Intern Med 1983;143:1705–1708.

123.  Thrupp LD, Leedom JM, Ivler D, et al. Ampicillin levels in the cerebrospinal fluid during treatment of bacterial meningitis. Antimicrob Agents Chemother 1965;5:206–213.

124.  Ruiz DE, Warner JF. Nafcillin treatment of Staphylococcus aureus meningitis. Antimicrob Agents Chemother 1976;9:554–555.

125.  Furesz S, Scotti R, Pallanza R, et al. Rifampicin: a new rifamyicin. Arzneimittelforschung 1967;17:534–537.

126.  Sippel JE, Mikhail IA, Girgis NI, et al. Rifampin concentrations in cerebrospinal fluid of patients with tuberculous meningitis. Am Rev Respir Dis 1974;109:579–580.

127.  Koch R. Blood and cerebrospinal fluid levels of intramuscular oxytetracycline. J Pediatr 1955;46:44–48.

128.  Marmo E, Cuppola L, Pempinello R, et al. Levels of amoxycillin in the liquor during continuous intravenous administration. Chemotherapy 1982;28:171–175.

129.  Humbert G, Leroy A, Rogez J, et al. Cefoxitin concentrations in the cerebrospinal fluids of patients with meningitis. Antimicrob Agents Chemother 1980;17:675–678.

130.  Humbert G, Veyssier P, Fourtillan JB, et al. Penetration of cefmenoxime into cerebrospinal fluid of patients with bacterial meningitis. J Antimicrob Chemother 1986;18:503–506.

131.  Tsacopoules M. The penetration of vibramycin (doxycycline) in human aqueous humor. Ophthalmologica 1969;159:418–429.

132.  Adenis JP, Denis F, Frokco JL, et al. Etude de la penetration intraoculaire de la fosfomycine chez l’homme et chez lapin. J Fr Ophthalmol 1986;9:533–537.

133.  Denis F, Adenis JP, Mounier M, et al. Intraocular passage (healthy eye and infected eye) of ceftriaxone in man and rabbit. Chemioterapia 1985;4(Suppl 2):338–339.

134.  Berger SA, Barza M, Haher J, et al. Penetration of antibiotics into decubitus ulcers. J Antimicrob Chemother 1981;7:193–195.

135.  Ryan DM, Cars O. A problem in the interpretation of beta-lactam antibiotic levels in tissue. J Antimicrob Chemother 1983;12:281–284.

136.  Traunmuller F, Fille M, Thallinger C, et al. Multiple-dose pharmacokinetics of telithromycin in peripheral soft tissues. Int J Antimicrob Agents 2009;34:72–75.

137.  Burkhard O, Brunner M, Schmidt S, et al. Penetration of ertapenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers measured by in vivo microdialysis. J Antimicrob Chemother 2006;58:632–636.

138.  Cunha BA, Gossling HR, Pasteinak HS, et al. The penetration characteristics of cefazolin, cephalothin, and cephradine into bone in patients undergoing total hip replacement. J Bone Joint Surg Am 1977;59:856–859.

139.  Schurman OJ, Hirshman HP, Burton DS. Cephalothin and cefamandole penetration into bone, synovial fluid, and wound drainage fluid. J Bone Joint Surg Am 1980;62:981–985.

140.  Rosdahl VT, Sorensen TS, Colding H. Determination of antibiotic concentrations in bone. J Antimicrob Chemother 1979;5:275–280.

141.  Adam D, Schalkhauser K, Boettger F. Zur Diffusion von Cefuroxim in das Prostataund andere Gewebe des urogenitalbereichs. Med Klin 1979;74:1867–1870.

142.  Wittmann DH, Kotthaus E. Further methodological improvement in antibiotic bone concentration measurements: penetration of ofloxacin into bone and cartilage. Infection 1986;14(Suppl 4):270–273.

143.  Fong IW, Ledbetter WH, Vandenbroucke AC, et al. Ciprofloxacin concentrations in bone and muscle after oral dosing. Antimicrob Agents Chemother 1986;29:405–408.

144.  Fitzgerald RH. Antibiotic distribution in normal and osteomyelitic bone. Orthop Clin North Am 1984;15:537–546.

145.  Williams DN, Gustilo RB, Bevesley R, et al. Bone and serum concentrations of five cephalosporin drugs: relevance to prophylaxis and treatment in orthopedic surgery. Clin Orthop 1983;179:254–265.

146.  Hughes SPF, Anderson FM. Penetration of antibiotics into bone. J Antimicrob Chemother 1985;15:517–519.

147.  Perry-Holly BA, Ritterbusch JK, Burdge RE, et al. Cefamandole levels in serum and necrotic bone. Clin Orthop 1985;1199:280–281.

148.  Soussy CJ, Deforges LP, Le Van Thoi J, et al. Cefotaxime concentration in the bile and wall of the gallbladder. J Antimicrob Chemother 1980;6(Suppl A):125–130.

149.  Kenady DE, Ram MB. Biliary levels of ceforanide. Antimicrob Agents Chemother 1983;23:706–709.

150.  Sales JE, Sutcliffe M, O’Grady F. Excretion of clindamycin in the bile of patients with biliary tract disease. Chemotherapy 1973;19:11–15.

151.  Wollmer P, Rhodes CG, Pike VW, et al. Measurement of pulmonary erythromycin concentration in patients with lobar pneumonia by means of positron tomography. Lancet 1982;2:1361–1363.

152.  Perea EJ, Garcia-Iglesias MC, Ayarra J, et al. Comparative concentration of cefoxitin in human lungs and sera. Antimicrob Agents Chemother 1983;23:323–324.

153.  Racz G. Tissue concentration of antibiotic following oral doses of tetracycline phosphate complex. Curr Ther Res 1971;13:553–557.

154.  Thadepalli H, Mandal AK, Bach VT, et al. Tissue levels of doxycycline in the human lung and pleura. Chest 1980;78:304–305.

155.  Warterberg K, Tohak J, Knapp W. Lung tissue concentrations of cefoperazone. Infection 1983;11:280–282.

156.  Reid TMS, Gould IM, Goulder D, et al. Brief report: respiratory tract penetration of ciprofloxacin. Am J Med 1989;87(Suppl 5A):60S–61S.

157.  Brun JN, Ostby N, Bredesen JE, et al. Sulfonamide and trimethoprim concentrations in human serum and skin blister fluid. Antimicrob Agents Chemother 1981;19:82–85.

158.  Galy J, Mantel O. Concentrations of cefotaxime in tissue and body fluids. Nouv Presse Med 1981;10:565–579.

159.  Hansen I, Lykkegaard Nielson M, Heerfordt L, et al. Trimethoprim in normal and pathological human lung tissue. Chemotherapy 1973;19:221–234.

160.  Farago E, Kiss IJ, Nabradi Z. Serum and lung tissue levels of fosfomycin in humans. Int J Clin Pharmacol Ther Toxicol 1980;18:554–558.

161.  Kiss IJ, Farago E, Juhasz I, et al. Investigation on the serum and lung tissue level of rifampicin in man. Int J Clin Pharmacol Biopharm 1976;13:42–47.

162.  Borrero AJ. Doxycycline levels in serum and prostatic tissue. Urology 1973;1:490–491.

163.  Evans WE, Schentag JJ, Jusko JJ. Applied pharmacokinetics: principles of therapeutic drug monitoring. 2nd ed. San Francisco: Applied Therapeutics, Inc, 1986.

164.  Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. 2nd ed. Philadelphia: Lea & Febiger, 1989.

165.  Wagner JG. Fundamentals of clinical pharmacokinetics. 2nd ed. Hamilton, IL: Drug Intelligence Publications, 1979.

166.  Zammit MC, Fiorentino L, Cassar K, et al. Factors affecting gentamicin penetration in lower extremity ischemic tissues with ulcers. Int J Lower Extrem Wounds 2011;10:130–137.

167.  Joukhadar C, Frossard M, Mayer BX, et al. Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med 2001;29:385–391.

168.  Buerger C, Plock N, Dehghanyar P, et al. Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of critically ill patients after multiple dosing using microdialysis. Antimicrob Agents Chemother 2006;50:2455–2463.

169.  Bergan T, Hellum KB, Schreiner A, et al. Passage of erythromycin into human suction skin blisters. Curr Ther Res 1982;32:597–603.

170.  Lanao JM, Dominguez A, Mactas JG, et al. The influence of ascites on the pharmacokinetics of amikacin. Int J Clin Pharmacol Ther Toxicol 1980;18:57–61.

171.  Gerding DN, Hall WH, Schierl EA. Antibiotic concentrations in ascitic fluid of patients with ascites and bacterial peritonitis. Ann Intern Med 1977;86:708–713.

172.  Ariza J, Xiol X, Esteve M, et al. Aztreonam vs. cefotaxime in the treatment of Gram-negative spontaneous peritonitis in cirrhotic patients. Hepatology 1991;14:91–98.

173.  Higuchi K, Ikawa K, Ikeda K, et al. Peritoneal pharmacokinetics of cefepime in laparotomy patients with inflammatory bowel disease, and dosage considerations for surgical intra-abdominal infections based on pharmacodynamic assessment. J Infect Chemother 2008;14:110–116.

174.  Gomez-Jimenez J, Ribera E, Gasser I, et al. Randomized trial comparing ceftriaxone with cefonicid for treatment of spontaneous bacterial peritonitis in cirrhotic patients. Antimicrob Agents Chemother 1993;37:1587–1592.

175.  Runyon BA, Akriviadis EA, Sattler FR, et al. Ascitic fluid and serum cefotaxime and desacetyl cefotaxime levels in patients treated for bacterial peritonitis. Dig Dis Sci 1991;36:1782–1786.

176.  Moreau L, Durand H, Biclet P. Cefotaxime concentrations in ascites. J Antimicrob Chemother 1980;6(Suppl A):121–122.

177.  Garcia MJ, Dominguez-Gil A, Diaz Perez F. Disposition of cefoxitin in patients with ascites. Eur J Clin Pharmacol 1981;20:371–374.

178.  Lechi A, Arosio E, Xerri L, et al. The kinetics of cefuroxime in ascitic and pleural fluid. Int J Clin Pharmacol Ther Toxicol 1982;20:493–496.

179.  Wilson DE, Chalmers TC, Medoff MA. The passage of cephalothin into and out of ascitic fluid. Am J Med Sci 1967;253:449–452.

180.  Arrigucci S, Garcea A, Fallani S, et al. Ertapenem peritoneal fluid concentrations in adult surgical patients. Int J Antimicrob Agents 2009;33:371–373.

181.  Soga Y, Ohge H, Ikawa K, et al. Peritoneal pharmacokinetics and pharmacodynamic target attainment of meropenem in patients undergoing abdominal surgery. J Chemother 2010;22(2):98–102.

182.  Rolando N, Wade JJ, Philpott-Howard JN, et al. The penetration of imipenem/cilastatin into ascitic fluid in patients with chronic liver disease. J Antimicrob Chemother 1994;33:163–167.

183.  Martin WJ, Nichols DR, Heilman FR. Penicillin V: further observations. Proc Staff Meet Mayo Clin 1955;30:521–526.

184.  Stass H, Rink AD, Delesen H, et al. Pharmacokinetics and peritoneal penetration of moxifloxacin in peritonitis. J Ant Chem 2006;58:693–696.

185.  Medina A, Fiske N, Hjelt-Harvey I, et al. Absorption, diffusion and excretion of a new antibiotic, lincomycin. Antimicrob Agents Chemother 1964;1963:189–196.

186.  Geraci JE, Heilman FR, Nichols DR, et al. Some laboratory and clinical experiences with a new antibiotic, vancomycin. Proc Staff Meet Mayo Clin 1956;31:564–582.

187.  Pulaski EJ, Tubbs RS. Inhibitory effects of kanamycin and diffusion into various body fluids. Antibiot Med Clin Ther 1959;6:589–593.

188.  Just HM, Eschenbruch E, Schmuziger M, et al. Penetration of netilmicin into heart valves, subcutaneous and muscular tissue of patients undergoing heart surgery. Clin Cardiol 1983;6:217–219.

189.  Beam TR Jr, Galask RP, Friedhoff LT, et al. Aztreonam concentration in human tissues obtained during thoracic and gynecologic surgery. Antimicrob Agents Chemother 1986;30:505–507.

190.  Cole DR, Pung J. Penetration of cefazolin into pleural fluid. Antimicrob Agents Chemother 1977;11:1033–1035.

191.  Yamada H, Iwanaga T, Nakanishi H, et al. Penetration and clearance of cefoperazone and moxalactam in pleural fluid. Antimicrob Agents Chemother 1985;27:93–95.

192.  Lode H, Kemmerich B, Gruhlke G, et al. Cefotaxime in bronchopulmonary infections: a clinical and pharmacological study. J Antimicrob Chemother 1980;6(Suppl A):193–198.

193.  Kafetzis DA. Penetration of cefotaximine into empyema fluid. J Antimicrob Chemother 1980;6(Suppl A):153.

194.  Webb D, Thadepalli H, Bach V, et al. Clinical and experimental evaluation of cefoxitin therapy. Chemotherapy 1978;26(Suppl 1):306–312.

195.  Dumont R, Guetat F, Andrews JM, et al. Concentrations of cefpodoxime in plasma and pleural fluid after a single oral dose of cefpodoxime proxetil. J Antimicrob Chemother 1990;26(Suppl E):41–46.

196.  Walstad RA, Hellum KB, Blika S, et al. Pharmacokinetics and tissue penetration of ceftazidine: studies on lymph, aqueous humor, skin blister, cerebrospinal fluid and pleural fluid. J Antimicrob Chemother 1983;12(Suppl A):275–282.

197.  Takamoto M, Ishibashi T, Harada S, et al. Experience with ceftizoxime in respiratory tract infection and its transfer into pleural effusion. Chemotherapy 1980;28(Suppl 5):394–404.

198.  Benoni G, Arosio E, Cuzzolin L, et al. Penetration of ceftriaxone into human pleural fluid. Antimicrob Agents Chemother 1986;29:906–908.

199.  Taryle DA, Good JT, Morgan EJ, et al. Antibiotic concentrations in human parapneumonic effusions. J Antimicrob Chemother 1981;7:171–177.

200.  Joseph J, Vaughan LM, Basran GS. Penetration of intravenous and oral ciprofloxacin into sterile and empyemic human pleural fluid. Ann Pharmacother 1994;28:313–315.

201.  Kimura M, Matsushima T, Nakamura J, et al. Comparative study of penetration of lomefloxacin and ceftriaxone into transudative and exudative pleural effusion. Antimicrob Agents Chemother 1992;36:2774–2777.

202.  Yew WW, Lee J, Chan CY, et al. Ofloxacin penetration into tuberculous pleural effusion. Antimicrob Agents Chemother 1991;35:2159–2160.

203.  Daschner FD, Gier E, Lentzen H, et al. Penetration into the pleural fluid after bacampicillin and amoxicillin. J Antimicrob Chemother 1981;7:585–588.

204.  Lode H, Dzwillo G. Investigation of the diffusion of antibiotics into the human pleural space. In: Proceedings of the 10th International Congress of Chemotherapy. Washington, DC: American Society for Microbiology, 1978;1:386–388.

205.  Giachetto G, Catalina M, Nanni L, et al. Ampicillin and penicillin concentration in serum and pleural fluid of hospitalized children with community-acquired pneumonia. Pediatr Infect Dis J 2004;23(7):625–629.

206.  Bronsveld W, Stam J, MacLaren DM. Concentrations of ampicillin in pleural fluid and serum after single and repetitive doses of bacampicillin. Scand J Infect Dis 1978;14(Suppl):274–278.

207.  Knoller J, Schonfeld W, Mayer M, et al. Mezlocillin in pleural effusions: analysis by HPLC. Zentralbl Bakteriol Hyg A 1988;268:370–375.

208.  Lode H, Gruhlke G, Hallermann W, et al. Significance of pleural and sputum concentrations for antibiotic therapy of bronchopulmonary infections. Infection 1980;8(Suppl 1):S49–S53.

209.  Simon C, Sommerwerck D, Friehoff J. Der Wert von Doxycycloin bei Atemwegsinfektionen (Serum, -Speichel, -Sputum-Lungen, und Pleuraexsudatspiegel). Prax Klin Pneumol 1978;32:266–270.

210.  Panzer JD, Brown DC, Epstein WL, et al. Clindamycin levels in various body tissues and fluids. J Clin Pharmacol 1972;12:259–262.

211.  Fernandez-Lastra C, Marino EL, Barrueco M, et al. Disposition of phosphomycin in patients with pleural effusion. Antimicrob Agents Chemother 1984;25:458–462.

212.  Boman G, Malmberg AS. Rifampin in plasma and pleural fluid after single oral doses. Eur J Clin Pharmacol 1974;7:51–58.

213.  Jacobs F, Rocmans P, Motte S, et al. Penetration and bactericidal activity of teichoplanin in post-thoracotomy pleural fluids. In: Program and abstracts of the 26th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1986. Abstract 1251.

214.  Byl B, Jacobs F, Wallemacq P, et al. Vancomycin penetration of uninfected pleural fluid exudates after continuous or intermittent infusion. Antimicrob Agents Chemother 2003;47:2015–2017.

215.  Honda DH, Adams HG, Barriere SL. Amikacin penetration into synovial fluid during treatment of septic arthritis. Drug Intell Clin Pharm 1981;15:284–286.

216.  Dee TH, Kozin F. Gentamicin and tobramycin penetration into synovial fluid. Antimicrob Agents Chemother 1977;12:548–549.

217.  Baciocco EA, Iles RL. Ampicillin and kanamycin concentrations in joint fluid. Clin Pharmacol Ther 1971;12:858–863.

218.  Valencia-Chinas A, Galindo-Hernandez F, Reyes-Sanchez J, et al. Concentrations of cefadroxil in osteoarticular tissues. In: Program and abstracts of the 11th International Congress of Chemotherapy and 19th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1979. Abstract 338.

219.  Vainiopaa S, Wilppula E, Lalla M, et al. Cefamandole and isoxazolyl penicillins in antibiotic prophylaxis of patients undergoing total hip or knee-joint arthroplasty. Arch Orthop Trauma Surg 1988;107:228–230.

220.  Schurman OJ, Hirshman HP, Kajiyama G, et al. Cefazolin concentrations in bone and synovial fluid. J Bone Joint Surg Am 1978;60:359–362.

221.  Harle A, Ritzerfeld W, Kluppelberg FH. Cefotaxime levels in synovial fluid following intravenous administration. Z Orthop 1988;126:425–430.

222.  Nelson JD, Howard JB, Shelton S. Oral antibiotic therapy for skeletal infections of children. Pediatrics 1978;92:131–134.

223.  Parker RH, Birbara C, Schmid FR. Passage of nafcillin and ampicillin into synovial fluid. Zentralbl Bakteriol 1976;(Suppl 5):1115–1123.

224.  Nelson JD. Antibiotic concentrations in septic joint effusions. N Engl J Med 1971;284:349–353.

225.  Viek P. Concentration of sodium nafcillin in pathological synovial fluid. Antimicrob Agents Chemother 1962;1961:379–383.

226.  Balboni VG, Shapiro IM, Kydd DM. The penetration of penicillin into joint fluid following intramuscular administration. Am J Med Sci 1945;210:588–591.

227.  Rana B, Butcher I, Grigoris P, et al. Linezolid penetration into osteo-articular tissues. J Antimicrob Chemother 2002;50:747–750.

228.  Rodvold KA, Gotfried MH, Cwik M, et al. Serum, tissue and body fluid concentrations of tigecycline after a singled 100 mg dose. J Antimicrob Chemother 2006;58:1221–1229.

229.  Solberg CO, Madsen ST, Digranes A, et al. High dose netilmicin therapy: efficacy, tolerance and tissue penetration. J Antimicrob Chemother 1980;6:133–141.

230.  Mazzei T, Novelli A, Esposito S, et al. New insight into the clinical pharmacokinetics of cefaclor: tissue penetration. J Chemother 2000;12:53–62.

231.  Nye KJ, Shi YG, Andrews JM, et al. Pharmacokinetics and tissue penetration of cefepime. J Antimicrob Chemother 1989;24:23–28.

232.  Stone JW, Linong G, Andrews JM, et al. Cefixime in-vitro activity, pharmacokinetics and tissue penetration. J Antimicrob Chemother 1989;23:221–228.

233.  Korting HC. Plasma and skin blister fluid levels of cefotriam and cefmenoxime after single intramuscular application of 1 gm in gonorrhea. Chemotherapy 1984;30:277–282.

234.  Korting HC, Schafer-Korting M, Maass L, et al. Cefodizime in serum and skin blister fluid after single intravenous and intramuscular doses in healthy volunteers. Antimicrob Agents Chemother 1987;31:1822–1825.

235.  Mazzei T, Novelli A, Esposito S, et al. Cefodizime in skin suction blister fluid and serum following a single intravenous or intramuscular dose in adult patients. J Chemother 2000;12:306–313.

236.  Shyu WC, Quintiliani R, Nightingale CH, et al. Effect of protein binding on drug penetration into blister fluid. Antimicrob Agents Chemother 1988;32:128–130.

237.  Frossard M, Joukhadar C, Erovic BM, et al. Distribution and antimicrobial activity of fosfomycin in the interstitial fluid of human soft tissues. Antimicrob Agents Chemother 2000;44:2728–2732.

238.  Bergan T, Kalager T, Hellum KB, et al. Penetration of cefotaxime and desacetylcefoxamine into skin blister fluid. J Antimicrob Chemother 1982;10:193–196.

239.  Mazzei T, Tonelli F, Novelli A, et al. Penetration of cefotetan into suction skin blister fluid and tissue homogenates in patients undergoing abdominal surgery. Antimicrob Agents Chemother 1994;38:2221–2223.

240.  Bryskier A, Elbaz P, Fourtillan JB, et al. Evaluation of the extravascular distribution of cefotiam (SLE 963) by the skin blister technic. Pathol Biol 1984;32:506–508.

241.  Kavi J, Andrews JM, Ashby JP, et al. Pharmacokinetics and tissue penetration of cefpirome, a new cephalosporin. J Antimicrob Chemother 1988;22:911–916.

242.  Borin MT, Hughes GS, Spillers CR, et al. Pharmacokinetics of cefpodoxime in plasma and skin blister fluid following oral dosing of cefpodoxime proxetil. Antimicrob Agents Chemother 1990;34:1094–1099.

243.  Barbhaiya RH, Shukla UA, Gleason CR, et al. Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration. Antimicrob Agents Chemother 1990;34:1204–1209.

244.  Findlay CD, Wise R, Allcock JE, et al. The tissue penetration, as measured by a blister technique, and pharmacokinetics of cefsulodin compared with carbenicillin and ticarcillin. J Antimicrob Chemother 1981;7:637–642.

245.  Hoffstedt B, Walder M. Penetration of ceftaxidime into extracellular fluid in patients. J Antimicrob Chemother 1981;8(Suppl B):289–292.

246.  Wise R, Nye K, O’Neill P, et al. Pharmacokinetics and tissue penetration of ceftibuten. Antimicrob Agents Chemother 1990;34:1053–1055.

247.  Shyu WC, Quintiliani R, Nightingale CH. An improved method to determine interstitial fluid pharmacokinetics. J Infect Dis 1985;152:1328–1331.

248.  LeBel M, Gregoire S, Caron M, et al. Difference in blister fluid penetration after single and multiple doses of ceftriaxone. Antimicrob Agents Chemother 1985;28:123–127.

249.  Adam D, Reichart B, Beyer J, et al. Diffusion of cephradine and cephalothin into interstitial fluid of human volunteers with tissue cages. Infection 1978;6:578–581.

250.  Wise R, Andrews JM, O’Neill P, et al. Pharmacokinetics and distribution in tissue of FK-037, a new parenteral cephalosporin. Antimicrob Agents Chemother 1994;38:2369–2372.

251.  Mouton JW, Michel MF. Pharmacokinetics of meropenem in serum and suction blister fluid during continuous and intermittent infusion. J Antimicrob Chemother 1991;28:911–918.

252.  Wise R, Gillett AP, Cadge B, et al. The influence of protein binding upon tissue fluid levels of six-lactam antibiotics. J Infect Dis 1980;42:77–82.

253.  Wise R, Bennett SA, Dent J. The pharmocokinetics of orally absorbed cefuroxime compared with amoxycillin/clavulanic acid. J Antimicrob Chemother 1984;13:603–610.

254.  Herlitz V, Langmaack H, Metzger M, et al. Serum and tissue levels of cefoxitin in perioperative prophylaxis. J Antimicrob Chemother 1980;6:717–722.

255.  Takase Z; Obstetrics and Gynecology Research Group. Basic and clinical research on cefsulodin in the field of obstetrics and gynecology. Jpn J Antibiot 1982;35:2861–2877.

256.  Hoffstedt B, Walder M, Forsgren A. Comparison of skin blisters and implanted cotton threads for the evaluation of antibiotic tissue concentrations. Eur J Clin Microbiol 1982;1:33–37.

257.  Bergan T, Engeset A, Olszewski W, et al. Extravascular penetration of highly protein-bound flucloxacillin. Antimicrob Agents Chemother 1986;30:729–732.

258.  Wise R, Logan M, Cooper M, et al. Pharmacokinetics and tissue penetration of tazobactam administered alone and with piperacillin. Antimicrob Agents Chemother 1991;35:1081–1084.

259.  Lockley MR, Brown RM, Wise R. Pharmacokinetics and tissue penetration of temocillin. Drugs 1985;29(Suppl 5):106–108.

260.  Walstad RA, Hellum KB, Thurmann-Nielsen E, et al. Pharmacokinetics and tissue penetration of timentin: a simultaneous study of serum, urine, lymph, suction blister and subcutaneous thread fluid. J Antimicrob Chemother 1986;17(Suppl C):71–80.

261.  Wise R, Lister D, McNulty CAM, et al. The comparative pharmacokinetics of five quinolones. J Antimicrob Chemother 1986;18(Suppl D):71–81.

262.  Wise R, Kirkpatrick B, Ashby J, et al. Pharmacokinetics and tissue penetration of Ro 23–6240, a new trifluoroquinolone. Antimicrob Agents Chemother 1987;31:161–163.

263.  Wise R, Andrews JM, Ashby JP, et al. A study to determine the pharmacokinetics and inflammatory fluid penetration of gatifloxacin following a single oral dose. J Antimicrob Chemother 1999;44:701–704.

264.  Cooper MA, Nye K, Andrews JM, et al. The pharmacokinetics and inflammatory fluid penetration of orally administered azithromycin. J Antimicrob Chemother 1990;26:533–538.

265.  McNulty CA, Garden GM, Ashby J, et al. Pharmacokinetics and tissue penetration of carumonam, a new synthetic monobactam. Antimicrob Agents Chemother 1985;28:425–427.

266.  Wise R, Webberly JM, Andrews JM, et al. The pharmacokinetics and tissue penetration of intravenously administered CGP31608. J Antimicrob Chemother 1988;21:85–91.

267.  Raeburn JAA. A method for studying antibiotic concentrations in inflammatory exudate. J Clin Pathol 1971;24:633–635.

268.  Nicolau D, Sun HK, Seltzer E, et al. Pharmacokinetics of dalbavancin in plasma and skin blister fluid. J Antimicrob Chemother 2007;60:681–684.

269.  Wise R, Gee T, Andrews JM, et al. Pharmacokinetics and inflammatory fluid penetration of intravenous daptomycin in volunteers. Antimicrob Agents Chemother 2002;46:31–33.

270.  Schreiner A, Digranes A. Pharmocokinetics of lymecycline and doxycycline in serum and suction blister fluid. Chemotherapy 1985;31:261–265.

271.  Tuominen RK, Mannisto PT, Solkinen A, et al. Antibiotic concentration in suction skin blister fluid and saliva after repeated dosage of erythromycin acistrate and erythromycin base. J Antimicrob Chemother 1988;21(Suppl D):57–65.

272.  Frossard M, Joukhadar C, Erovic BM, et al. Distribution and antimicrobial activity of fosfomycin in the interstitial fluid of human soft tissues. Antimicrob Agents Chemother 2000;44:2728–2732.

273.  Vaillant L, Machet L, Taburet AM, et al. Levels of fusidic acid in skin blister fluid and serum after repeated administration of two dosages (250 and 500 mg). Br J Dermatol 1992;126:591–595.

274.  Gee T, Ellis R, Marshall G, et al. Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. J Antimicrob Chemother 2001;45:1843–1846.

275.  Bergan T, Bruun JN, Ostby N, et al. Human pharmacokinetics and skin blister levels of sulfonamides and dihydrofolate reductase inhibitors. Chemotherapy 1986;32:319–328.

276.  Solberg CO, Halstensen A, Digranes A, et al. Penetration of antibiotics into human leukocytes and dermal suction blisters. Rev Infect Dis 1983;5:S468–S473.

277.  McNulty CA, Garden GM, Wiser R, et al. The pharmacokinetics and tissue penetration of teicoplanin. J Antimicrob Chemother 1985;16:743–749.

278.  Namour F, Sultan E, Pascual MH, et al. Penetration of telithromycin (HMR 3647) a new ketolide antimicrobial, into inflammatory blister fluid following oral administration. J Antimicrob Chemother 2002;49:1035–1038.

279.  Sun HK, Ong CT, Umer A, et al. Pharmacokinetic profile of tigecycline in serum and skin blister fluid of healthy subjects after multiple intravenous administrations. Antimicrob Agents Chemother 2005;49:1629–1932.

280.  Hansbrough SF, Clark JE, Reimer LG. Concentrations of kanamycin and amikacin in human gallbladder bile and wall. Antimicrob Agents Chemother 1981;20:515–517.

281.  Pulaski EJ, Fusillo MH. Gallbladder bile concentrations of the major antibiotics following intravenous administration. Surg Gynecol Obstet 1955;100:571–574.

282.  Moseley JG, Chaudhuri AK, Desai AL, et al. The distribution of aztreonam in serum, bile, skin and subcutaneous tissues in patients undergoing cholecystectomy. J Hosp Infect 1990;15:389–392.

283.  Ohnhaus EE, Halter F, Lebek G. Estimation of the biliary excretion of different cephalosporins utilizing retrograde cholongiopancreatography (ERCP). Endoscopy 1981;13:13–32.

284.  Palmu A, Jarvinen H, Hallynck T, et al. Cefadroxil levels in bile in biliary infection. In: Nelson JD, Grassi C, eds. Current chemotherapy and infectious disease: proceedings of the 11th International Congress of Chemotherapy and 19th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1979:643–644.

285.  Ratzan KR, Baker HB, Lauredo I. Excretion of cefamandole, cefazolin and cephalothin into T-tube bile. Antimicrob Agents Chemother 1978;13:985–987.

286.  Ratzan KR, Ruiz C, Irvin GL III. Biliary tract excretion of cefazolin, cephalothin, and cephaloridine in the presence of biliary tract disease. Antimicrob Agents Chemother 1974;6:426–431.

287.  Tanaka H, Nishino H, Sawada T, et al. Biliary penetration of cefbuperazone in the presence and absence of obstructive jaundice. J Antimicrob Chemother 1987;20:417–420.

288.  Okamoto MP, Gill MA, Nakahiro RK, et al. Tissue concentrations of cefepime in acute cholecystitis patients. Ther Drug Monit 1992;14:220–225.

289.  Petrikkos G, Kastanakis M, Markogiannakis A, et al. Pharmacokinetics of cefepime in bile and gall bladder tissue after prophylactic administration in patients with extrahepatic biliary diseases. Int J Antimicrob Agents 2006;27:331–334.

290.  Smith BR, LeFrock J, Carr BB. Cefmenoxime penetration into gallbladder bile and tissue. Antimicrob Agents Chemother 1983;23:941–943.

291.  Orda R, Berger SA, Levy Y, et al. Penetration of ceftriaxone and cefoperazone into bile and gallbladder tissue in patients with acute cholecystitis. Dig Dis Sci 1992;37:1691–1693.

292.  Brogard JM, Jehl F, Blickle JF, et al. Experimental and clinical evaluation of the biliary phamacokinetic profile of cefpiramide, a new cephalosporin with high hepatic elimination. Drugs Exp Clin Res 1988;14:519–527.

293.  Walstad RA, Wiig JN, Thurmann-Nielsen E, et al. Pharmacokinetics of ceftazidime in patients with biliary tract disease. Eur J Clin Pharmacol 1986;31:327–331.

294.  Severn M, Powis SJA. Biliary excretion and tissue levels of cefuroxime: a study in eleven patients undergoing cholecystectomy. J Antimicrob Chemother 1979;5:183–188.

295.  Mayer M, Tophof C, Opferkuch W. Bile levels of imipenem in patients with T-drain following the administration of imipenem/cilastatin. Infection 1988;16:225–228.

296.  Condon RE, Walker AP, Hanna CB, et al. Penetration of meropenem in plasma and abdominal tissues from patients undergoing intraabdominal surgery. Clin Infect Dis 1997;24(Suppl 2):S181–S183.

297.  Kiss IJ, Farago E, Schnitzler J, et al. Amoxycillin levels in human serum, bile, gallbladder, lung and liver tissue. Int J Clin Pharmacol Ther Toxicol 1981;19:69–74.

298.  Morris DL, Ubhi CS, Robertson CS, et al. Biliary pharmacokinetics of sulbactam plus ampicillin in humans. Rev Infect Dis 1986;8(Suppl 5):S589–S592.

299.  Brogard JM, Arnaud JP, Blickle JF, et al. Biliary elimination of apalcillin. Antimicrob Agents Chemother 1984;26:428–430.

300.  Henegar GC, Silverman M, Gardner RJ, et al. Excretion of methicillin in human bile. Antimicrob Agents Chemother 1962;1961:348–351.

301.  Green GR, Geraci JE. A note on the concentration of nafcillin in human bile. Mayo Clin Proc 1965;40:700–704.

302.  Wittke RR, Adam D, Klein HE. Therapeutic results and tissue concentrations of temocillin in surgical patients. Drugs 1985;29(Suppl 5):221–226.

303.  Owen AWMC, Faragher EB. Biliary pharmacokinetics of ticarcillin and clauvulanic acid. J Antimicrob Chemother 1986;17(Suppl C):65–70.

304.  Zurbuchen U, Ritz JP, Lehmann KS, et al. Oral vs intravenous antibiotic prophylaxis in elective laparoscopic cholecystectomy—an exploratory trial. Langenbecks Arch Surg 2008;393:479–485.

305.  Kunin CM, Finland M. Excretion of demethylchlortetracycline into the bile. N Engl J Med 1959;261:1069–1071.

306.  Dull WL, Alexander MR, Kasik JE. Bronchial secretion levels of amikacin. Antimicrob Agents Chemother 1979;16:767–771.

307.  Klastersky J, Greening C, Mouawad E, et al. Endotracheal gentamicin in bronchial infections in patients with tracheostomy. Chest 1971;61:117–120.

308.  Panidis D, Markantonis SL, Boutzouka E, et al. Penetration of gentamicin into the alveolar lining fluid of critically ill patients with ventilator-associated pneumonia. Chest 2005;128(2):545–552.

309.  Valcke YJ, Vogelaers DP, Colardyn FA, et al. Penetration of netilmicin in the lower respiratory tract after once-daily dosing. Chest 1992;101:1028–1032.

310.  Boselli E, Breilh D, Djabarouti S, et al. Reliability of mini-bronchioalveolar lavage for the measurement of epithelial lining fluid concentrations of tobramycin in critically ill patients. Intensive Care Med 2007;33:1519–1523.

311.  Klastersky J, Carpentier-Meunier F, Kahan-Coppens L, et al. Endotracheally administered antibiotics for Gram-negative bronchopneumonia. Chest 1979;75:586–591.

312.  Alexander M, Schoell S, Hicklin G, et al. Bronchial secretion concentrations of tobramycin. Am Rev Respir Dis 1982;125:208–209.

313.  Barrera V, Sinues B, Martinez P, et al. Penetration de l’amikacine daus la chambre anterieure de l’oell humain. J Fr Ophthalmol 1984;7:539–543.

314.  Cook PJ, Andrews JM, Wise R, et al. Distribution of cefdinir, a third generation cephalosporin antibiotic, in serum and pulmonary compartments. J Antimicrob Chemother 1996;37:331–339.

315.  Chadha D, Wise R, Baldwin DR, et al. Cefepime concentrations in bronchial mucosa and serum following a single 2 gram intravenous dose. J Antimicrob Chemother 1990;25:959–963.

316.  Serieys C, Bergogne-Berezin E, Kafe H, et al. Study of the diffusion of cefmenoxine into the bronchial secretions. Chemotherapy 1986;32:1–6.

317.  Bergogne Berezin E, Kafe H, Berthelot G, et al. Pharmacokinetic study of cefoxitin in bronchial secretions. In: Siegenthaler W, Luethy R, eds. Current chemotherapy: proceedings. Washington, DC: American Society for Microbiology, 1978:758–760.

318.  Baldwin DR, Maxwell SRJ, Honeybourne D, et al. The penetration of cefpirome into the potential sites of pulmonary infection. J Antimicrob Chemother 1991;28:79–86.

319.  Bergogne-Berezin E, Berthelot G, Safran D, et al. Penetration of cefsulodin into bronchial secretions. Chemotherapy 1984;30:205–210.

320.  Bergogne-Berezin E, Pierre J, Berthelot G, et al. Diffusion bronchique des nouvelles beta-lactimes anti-pseudomonas. Pathol Biol 1984;32:421–425.

321.  Husson MO, Debout J, Krivosic-Horber R. Etude de la diffusion bronchique de la ceftriaxone. Pathol Biol 1986;34:325–327.

322.  Halprin GM, McMahon SM. Cephalexin concentrations in sputum during acute respiratory infections. Antimicrob Agents Chemother 1973;3:703–707.

323.  Bergogne-Berezin E, Morel C, Benard Y, et al. Pharmacokinetic study of beta-lactam antibiotics in bronchial secretions. Scand J Infect Dis 1978;14(Suppl):267–272.

324.  Boselli E, Breilh D, Saux MC, et al. Pharmacokinetics and lung concentrations of ertapenem in patients with ventilator-associated pneumonia. Intensive Care Med 2006;32:2059–2062.

325.  Bergogne-Berezin E, Muller-Serieys C, Aubier M, et al. Concentration of meropenem in serum and in bronchial secretions in patients undergoing fiberoptic bronchoscopy. Eur J Clin Pharmacol 1994;46:87–88.

326.  Allegranzi B, Cazzadori A, Di Perri G, et al. Concentrations of single-dose meropenem (1 g IV) in bronchoalveolar lavage and epithelial lining fluid. J Antimicrob Chemother 2000;46:319–322.

327.  Conte JE Jr, Golden JA, Kelley MG, et al. Intrapulmonary pharmacokinetics and pharmacodynamics of meropenem. Int J Antimicrob Agents 2005;26:449–456.

328.  Mouton Y, Caillaux M, Beaucaire G, et al. Penetration of moxalactam in bronchial secretions and clinical evaluation in intensive care patients. In: Program and abstracts of the 21st Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1981. Abstract 732.

329.  Cook PJ, Andrews JM, Woodcock J, et al. Concentrations of amoxycillin and clavulante in lung compartments in adults without pulmonary infection. Thorax 1994;49:1134–1138.

330.  Wildfeuer A, Rühle KH, Balk PL, et al. Concentrations of ampicillin and sulbactam in serum and in various compartments of the respiratory tract of patients. Infection 1994;22:149–151.

331.  Bergogne-Berezin E, Pierre J, Chastre J, et al. Pharmacokinetics of apalcillin in intensive-care patients: study of penetration into the respiratory tract. J Antimicrob Chemother 1984;14:67–73.

332.  Hafez FF, Stewart SM, Burnet ME. Penicillin levels in sputum. Thorax 1965;20:219–225.

333.  Saggers BA, Lawson D. In vivo penetration of antibiotics into sputum in cystic fibrosis. Arch Dis Child 1968;43:404–409.

334.  Mouton Y, Caillaux M, Deboscker Y, et al. Etude de la diffusion bronchique de la piperacilline chez dix-huit patients de reanimation. Pathol Biol 1985;33:359–362.

335.  Vacek V, Hejzlar M, Skalova M. Penetration of antibiotics into the cerebrospinal fluid in inflammatory conditions. I. Preface and comparative study of ampicillin with hetacillin. Int J Clin Pharmacol 1968;1:87–90.

336.  Hoogkamp-Korstanje JAA, Klein SJ. Ciprofloxacin in acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1986;18:407–413.

337.  Gotfried MH, Danziger LH, Rodvold KA. Steady-state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects. Chest 2001;119:1114–1122.

338.  Davies BI, Maesen FPV, Teengs JP. Serum and sputum concentrations of enoxacin after single oral dosing in a clinical and bacteriological study. J Antimicrob Chemother 1984;14(Suppl C):83–89.

339.  Begg EJ, Robson RA, Saunders DA, et al. The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing. J Clin Pharmacol 2000;49:32–38.

340.  Andrews J, Honeybourne D, Jevons G, et al. Concentrations of garenoxacin in plasma, bronchial mucosa, alveolar macrophages and epithelial lining fluid following a single oral 600 mg dose in healthy adult subjects. J Antimicrob Chemother 2003;51:727–730.

341.  Honeybourne D, Banerjee D, Andrews J, et al. Concentrations of gatifloxacin in plasma and pulmonary compartments following a single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother 2001;48:63–66.

342.  Cazzola M, Matera MG, Tufano MA, et al. Pulmonary disposition of lomefloxacin in patients with acute exacerbation of chronic obstructive pulmonary disease. A multiple-dose study. J Chemother 2001;13:407–412.

343.  Soman A, Honeybourne D, Andrews J, et al. Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother 1999;44:835–838.

344.  Pedersen SS, Jensen T, Hvidberg EF. Comparative pharmacokinetics of ciprofloxacin and ofloxacin in cystic fibrosis patients. J Antimicrob Chemother 1987;20:575–583.

345.  Davies BI, Maesen FPV, Teengs JP, et al. The quinolones in chronic bronchitis. Pharm Weekbl Sci 1986;8:53–59.

346.  Ruhen RW, Tandon MK. Minocycline, doxycycline and tetracycline levels in serum and bronchial secretions of patients with chronic bronchitis. Pathology 1975;7:193–197.

347.  Naline E, Sanceaume M, Taty L, et al. Penetration of minocycline into lung tissues. Br J Clin Pharmacol 1991;32:402–404.

348.  Baldwin DR, Wise R, Andrews JM, et al. Azithromycin concentrations at the sites of pulmonary infection. Eur Respir J 1990;3:886–890.

349.  Lucchi M, Damle B, Fang A, et al. Pharmacokinetics of azithromycin in serum, bronchial washings, alveolar macrophages and lung tissue following a single oral dose of extended or immediate release formulations of azithromycin. J Antimicrob Chemother 2008;61:884–891.

350.  Honeybourne D, Kees F, Andrews JM, et al. The levels of clarithromycin and its 14-hydroxy metabolite in the lung. Eur Respir J 1994;7:1275–1280.

351.  Bergogne-Berezin E, Morel C, Even P, et al. Pharmacocinetique des antibiotiques dans les voies respiratoires. Nouv Presse Med 1978;7:2831–2836.

352.  Imberti R, Cusato M, Villani P, et al. Steady-state pharmacokinetics and BAL concentration of colistin in critically ill patients after IV colistin methanesulfonate administration. Chest 2010;138(6):1333–1339.

353.  Leroyer C, Muller-Serieys C, Quiot JJ, et al. Dirithromycin concentrations in bronchial mucosa and secretions. Respiration 1998;65:381–385.

354.  Pierre J, Bergogne-Berezin E, Kafe H, et al. The penetration of macrolides into bronchial secretions. J Antimicrob Chemother 1985;16(Suppl A):217–220.

355.  Brun Y, Forey F, Gamondes JP, et al. Levels of erythromycin in pulmonary tissue and bronchial mucus compared to those of amoxicillin. J Antimicrob Chemother 1981;8:459–466.

356.  Ricevuti G, Pasotti D, Mazzone A, et al. Serum, sputum and bronchial concentrations of erythromycin in chronic bronchitis after single and multiple treatments with either propionate-17-acetylcysteinate or stearate erythromycin. Chemotherapy 1988;34:374–379.

357.  Panteix G, Harf R, deMontclos H, et al. Josamycin pulmonary penetration determined by bronchoalveolar lavage in man. J Antimicrob Chemother 1988;22:917–921.

358.  Conte JE Jr, Golden JA, Kipps J, et al. Intrapulmonary pharmacokinetics of linezolid. Antimicrob Agents Chemother 2002;46:1475–1480.

359.  Boselli E, Breilh D, Rimmele T, et al. Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. Crit Care Med 2005;33(7):1529–1533.

360.  Chyo N, Sunada H, Nohara S. Clinical studies of kanamycin applied in the field of obstetrics and gynecology. Asian Med J 1962;5:293–297.

361.  Takase Z. Laboratory and clinical studies of tobramycin in the field of obstetrics and gynecology. Chemotherapy 1975;23:1390–1403.

362.  Fleiss PM, Richward GA, Gordon J, et al. Aztreonam in human serum and breast milk. Br J Clin Pharmacol 1985;19:509–511.

363.  Kafetzis DA, Siafas CA, Georgakopoulos PA, et al. Passage of cephalosporins and amoxicillin into the breast milk. Acta Paediatr Scand 1981;70:285–288.

364.  Lily and Co. Mandol in lactating mothers. Data on file. Indianapolis, IN: Elilily and Co.

365.  Yoshioka H, Cho K, Takimoto M, et al. Transfer of cefazolin into human milk. J Pediatr 1979;94:151–152.

366.  Weissenbacher ER, Adams D, Gutschow K, et al. Clinical results and concentrations of cefmenoxime in serum, amniotic fluid, mother’s milk, and placenta. Am J Med 1984;77(Suppl 6A):11–12.

367.  Lou MA, Wu YH, Jacob LS, et al. Penetration of cefonicid into human breast milk and various body fluids and tissues. Rev Infect Dis 1984;6(Suppl 4):5816–5820.

368.  Takase Z, Shirafuji H, Uchida M. Fundamental and clinical studies of cefoperazone in the field of obstetrics and gynecology. Chemotherapy 1980;28(Suppl 6):825–836.

369.  Dresse A, Lambotte R, Dubois M, et al. Transmammary passage of cefoxitin: additional results. J Clin Pharmacol 1983;23:438–440.

370.  Takase Z, Shirafuji H, Uchida M. Clinical and laboratory studies on cefoxitin in the field of obstetrics and gynecology. Chemotherapy 1978;26:502–505.

371.  Shyu WC, Shah VR, Campbell DA, et al. Excretion of cefprozil into human breast milk. Antimicrob Agents Chemother 1992;36:938–941.

372.  Blanco JD, Jorgensen JH, Castaneda YS, et al. Ceftazidime levels in human breast milk. Antimicrob Agents Chemother 1983;23:479–480.

373.  Kafetzis DA, Brater DC, Fanourgakis JE, et al. Ceftriaxone distribution between maternal blood and fetal blood and tissues at parturition and between blood and milk postpartum. Antimicrob Agents Chemother 1983;23:870–873.

374.  Mischler TW, Corson SL, Larranaga A, et al. Cephradine and epicillin in body fluids of lactating and pregnant women. J Reprod Med 1973;26:130–136.

375.  Prigot A, Froix KJ, Rubin E. Absorption, diffusion and excretion of a new penicillin, oxacillin. Antimicrob Agents Chemother 1962;1962:402–409.

376.  Greene HJ, Burkhart B, Hobby GL. Excretion of penicillin in human milk following parturition. Am J Obstet Gynecol 1946;51:732–733.

377.  Rosansky R, Brzczinsky A. The excretion of penicillin in human milk. J Lab Clin Med 1949;34:497–500.

378.  Matheson I, Samseth M, Loberg R, et al. Milk transfer of phenoxymethyl-penicillin during puerperal mastitis. Br J Clin Pharmacol 1988;25:33–40.

379.  Lederle Laboratories. Piperacil [package insert]. Data on file. Lederle Laboratories, 1982.

380.  Braneberg PE, Heisterberg L. Blood and milk concentrations of ampicillin in mothers treated with pivampicillin and in their infants. J Perinatal Med 1987;15:555–558.

381.  Foulds G, Miller RD, Knirsch AK, et al. Sulbactam kinetics and excretion into breast milk in postpartum women. Clin Pharmacol Ther 1985;38:692–696.

382.  Cho N, Nakayama T, Uehara K, et al. Laboratory and clinical evaluation of ticarcillin in the field of obstetrics and gynecology. Chemotherapy 1977;25:2911–2923.

383.  Amsden GW, Nicolau DP, Whitaker AM, et al. Characterization of the penetration of garenoxacin into the breast milk of lactating women. J Clin Pharmacol 2004;44:188–192.

384.  Guilbeau JA, Schoenbach EB, Schaub IG, et al. Aureomycin in obstetrics. JAMA 1950;143:520–526.

385.  Posner AC, Prigot A, Konicoff NG. Further observations on the use of tetracycline hydrochloride in prophylaxis and treatment of obstetric infections. Antibiot Annu 1954;5:594–598.

386.  Morgan G, Ceccarelli G, Ciaffi G. Comparative concentrations of a tetracycline antibiotic in serum and maternal milk. Antibiotica 1968;6:216–222.

387.  Plomp TA, Thiery M, Maes RAA. The passage of thiamphenicol and chloramphenicol into human milk after single and repeated oral administration. Vet Hum Toxicol 1983;25:167–172.

388.  Steen B, Rane A. Clindamycin passage into milk. Br J Clin Pharmacol 1982;13:661–664.

389.  Heisterberg L, Branebjerg PE. Blood and milk concentrations of metronidazole in mothers and infants. J Perinat Med 1983;11:114–120.

390.  Varsano J, Fischl J, Shochet SB. The excretion of orally ingested nitrofurantoin in human milk. J Pediatr 1973;82:886–887.

391.  Stoehr GP, Juhl RP, Veals J, et al. The excretion of rosaramicin into breast milk. J Clin Pharmacol 1985;25:89–94.

392.  Mannisto PT, Karhunen M, Koskela O, et al. Concentrations of tinidazole in breast milk. Acta Pharmacol Toxicol 1983;53:254–256.

393.  Ernstson S, Anari M, Eden T, et al. Penetration of cefaclor to adenoid tissue and middle ear effusion in chronic OME. Acta Otolaryngol 1985;424(Suppl):7–12.

394.  Santacroce F, Dainelli B, Mignini F, et al. Determination of cefatrizine levels in blood, tonsils, paranasal sinuses and middle ear. Drugs Exp Clin Res 1985;11:453–456.

395.  Harrison CJ, Chartrand SA, Rodriguez W, et al. Middle ear fluid concentrations of cefixime in acute otitis media and otitis media with effusion. In: Program and abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1994. Abstract A67.

396.  Danon J. Cefotaxime concentrations in otitis media effusions. J Antimicrob Chemother 1980;6(Suppl A):131–132.

397.  Shyu WC, Haddad J, Reilly J, et al. Penetration of cefprozil into middle ear fluid of patients with otitis media. Antimicrob Agents Chemother 1994;38:2210–2212.

398.  Nicolau DP, Sutherland CA, Arguedas A, et al. Pharmacokinetics of cefprozil in plasma and middle ear fluid. Pediatr Drugs 2007;9:119–123.

399.  Kusmiesz H, Shelton S, Brown O, et al. Loracarbef concentrations in middle ear fluid. Antimicrob Agents Chemother 1990;34:2030–2031.

400.  Ginsburg CM, McCracken GH, Nelson JD. Pharmacology of oral antibiotics used for treatment of otitis media and tonsillopharyngitis in infants and children. Ann Otol Rhinol Laryngol 1981;90(Suppl 84):37–43.

401.  Krause PJ, Owens NJ, Nightingale CH, et al. Penetration of amoxicillin, cefaclor, erythromycin-sulfisoxazole, and trimethoprim-sulfamethoxazole into the middle ear fluid of patients with chronic serous otitis media. J Infect Dis 1982;145:815–821.

402.  Lahikainen EA, Vuori M, Virtanen S. Azidocillin and ampicillin concentrations in middle ear effusion. Acta Otolaryngol 1977;84:227–232.

403.  Lahikainen EA. Penicillin concentration in middle ear secretion in otitis. Acta Otolaryngol 1970;70:358–362.

404.  Kamme C, Lundgren K, Rundcrantz H. The concentration of penicillin V in serum and middle ear exudate in acute otitis media in children. Scand J Infect Dis 1969;1:77–83.

405.  Sundberg L, Eden T, Ernstson S. Penetration of doxycycline in respiratory mucosa. Acta Otolaryngol 1983;96:501–508.

406.  Silverstein H, Bernstein JM, Lerner PI. Antibiotic concentrations in middle ear effusions. Pediatrics 1966;38:33–39.

407.  Jokipii AM, Jokipii L. Metronidazole, tinidazole, ornidazole and anaerobic infections of the middle ear, maxillary sinus and central nervous system. Scand J Infect Dis 1981;26(Suppl):123–129.

408.  Kohonen A, Palmgren O, Renkonen O. Penetration of trimethoprim-sulfadiazine into middle ear fluid in secretory otitis media. Int J Pediatr Otorhinolaryngol 1983;6:89–94.

409.  Cherrier P, Tod M, Le Gros V, et al. Cefotiam concentrations in the sinus fluid of patients with chronic sinusitis after administration of cefotiam hexetil. Eur J Clin Microbiol Infect Dis 1993;12:211–215.

410.  Kohonen A, Paavolainen M, Renkonen OV. Concentration of cephalexin in maxillary sinus mucosa and secretion. Ann Clin Res 1975;7:50–53.

411.  Stenquist M, Olen L, Jannert M, et al. Penetration of loracarbef into the maxillary sinus: a pharmacokinetic assessment. Clin Ther 1996;18:273–284.

412.  Gnarpe H, Lundberg C. L-phase organisms in maxillary sinus secretions. Scand J Infect Dis 1971;3:257–259.

413.  Jokinen K, Raunto V. Penetration of azidocillin into the secretion and tissues in chronic maxillary sinusitis and tonsilitis. Acta Otolaryngol 1975;79:460–465.

414.  Jones S, Yu VL, Johnson JT, et al. Pharmacokinetic and therapeutic trial of sultamicillin in acute sinusitis. Antimicrob Agents Chemother 1985;28:832–833.

415.  Malmborg AS, Kumlien J, Samuelsson A, et al. Concentrations of enoxacin in sinus secretions. Rev Infect Dis 1989;11(Suppl 5):S1205–S1206.

416.  Eneroth C-M, Lundberg C, Wretlind B. Antibiotic concentrations in maxillary sinus secretions and in the sinus mucosa. Chemotherapy 1975;21(Suppl 1):1–7.

417.  Worgan D, Daniel RJE. The penetration of minocycline into human sinus secretions. Scott Med J 1976;21:197–199.

418.  Ehnhage A, Rautiainen M, Fang AF, et al. Pharmacokinetics of azithromycin in serum and sinus fluid after administration of extended-release and immediate-release formulations in patients with acute bacterial sinusitis. Int J Antimicrob Agents 2008;31:561–566.

419.  Kalm O, Kamme C, Bergstrom B, et al. Erythromycin stearate in acute maxillary sinusitis. Scand J Infect Dis 1973;7:209–217.

420.  Paavolainen M, Kohonen A, Palva T, et al. Penetration of erythromycin stearate into maxillary sinus mucosa and secretion in chronic maxillary sinusitis. Acta Otolargyngol 1977;84:292–295.

421.  Mattila J, Mannisto PT, Luodeslampi M. Penetration of trimethoprim and sulfadiazine into sinus secretion in acute maxillary sinusitis. Chemotherapy 1983;29:174–177.

422.  Goto T, Makinose S, Ohi Y, et al. Diffusion of piperacillin, cefotiam, minocycline, amikacin and ofloxacin into the prostate. Int J Urol 1998;5:243–246.

423.  Williams CB, Litvak AS, McRoberts JW. Comparison of serum and prostatic levels of tobramycin. Urology 1979;13:589–591.

424.  Shimada J, Ueda Y. Moxalactam: absorption, excretion, distribution, and metabolism. Rev Infect Dis 1982;4(Suppl):S569–S580.

425.  Frongillo RF, Galuppo L, Moretti A. Suction skin blisters, skin window, and skin chamber techniques to determine extravascular passage of cefotaxime in humans. Antimicrob Agents Chemother 1981;19:22–28.

426.  Borski AA, Pulaski EJ, Kimbrough JC, et al. Prostatic fluid, semen, and prostatic tissue concentrations of the major antibiotics following intravenous administration. Antibiot Chemother 1954;4:905–910.

427.  Boerma JBJ, Dalhoff A, Debruyne FMY. Ciprofloxacin distribution in prostatic tissue and fluid following oral administration. Chemotherapy 1985;31:13–18.

428.  Bulitta JB, Kinzig M, Naber CK, et al. Population pharmacokinetics and penetration into prostatic, seminal and vaginal fluid for ciprofloxacin, levofloxacin and their combination. Chemotherapy 2011;57:402–416.

429.  Kees F, Naber KG, Schumacher H, et al. Penetration of fleroxacin into prostatic secretion and prostatic adenoma tissue. Chemotherapy 1988;34:437–443.

430.  Naber CK, Steghafner M, Kinzig-Schippers M, et al. Concentrations of gatifloxacin in plasma and urine and penetration into prostatic and seminal fluid, ejaculate, and sperm cells after single oral administrations of 400 milligrams to volunteers. Antimicrob Agents Chemother2001;45:293–297.

431.  Wagenlehner FME, Kees F, Weidner W, et al. Concentrations of moxifloxacin in plasma and urine, and penetration into prostatic fluid and ejaculate, following single oral administration of 400 mg to healthy volunteers. Int J Antimicrob Agents 2008;31:21–26.

432.  Nielson ML, Hansen IT. Trimethoprim in human prostatic tissue and prostatic fluid. Scand J Urol Nephrol 1972;6:244–248.

433.  Yogev R, Kolling WM. Intraventricular levels of amikacin after intravenous administration. Antimicrob Agents Chemother 1981;20:583–586.

434.  Vacek V, Hejzlar M, Skalova M. Penetration of antibiotics into the cerebrospinal fluid in inflammatory conditions. III. Gentamicin. Int J Clin Pharmacol 1969;2:277–279.

435.  Howard JB, McCracken GH. Reappraisal of kanamycin usage in neonates. J Pediatr 1975;86:949–956.

436.  Greenman RL, Arcey SM, Dickenson GM, et al. Penetration of aztreonam into human cerebrospinal fluid in the presence of meningeal inflammation. J Antimicrob Chemother 1985;15:637–640.

437.  Korzeniowski OM, Carvalho EM Jr, Rocha H, et al. Evaluation of cefamandole therapy in patients with bacterial meningitis. J Infect Dis 1978;137:S169–S179.

438.  Thys JP, Vanderkelen B, Klastersky J. Pharmacological study of cefazolin during intermittent and continuous infusion: a crossover investigation in humans. Antimicrob Agents Chemother 1976;10:395–398.

439.  Nahata MC, Kohlbrenner VM, Barson WJ. Pharmacokinetics and cerebrospinal fluid concentrations of cefixime in infants and young children. Chemotherapy 1993;39:1–5.

440.  Cable D, Overturf G, Edralin G. Concentrations of cefoperazone in cerebrospinal fluid during bacterial meningitis. Antimicrob Agents Chemother 1983;23:688–691.

441.  Belohradsky BH, Geiss D, Marget W, et al. Intravenous cefotaxime in children with bacterial meningitis. Lancet 1980;1:61–63.

442.  Asmar BI, Thirumoorthi MC, Buckley JA, et al. Cefotaxime diffusion into cerebrospinal fluid of children with meningitis. Antimicrob Agents Chemother 1985;28:138–140.

443.  Wolff M, Chavanet P, Kazmierczak A, et al. Diffusion of cefpirome into the cerebrospinal fluid of patients with purulent meningitis. J Antimicrob Chemother 1992;29(Suppl A):59–62.

444.  Bruckner O, Friess D, Schaaf D, et al. Cure of pseudomonal meningitis dependent on levels of cefsulodin in cerebrospinal fluid. Drugs Exp Clin Res 1983;9:291–297.

445.  Modai J, Decazes JM, Wolff M, et al. Penetration of ceftazidime into cerebrospinal fluid of patients with bacterial meningitis. Antimicrob Agents Chemother 1983;24:126–128.

446.  Steele RW, Bradsher RW. Comparison of ceftriaxone with standard therapy for bacterial meningitis. J Pediatr 1983;103:138–141.

447.  Cable D, Edralin G, Overturf GP. Human cerebrospinal fluid pharmacokinetics and treatment of bacterial meningitis with ceftizoxime. J Antimicrob Chemother 1982;10(Suppl C):121–127.

448.  Overturf GD, Cable DC, Forthal DN, et al. Treatment of bacterial meningitis with ceftizoxime. Antimicrob Agents Chemother 1984;25:258–262.

449.  Swedish Study Group. Cefuroxime versus ampicillin and chloramphenicol for the treatment of bacterial meningitis. Lancet 1982;1:295–298.

450.  Lerner PI. Penetration of cephaloridine into cerebrospinal fluid. Am J Med Sci 1971;262:321–326.

451.  Dealy DH, Duma RJ, Tarktaglione TA, et al. Penetration of primaxin (N-formimidoyl thienamicin and cilastatin) into human cerebrospinal fluid. In: Proceedings of the 14th International Congress of Chemotherapy. Kyoto, Japan: International Society of Chemotherapy, 1985. Abstract S-78–4.

452.  Dagan R, Velghe L, Rodda JL, et al. Penetration of meropenem into the cerebrospinal fluid of patients with inflamed meninges. J Antimicrob Chemother 1994;34:175–179.

453.  Lacut JY, Humbert G, Aubertin J, et al. Treatment of purulent meningitis in adults with injectable amoxycillin: clinical and pharmacokinetic results. Curr Ther Res 1981;29:36–46.

454.  Combined Clinical Staff Conference of the National Institutes of Health. A new penicillin derivative resistant to penicillinase, dimethoxyphenyl penicillin. Antibiot Chemother 1961;11:537.

455.  Yogev R, Schultz WE, Rosenman SB. Penetrance of nafcillin into human ventricular fluid: correlation with ventricular pleocytosis and glucose levels. Antimicrob Agents Chemother 1981;19:545–548.

456.  Kane JG, Parker RH, Jordan GW, et al. Nafcillin concentration in cerebrospinal fluid during treatment of staphylococcal infections. Ann Intern Med 1977;87:309–311.

457.  Hieber JP, Nelson JD. A pharmacologic evaluation of penicillin in children with purulent meningitis. N Engl J Med 1977;197:410–413.

458.  Dickinson GM, Droller DG, Greeman RL, et al. Clinical evaluation of piperacillin with observations on penetrability into cerebrospinal fluid. Antimicrob Agents Chemother 1981;20:481–486.

459.  Goh BT, Smith GW, Samarasinghe L, et al. Penicillin concentrations in serum and cerebrospinal fluid after intramuscular injection of aqueous procaine penicillin 0.6 MU with and without probenecid. Br J Vener Dis 1984;60:371–373.

460.  Stahl JP, Bru JP, Fredji G, et al. Penetration of sulbactam into the cerebrospinal fluid of patients with bacterial meningitis receiving ampicillin therapy. Rev Infect Dis 1986;8(Suppl 5):S612–S616.

461.  Bruckner O, Trautmann M, Borner K. A study of the penetration of temocillin in the cerebrospinal fluid. Drugs 1985;29(Suppl 5):162–166.

462.  Gerding DN, Hitt JA. Tissue penetration of new quinolones in humans. Rev Infect Dis 1989;11(Suppl 5):S1046–S1057.

463.  Kanellakopoulou K, Pagoulatou A, Stroumpoulis K, et al. Pharmacokinetics of moxifloxacin in non-inflamed cerebrospinal fluid of humans: implication for a bactericidal effect. J Antimicrob Chemother 2008;61:1328–1331.

464.  Van Niekerk CH, Steyn DL, Davis WG, et al. Chloramphenicol levels in cerebrospinal fluid in meningitis. S Afr Med J 1980;58:159–160.

465.  Kullar R, Chin JN, Edwards DJ, et al. Pharmacokinetics of single-dose daptomycin in patients with suspected or confirmed neurological infections. Antimicrob Agents Chemother 2011;55:3505–3509.

466.  Boger WP, Gavin JJ. Demethylchlortetracycline: serum concentration studies and cerebrospinal fluid diffusion. Antibiot Annu 1960;1959:393–400.

467.  Yim CW, Flyan NM, Fitzgerald FT. Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent neurosyphilis. Antimicrob Agents Chemother 1985;28:347–348.

468.  Dotevall L, Hagberg L. Penetration of doxycycline into cerebrospinal fluid in patients treated for suspected Lyme neuroborreliosis. Antimicrob Agents Chemother 1989;33:1078–1080.

469.  Vacek V, Hejzlar M, Skalova M. Penetration of antibiotics into the cerebrospinal fluid in inflammatory conditions. II. Lincomycin. Int J Clin Pharmacol 1968;1:501–503.

470.  Tsona A, Metallidis S, Foroglou N, et al. Linezolid penetration into cerebrospinal fluid and brain tissue. J Chemother 2010;22:17–19.

471.  Jokipii AMM, Myllvia VV, Hokkanen E, et al. Penetration of the blood brain barrier by metronidazole and tinidazole. J Antimicrob Chemother 1977;3:239–245.

472.  Wang EEL, Prober CG. Ventricular cerebrospinal fluid concentrations of trimethoprim-sulphamethoxazole. J Antimicrob Chemother 1983;11:385–389.

473.  Wingfield DL, McDougal RL, Roy FH, et al. Ocular penetration of amikacin following intramuscular injection. Arch Ophthalmol 1983;101:117–120.

474.  Sinues B, Martinez P, Palomar A, et al. Niveles de gentamicina en humor acuoso y plasma segun la via de administracion. Ard Farmacol Toxicol 1982;8:219–226.

475.  Orr W, Jackson WB, Colden K. Intraocular penetration of netilmicin. Can J Ophthalmol 1985;20:171–175.

476.  Sinues B, Martinez P, Barrera V, et al. Taux de la tobramycine dans l’humeur aqueuse et le plasma humains apres administration par voie intraveineuse et sous-conjonctivale. Therapie 1983;38:345–353.

477.  Petounis A, Papapanos G, Karageorgiou-Makromihelaki C. Penetration of tobryamycin sulfate into the human eye. Br J Ophthalmol 1978;62:660–662.

478.  Haroche G, Salvanet A, Lafaix C, et al. Pharmacokinetics of aztreonam in the aqueous humor. J Antimicrob Chemother 1986;18:195–198.

479.  Axelrod JL, Damask LJ, Kochman RS. Cefaclor levels in human aqueous humor. In: Program and abstracts of the 17th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1977. Abstract 311.

480.  Bidart B, Galindo Hernandez E, Flores Mercado F. Cefadroxil levels in human aqueous humors. In: Program and abstracts of the 11th International Congress of Chemotherapy and 19th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1979. Abstract 339.

481.  Axelrod JL, Kochman RS. Cefamandole levels in primary aqueous humor in man. Am J Ophthalmol 1978;85:342–348.

482.  MacIlwaine WA, Sande MA, Mandell GL. Penetration of antistaphylococcal antibiotics into the human eye. Am J Ophthalmol 1974;77:589–592.

483.  Ozdamar A, Aras C, Ozturk R, et al. Ocular penetration of cefepime following systemic administration in humans. Ophthalmic Surg Lasers 2001;32:25–29.

484.  Axelrod JL, Kochman RS, Horowitz MA, et al. Comparison of ceftizoxime and cefmenoxime levels in human aqueous humor. In: Program and abstracts of the 23rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1983. Abstract 644.

485.  Axelrod JL, Kochman RS. Cefonicid concentrations in human aqueous humor. Arch Ophthalmol 1984;102:433–434.

486.  Giamarellou H, Kavouklis E, Grammatikou M, et al. Penetration of four-lactam antibiotics with antipseudomonal activity into human aqueous humor. In: Periti P, Grassi G, eds. Current chemotherapy and immunotherapy: proceedings. Washington, DC: American Society for Microbiology, 1982:153–155.

487.  Quentin CD, Ansorg R. Penetration of cefotaxime into the aqueous humour after intravenous application. Graefes Arch Clin Exp Ophthalmol 1983;220:245–247.

488.  Axelrod JL, Kochman RS. Cefoxitin levels in human aqueous humor. Am J Ophthalmol 1980;90:388–393.

489.  Egger SF, Alzner E, Georgopoulos M, et al. Penetration of cefpirome into the anterior chamber of the human eye after intravenous application. J Antimicrob Chemother 2000;45:213–216.

490.  Rubinstein E, Avni I, Tuizer H, et al. Cefsulodin levels in the human aqueous humor. Arch Ophthalmol 1985;103:426–427.

491.  Axelrod JL, Kochman RS, Horowitz MA, et al. Ceftazidime concentrations in human aqueous humor. Arch Ophthalmol 1984;102:923–925.

492.  Martinelli D, Mazzei T, Fallani S, et al. Ceftizoxime concentrations in human aqueous humor following intravenous administration. Chemioterapia 1988;7:317–319.

493.  Ziak E, Schuhmann G, Konstantinou D, et al. Levels in aqueous humour of eight relevant antibiotics in humans. In: Recent advances in chemotherapy: proceedings of the 14th International Congress of Chemotherapy. Kyoto, Japan: University of Tokyo Press, 1985.

494.  Guerra R, Casu L, Giola K, et al. Penetration of parenteral cefuroxime into the human aqueous humor. Arzneimittelforschung 1981;31:861–863.

495.  Records RE. The human intraocular penetration of a new orally effective cephalosporin antibiotic, cephalexin. Ann Ophthalmol 1971;3:309–313.

496.  Riley FC, Boyle GL, Leopold IH. Intraocular penetration of cephaloridine in humans. Am J Ophthalmol 1968;66:1042–1049.

497.  Records RE. Intraocular penetration of cephalothin. Am J Ophthalmol 1968;66:441–443.

498.  Axelrod JL, Kochman RS. Cephradine levels in human aqueous humor. Arch Ophthalmol 1981;99:2034–2036.

499.  Axelrod JL, Newton JC, Klein RM, et al. Penetration of imipenem into human aqueous and vitreous humor. Am J Ophthalmol 1987;104:649–653.

500.  Schauersberger J, Amon M, Wedrich A, et al. Penetration and decay of meropenem into the human aqueous humor and vitreous. J Ocul Pharmacol Ther 1999;15:439–445.

501.  Axelrod JL, Kochman RS. Moxalactam concentration in human aqueous humor after intravenous administration. Arch Ophthalmol 1982;100:1334–1336.

502.  Hariprasad SM, Mieler WF, Holz ER. Vitreous and aqueous penetrations of orally administered gatifloxacin in humans. Arch Ophthalmol 2003;121:345–350.

503.  Garcia-Vazquez E, Mensa J, Sarasa M, et al. Penetration of levofloxacin into the anterior chamber (aqueous humor) of the human eye after intravenous administration. Eur J Clin Microbiol Infect Dis 2007;26:137–140.

504.  Vedantham V, Lalitha P, Velpandian T, et al. Vitreous and aqueous penetration of orally administered moxifloxacin in humans. Eye 2006;20:1273–1278.

505.  Hariprasad SM, Shah GK, Mieler WF, et al. Vitreous and aqueous penetration of orally administered moxifloxacin in humans. Arch Ophthalmol 2006;124:178–182.

506.  Von Gunten S, Lew D, Paccolat F, et al. Aqueous humor penetration of ofloxacin given by various routes. Am J Ophthalmol 1994;117:87–89.

507.  Johnson AP, Scoper SV, Woo FL, et al. Azlocillin levels in human tears and aqueous humor. Am J Ophthalmol 1985;99:469–472.

508.  Uwaydah MM, Faris BM, Samara IN, et al. Cloxacillin penetration. Am J Ophthalmol 1976;82:114–116.

509.  Records RE. The human intraocular penetration of methicillin. Arch Ophthalmol 1966;76:720–722.

510.  Behrens-Baumann W, Ansorg R. Mezlocillin concentrations in human aqueous humor after intravenous and subconjunctival administration. Chemotherapy 1985;31:169–172.

511.  Records RE. Human intraocular penetration of sodium oxacillin. Arch Ophthalmol 1967;77:693–695.

512.  Woo FL, Johnson AP, Caldwell DR, et al. Piperacillin levels in human tears and aqueous humor. Am J Ophthalmol 1984;98:17–20.

513.  Poirier RH, Ellison AC. Ocular penetration of orally administered minocycline. Ann Ophthalmol 1979;11:1859–1861.

514.  Abraham RK, Burnett HH. Tetracycline and chloramphenicol studies on rabbit and human eyes. Arch Ophthalmol 1955;54:641–659.

515.  Tabbara KF, Al-Kharashi SA, Al-Mansouri SM, et al. Ocular levels of azithromycin. Arch Ophthalmol 1998;116:1625–1628.

516.  Al-Sibai MB, Al-Kaff AS, Raines D, et al. Ocular penetration of oral clarithromycin in humans. J Ocul Pharmacol Ther 1998;14:575–583.

517.  Becker EF. The intraocular penetration of lincomycin. Am J Ophthalmol 1969;67:963–965.

518.  Fiscella RG, Lai WW, Buerk B, et al. Aqueous and vitreous penetration of linezolid (Zyvox) after oral administration. Ophthalmology 2004;111:1191–1195.

519.  Mattila J, Nerdrum K, Rouhiainen H, et al. Penetration of metronidazole and tinidazole into the aqueous humor in man. Chemotherapy 1983;29:188–191.

520.  Souli M, Kopsinis G, Kavouklis E, et al. Vancomycin levels in human aqueous humour after intravenous and subconjunctival administration. Int J Antimicrob Agents 2001;18:239–243.

521.  Daschner F, Reiss E, Engert J. Distribution of amikacin in serum, muscle, and fat in children after a single intramuscular injection. Antimicrob Agents Chemother 1977;11:1081–1083.

522.  Quintiliani R. A review of the penetration of cefadroxil into human tissue. J Antimicrob Chemother 1982;19(Suppl B):33–38.

523.  Robens W. Concentrations of cefmenoxime in human tissues. Am J Med 1984;77(Suppl 6A):32–33.

524.  Just HM, Bassler M, Frank U, et al. Penetration of cefotaxime into heart valves, subcutaneous and muscle tissue of patients undergoing open-heart surgery. J Antimicrob Chemother 1984;14:431–434.

525.  Adam D, Wittke RR, Eisenberger F. Tissue penetration of cefsulodin, a new antipseudomonas-cephalosporin antibiotic. Drugs Exp Clin Res 1981;7:227–231.

526.  Adam D, Reichart B, Williams KJ. Penetration of ceftazidime into human tissue in patients undergoing cardiac surgery. J Antimicrob Chemother 1983;12(Suppl A):269–273.

527.  Beam TR, Raab TA, Spooner JA, et al. Comparison of ceftriaxone and cefazolin prophylaxis against infection in open heart surgery. Am J Surg 1984;148(Suppl 4A):8–14.

528.  Bullen BR, Ramsden CT, Kester RC. Tissue levels of cephradine in ischemic limbs, following a single intravenous injection. Curr Med Res Opin 1980;6:585–588.

529.  Kummel A, Scholsser V, Petersen E, et al. Pharmacokinetics of imipenem-cilastatin in serum and tissue. Eur J Clin Microbiol 1985;4:609–610.

530.  Jorgensen LN, Andreasen JJ, Nielsen PT, et al. Dicloxacillin concentrations in amputation. Acta Orthop Scand 1989;60:617–620.

531.  Fraschini F, Braga PC, Copponi V, et al. Tropism of erythromycin for the respiratory system. In: Nelson JD, Grassi C, eds. Current chemotherapy and infectious disease: proceedings. Washington, DC: American Society for Microbiology, 1979:659–662.

532.  Helwing E, Lux M, Duben W, et al. Mezlocillin: Zur Gewebekonzentration und Wirksamkeit. Med Klin 1979;74:112–116.

533.  Nunes HL, Pecora CC, Judy K. Turnover and distribution of nafcillin in tissues and body fluids of surgical patients. Antimicrob Agents Chemother 1965;1964:237–249.

534.  Adam D, Wilhelm K, Chysky V. Antibiotic concentrations in blood and tissue. Arzneimittelforschung 1981;31:1972–1976.

535.  Russo J, Thompson MIB, Russo ME. Piperacillin distribution into bile, gallbladder wall, abdominal skeletal muscle, and adipose tissue in surgical patients. Antimicrob Agents Chemother 1982;22:488–492.

536.  Silbermann M, Niederdellmann H, Kluge D, et al. Concentration of piperacillin and cefotaxime in human muscle and fat tissue. In: Program and abstracts of the 20th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1980. Abstract 755.

537.  Gould JG, Meikle G, Cooper DL, et al. Temocillin concentrations in human tissues. Drugs 1985;29(Suppl 5):167–169.

538.  Daschner FD, Thema G, Langmaack H, et al. Ticarcillin concentrations in serum, muscle, and fat after a single intravenous injection. Antimicrob Agents Chemother 1980;17:738–739.

539.  Bell MJ, Shackelford PG, Schroeder KF. Penetration of clindamycin into peritoneal fluid, intestine and muscle in neonates and infants. Curr Ther Res 1983;33:751–757.

540.  Lovering AM, Zhang J, Bannister GC, et al. Penetration of linezolid into bone, fat, muscle and haematoma of patients undergoing routine hip replacement. J Antimicrob Chemother 2002;50:73–77.

541.  Frank UK, Schmidt-Eisenlohr E, Mlangeni D, et al. Penetration of teicoplanin into heart valves and subcutaneous and muscle tissues of patients undergoing open-heart surgery. Antimicrob Agents Chemother 1997;41:2559–2561.

542.  Daschner FD, Frank U, Kummel A, et al. Pharmacokinetics of vancomycin in serum and tissue of patients undergoing open heart surgery. J Antimicrob Chemother 1987;19:359–362.

543.  Smilak JD, Flittie WH, Williams TW. Bone concentrations of antimicrobial agents after parenteral administration. Antimicrob Agents Chemother 1976;9:169–171.

544.  Boselli E, Breilh D, Bel JC, et al. Diffusion of isepamicin into cancellous and cortical bone tissue. Chemother 2002;14(4):361–365.

545.  Wilson APR, Taylor B, Treasure T, et al. Antibiotic prophylaxis in cardiac surgery: serum and tissue levels of teicoplanin, flucloxacillin and tobramycin. J Antimicrob Chemother 1988;21:210–212.

546.  MacLeod CM, Bartley EA, Galante JO, et al. Aztreonam penetration into synovial fluid and bone. Antimicrob Agents Chemother 1986;29:710–712.

547.  Akimoto Y, Mochizuki Y, Uda A, et al. Cefaclor concentrations in human serum, gingiva, mandibular bone, and dental follicle following a single oral administration. Gen Pharmacol 1992;23:639–642.

548.  Hume AL, Polk R, Kline B, et al. Comparative penetration of latamoxef (moxalactam) and cefazolin into human knee following simultaneous administration. J Antimicrob Chemother 1983;12:623–627.

549.  Tetzlaff TR, Howard JB, McCracken GH, et al. Antibiotic concentrations in pus and bone of children with osteomyelitis. J Pediatr 1978;92:135–140.

550.  Parsens RL, Beavis JP, David JA, et al. Plasma, bone, hip capsule, and drain fluid concentrations of cephazolin during total hip replacement. Br J Clin Pharmacol 1978;5:331–336.

551.  Breilh D, Boselli E, Bel JC, et al. Diffusion of cefepime into cancellous and cortical bone tissue. J Chemother 2003;15(2):134–138.

552.  Scaglione F, De Martini G, Peretto L, et al. Pharmacokinetic study of cefodizime and ceftriaxone in sera and bones of patients undergoing hip arthroplasty. Antimicrob Agents Chemother 1997;41:2292–2294.

553.  Nightingale CH, Quintiliani R, Dudley MN, et al. Tissue penetration and half-life of cefonicid. Rev Infect Dis 1984;6(Suppl 4):821–828.

554.  Braga PC, Scaglione F, Villa S, et al. Cefoperazone pharmacokinetics and sputum levels after single/multiple I.M. injections in bronchopneumopathic patients and bone, pulmonary and prostatic tissue penetration. Int J Clin Pharmacol Res 1983;5:349–355.

555.  Wittmann DH, Schassan HH. Bone levels, tissue fluid and peritoneal fluid measurements following piperacillin administration. In: Program and abstracts of the 20th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society of Microbiology; 1980. Abstract 757.

556.  Dehne MG, Muhling J, Sablotzki A, et al. Pharmacokinetics of antibiotic prophylaxis in major orthopedic surgery and blood-saving techniques. Orthopedics 2001;24(7):665–669.

557.  Plaue R, Muller O, Fabricius K, et al. Verlaufiger Bericht uber Cefoxitinspiegel-Bestimmungen in menschlichen geweben. Infection 1979;7(Suppl 1):S80–S84.

558.  Leigh DA, Griggs J, Tighe CM, et al. Pharmacokinetic study of ceftazidime in bone and serum of patients undergoing hip and knee arthroplasty. J Antimicrob Chemother 1985;16:637–642.

559.  Wittmann DH, Schassan HH, Seidel H. Untersuchungen uber die Bioverfugbarkeit von Cefuroxim im Knochen und im Wiundsekret. Med Welt 1979;30:227–232.

560.  Akimoto Y, Uda A, Omata H, et al. Cephalexin concentrations in human serum, gingiva, and mandibular bone following a single oral administration. Clin Pharmacol 1990;21:621–623.

561.  Fitzgerald RH, Kelly PJ, Snyder RJ, et al. Penetration of methicillin, oxacillin, and cephalothin into bone and synovial tissues. Antimicrob Agents Chemother 1978;14:723–726.

562.  Davies AJ, Lockley RM, Jones A, et al. Comparative pharmacokinetics of cefamandole, cefuroxime and cephradine during total hip replacement. J Antimicrob Chemother 1986;17:637–640.

563.  Brooks S, Dent AR. Comparison of bone levels after intramuscular administration of cephradine (Velosef) or flucloxacillin/ampicillin in hip replacement. Pharmatherapeutica 1984;3:642–649.

564.  Boselli E, Breilh D, Djabarouti S, et al. Diffusion of ertapenem into bone and synovial tissues. J Antimicrob Chemother 2007,60:893–896.

565.  MacGregor RR, Gibson GA, Bland JA. Imipenem pharmacokinetics and body fluid concentrations in patients receiving high-dose treatment for serious infections. Antimicrob Agents Chemother 1986;29:188–192.

566.  Grimer RJ, Karpinski MRK, Andrews JM, et al. Penetration of amoxycillin and clavulanic acid into bone. Chemotherapy 1986;32:185–191.

567.  Bystedt H, Dahlback A, Dornbusch K, et al. Concentration of azidocillin, erythromycin, doxycycline plus clindamycin in human mandibular bone. Int J Oral Surg 1978;7:442–449.

568.  Wittmann DH, Schassan HH, Seidel H. Pharmakokinetische Untersuchungen zur Penetration von Azlocillin und Mezlocillin in den Knochen und in die Gewebsflussigkeit. Arzneimittelforschung 1981;31:1157–1162.

569.  Kramer J, Weuta H. Utersuchungen uber Serumund Knocheuspiegel nach Injektion von Oxacillin und Carbenicillin. Z Orthop 1972;110:216–233.

570.  Kondell PA, Nord CE, Nordeniam A. Concentrations of cloxacillin, dicloxacillin, and flucloxacillin in dental alveolar serum and mandibular bone. Int J Oral Surg 1982;11:40–43.

571.  Sirot J, Lopitaux R, Sirot J, et al. Diffusion de la cloxacilline dans le tissue osseux human apies administration par voie orale. Pathol Biol 1982;30:332–335.

572.  Schurman DJ, Johnson BL, Finerman G, et al. Antibiotic bone penetration concentration of methicillin and clindamycin phosphate in human bone taken during total hip replacement. Clin Orthop 1975;111:142–146.

573.  Incavo SJ, Ronchetti PJ, Choi JH, et al. Penetration of piperacillin-tazobactam into cancellous and cortical bone tissues. Antimicrob Agents Chemother 1994;38:905–907.

574.  Adam D, Heilmann HD, Weismeier K. Concentrations of ticarcillin and clavulanic acid in human bone after prophylactic administration of 5.2 g of Timentin. Antimicrob Agents Chemother 1987;31:935–939.

575.  Fong IW, Rittenhouse BR, Simbul M, et al. Bone penetration of enoxacin in patients with and without osteomyelitis. Antimicrob Agents Chemother 1988;32:834–837.

576.  von Baum H, Bottcher S, Abel R, et al. Tissue and serum concentrations of levofloxacin in orthopaedic patients. Int J Antimicrob Agents 2001;18:335–340.

577.  Akimoto Y, Mochizuki Y, Uda A, et al. Concentrations of lomefloxacin in radicular cyst and oral tissues following single or multiple oral administration. Univ Sch Dent 1993;35:267–275.

578.  Malincarne L, Ghebregzabher M, Moretti MV, et al. Penetration of moxifloxacin into bone in patients undergoing total knee arthroplasty. J Antimicrob Chemother 2006;57:950–954.

579.  Dellamonica P, Bernard E, Etesse H, et al. The diffusion of pefloxacin into bone and the treatment of osteomyelitis. J Antimicrob Chemother 1986;17(Suppl B):93–102.

580.  Traunmüller F, Schintler MV, Metzler J, et al. Soft tissue and bone penetration abilities of daptomycin in diabetic patients with bacterial foot infections. J Antimicrob Chemother 2010;65:1252–1257.

581.  Sorensen TS, Colding H, Schroeder E, et al. The penetration of cefazolin, erythromycin and methicillin into human bone tissue. Acta Orthop Scand 1978;49:549–553.

582.  Schintler MV, Traunmüller F, Metzler J et al. High fosfomycin concentrations in bone and peripheral soft tissue in diabetic patients resenting with bacterial foot infection. J Antimicrob Chemother 2009;64:574–578.

583.  Benoni G, Cuzzolin L, Leone R, et al. Pharmacokinetics and human tissue penetration of flurithromycin. Antimicrob Agents Chemother 1988;32:1875–1878.

584.  Vacek V, Hejzlar M, Pavlansky R. Certain problems of rational lincomycin therapy of staphylococcal osteomyelitis. Rev Czech Med 1969;15:92–102.

585.  Linzenmeier G, Schafer P, Volk H, et al. Determination of lincomycin concentration in chronically inflamed bone and soft tissue of man. Arzneimittelforschung 1968;18:204–207.

586.  Kutscha-Lissberg F, Hebler U, Muhr G, et al. Linezolid penetration into bone and joint tissues infected with methicillin-resistant staphylococci. Antimicrob Agents Chemother 2003;47:3964–3966.

587.  Traunmüller F, Schintler MV, Spendel S, et al. Linezolid concentrations in infected soft tissue and bone following repetitive doses in diabetic patients with bacterial foot infections. Int J Antimicrob Agents 2010;36:84–86.

588.  Rood JP, Collier J. Metronidazole levels in alveolar bone. In: Metronidazole. Royal Society of Medicine International Congress and Symposium, series 18. London: Royal Society of Medicine and Academic Press, 1979:45–47.

589.  Fraschini F, Scaglione F, Mezzetti M, et al. Pharmacokinetic profile of cefotetan in different clinical conditions. Drugs Exp Clin Res 1988;14:547–553.

590.  Sirot J, Prive L, Lopitaux R, et al. Etude de la diffusion de la rifampicine dans le tissu osseux spong ieux et compact au cours de protheses totales de hanches. Pathol Biol 1983;31:438–441.

591.  Roth B. Penetration of parenterally administered rifampicin into bone tissue. Chemotherapy 1984;30:358–365.

592.  Del Tacca M, Danesi R, Bernardini N, et al. Roxithromycin penetration into gingiva and alveolar bone of odontoiatric patients. Chemotherapy 1990;36:332–336.

593.  Kuehnel TS, Schurr C, Lotter K, et al. Penetration of telithromycin into the nasal mucosa and ethmoid bone of patients undergoing rhinosurgery for chronic sinusitis. J Antimicrob Chemother 2005;55:591–594.

594.  Graziani AL, Lawson LA, Gibson GA, et al. Vancomycin concentrations in infected and noninfected human bone. Antimicrob Agents Chemother 1988;32:1320–1322.

595.  Farago E, Kiss J, Gomory A, et al. Amikacin: in vitro bacteriologic studies, levels in human serum, lung, and heart tissue, and clinical results. Int J Clin Pharmacol Biopharm 1979;17:421–428.

596.  Olson NH, Nightingale CH, Quintiliani R. Penetration characteristics of cefamandole into the right atrial appendage and pericardial fluid in patients undergoing open heart surgery. Ann Thorac Surg 1979;29:104–108.

597.  Archer GL, Polk RE, Dumg RJ, et al. Comparison of cephalothin and cefamandole prophylaxis during insertion of prosthetic heart valves. Antimicrob Agents Chemother 1978;13:924–929.

598.  Nightingale CH, Klimek JJ, Quintiliani R. Effect of protein binding on the penetration of nonmetabolized cephalosporins into atrial appendage and pericardial fluids in open heart surgical patients. Antimicrob Agents Chemother 1980;17:595–598.

599.  Polk RE, Smith JE, Ducey K, et al. Penetration of moxalactam and cefazolin into atrial appendage after simultaneous intramuscular or intravenous administration. Antimicrob Agents Chemother 1982;22:201–203.

600.  Kanellakopoulou K, Tselikos D, Giannitsioti E, et al. Pharmacokinetics of fusidic acid and cefepime in heart tissues: implications for a role in surgical prophylaxis. J Chemother 2008;20:468–471.

601.  Sterling RP, Connor DJ, Norman JC, et al. Cefonicid concentration in serum and atrial tissue during open heart surgery. Antimicrob Agents Chemother 1983;23:790–792.

602.  Mullany LD, French MA, Nightingale CH, et al. Penetration of ceforanide and cefamandole into the right atrial appendage, pericardial fluid, sternum, and intercostal muscle of patients undergoing open heart surgery. Antimicrob Agents Chemother 1982;21:416–420.

603.  Martin CM. Tissue levels and body fluid levels of cefoxitin in man after therapeutic doses of the antibiotic. Data on file. Rahway, NJ: Merck Sharp & Dohme, 1979.

604.  Kobayashi M, Washio M, Eishin H, et al. Ceftizoxime level in the myocardium (right atrial muscle and mitral papillary muscle) during open heart surgery. Jpn J Surg 1988;18:136–141.

605.  Quintiliani R, Klimek J, Nightingale CH. Penetration of cephapirin and cephalothin into the right atrial appendage and pericardial fluid of patients undergoing open heart surgery. J Infect Dis 1979;139:348–352.

606.  Mertes PM, Voiriot P, Dopff C, et al. Penetration of ciprofloxacin into heart valves, myocardium, mediastinal fat, and sternal bone marrow in humans. Antimicrob Agents Chemother 1990;34:398–401.

607.  Mertes PM, Jehl F, Burtin P, et al. Penetration of ofloxacin into heart valves, myocardium, mediastinal fat, and sternal bone marrow in humans. Antimicrob Agents Chemother 1992;36:2493–2496.

608.  Brion N, Lessana A, Mosset F, et al. Penetration of pefloxacin in human heart valves. J Antimicrob Chemother 1986;17(Suppl B):89–92.

609.  Adam D, Reichart B, Rothenfusser B. Diffusion of piperacillin into human heart muscle. In: Nelson JD, Grassi C, eds. Current chemotherapy and infectious disease: proceedings. Washington, DC: American Society for Microbiology, 1980:307–308.

610.  Mandal AK, Thadepalli H, Bach VT, et al. Antibiotic concentration in the human right atrial appendage. Curr Ther Res 1980;28:504–510.

611.  Vitt TG, Panzer JD. Lincomycin at the tissue level following intramuscular lincocin. Kalamazoo, MI: The Upjohn Co, 1973. Lincocin Study C5 034. Data on file.

612.  Archer GL, Armstrong BC, Kline BJ. Rifampin blood and tissue levels in patients undergoing cardiac valve surgery. Antimicrob Agents Chemother 1982;21:800–803.

613.  Foucault P, Desauliniers D, Saginur R, et al. Concentration of teicoplanin in human heart tissue. In: Program and abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1988. Abstract 937.

614.  Frank UK, Schmidt-Eisenlohr E, Mlangeni D, et al. Penetration of teicoplanin into heart valves and subcutaneous and muscle tissues of patients undergoing open-heart surgery. Antimicrob Agents Chemother 1997;41:2559–2561.

615.  Wildfeuer A, Laufen H, Muller-Wening D, et al. The effect of antibiotics on the intracellular survival of bacteria in human phagocytic cells. Arzneimittelforschung 1987;37:1367–1370.

616.  Swoboda S, Oberdorfer K, Klee F, et al. Tissue and serum concentrations of levofloxacin 500 mg administered intravenously or orally for antibiotic prophylaxis in biliary surgery. J Antimicrob Chemother 2003;51:459–462.

617.  Ober MC, Hoppe-Tichy T, Koninger J, et al. Tissue penetration of moxifloxacin into human gallbladder wall in patients with biliary tract infections. J Antimicrob Chemother 2009;64:1091–1095.

618.  Fabre J, Milek E, Kalfopoulos P, et al. The kinetics of tetracyclines in man. II. Excretion, penetration in normal and inflammatory tissues, behavior in renal insufficiency and hemodialysis. Schweiz Med Wochenschr 1971;101:625–633.

619.  Burroughs Wellcome Company. Septra: a monograph. Research Triangle Park, NC: Burroughs Wellcome Company, 1973;73.

620.  Daschner F, Blume E, Langmaack H, et al. Cefamandole concentrations in pulmonary and subcutaneous tissue. J Antimicrob Chemother 1979;5:474–475.

621.  Breilh D, Saux MC, Delaisement C, et al. Pharmacokinetic population study to describe cefepime lung concentrations. Pulm Pharmacol Ther 2001;14:69–74.

622.  Cozzola M, Polverino M, Guidetti E, et al. Penetration of cefonicid into human lung tissue and lymph nodes. Chemotherapy 1990;36:325–331.

623.  Fraschini F, Scaglione F, Pintucci G, et al. The diffusion of clarithromycin and roxithromycin into nasal mucosa, tonsil and lung in humans. J Antimicrob Chemother 1991;27(Suppl A):61–65.

624.  Just HM, Frank U, Simon A, et al. Concentrations of ceftriaxone in serum and lung tissue. Chemotherapy 1984;30:81–83.

625.  Benoni G, Cuzzolin L, Bertrand C, et al. Imipenem kinetics in serum, lung tissue and pericardial fluid in patients undergoing thoracotomy. J Antimicrob Chemother 1987;20:725–728.

626.  Kiss IJ, Farago E, Gomory A, et al. Investigations on the flucloxacillin levels in human serum, lung tissue, pericardial fluid and heart tissue. Int J Clin Pharmacol Ther Toxicol 1980;18:405–411.

627.  Marlin GE, Burgess KR, Burgoyne J, et al. Penetration of piperacillin into bronchial mucosa and sputum. Thorax 1981;36:774–780.

628.  Kinzig M, Sorgel F, Naber KG, et al. Tissue penetration of piperacillin/tazobactam. In: Proceedings of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1991. Abstract 862.

629.  Kiss IJ, Farago E, Fabian E. Study of oxacillin levels in human serum and lung tissue. Ther Hung 1974;22:55–59.

630.  Zeitlinger MA, Traunmuller F, Abrahim A, et al. A pilot study testing whether concentrations of levofloxacin in interstitial space fluid of soft tissues may serve as a surrogate for predicting its pharmacokinetics in lung. Int J Antimicrob Agents 2007;29:44–50.

631.  Fraschini F, Braga PC, Scaglione F, et al. Study on pulmonary, prostatic and renal (medulla and cortex) distribution of sagamicin at different time intervals. Int J Clin Pharmacol Res 1987;7:51–58.

632.  Friesen VA, Streifinger W, Hofstetter A, et al. Minocyclin-und Doxycyclin-Konzentrationen in Serum, Urin, Prostata-exprimat und -gewebe. Fortschr Med 1982;100:605–608.

633.  Kitzis M, Desnottes JF, Brunel D, et al. Spiramycin concentrations in lung tissue. J Antimicrob Chemother 1988;22(Suppl B):123–126.

634.  Fraschini F, Scaglione F, Cicchetti F, et al. Prostatic tissue concentrations and serum levels of myocamicin in human subjects. Drugs Exp Clin Res 1988;24:253–255.

635.  Madsen PO, Dhruv R, Friedhoff LT. Aztreonam concentrations in human prostatic tissue. Antimicrob Agents Chemother 1984;26:20–21.

636.  Smith RP, Schmid GP, Baltch AL, et al. Concentration of cefaclor in human prostatic tissue. Am J Med Sci 1981;281:19–24.

637.  Adam D, Hofstetter AG, Eisenberger F. Zur Diffusion von Cefamandol in das Prostatagewebe. Med Klin 1979;74:235–238.

638.  Adam D, Hofstetter AG, Reichart B, et al. Zur Diffusion von Cefazedon in das Herzmuskel-, Prostataund Hautgewebe sowie in die Gallenflussigkeit. Arzneimittelforschung 1979;29:1901–1906.

639.  Iversen P, Madsen PO. Short-term cephalosporin prophylaxis in transurethral surgery. Clin Ther 1982;5(Suppl A):58–66.

640.  Arkell D, Ashrap M, Andrews JM, et al. An evaluation of the penetration of cefepime into prostate tissue in patients undergoing elective prostatectomy. J Antimicrob Chemother 1992;29:473–474.

641.  Sasagawa I, Yamaguchi O, Shiraiwa Y. Cefminox sodium penetration into prostatic tissue with and without inflammation. Int Urol Nephrol 1991;23:569–572.

642.  Melloni D, Ammatuna P, Formica P, et al. Pharmacokinetic study on adenomatous prostate tissue concentration of cefoperazone. Chemotherapy 1989;35:410–415.

643.  Schalkhauser K, Adam D. Zur diffusion von Cefotaxim in verschiedene Gewebe des urologischen Bereichs. Infection 1980;8(Suppl 3):S327–S329.

644.  Grabe M, Andersson K-E, Forsgren A, et al. Concentrations of cefotaxime in serum, urine and tissues of urological patients. Infection 1981;9:154–158.

645.  Saxby MF, Arkell DG, Andrews JM, et al. Penetration of cefpirome into prostatic tissue. J Antimicrob Chemother 1990;25:488–490.

646.  Whitby M, Hempenstall J, Gilpin C, et al. Penetration of monobactam antibiotics (aztreonam, carumonam) into human prostatic tissue. Chemotherapy 1989;35:7–11.

647.  Abbas AMA, Taylor MC, DaSilva C, et al. Penetration of ceftazidime into the human prostate gland following intravenous injection. J Antimicrob Chemother 1985;15:119–121.

648.  Smith Kline & French Laboratories. Data on file. Philadelphia, PA.

649.  Adam D, Naber KG. Concentrations of ceftriaxone in prostate adenoma tissue. Chemotherapy 1984;30:16.

650.  Adam D, Hofstetter AG, Eisenberger F, et al. Zur Diffusion von Cefacetril in das Prostatagewebe. Med Welt 1978;29:1216–1217.

651.  Symes JM, Jarvic JD, Tresidder GC. An appraisal of cephalexin monohydrate levels in semen and prostatic tissue. Chemotherapy 1975;20:257–262.

652.  Litvak AS, Franks CD, Vaught SK, et al. Cefazolin and cephalexin levels in prostatic tissue and sera. Urology 1976;7:497–498.

653.  Adam D, Hofstetter AG, Staehler G. Studies on diffusion of cephapirin into prostatic tissue. Fortschr Med 1977;95:2107–2109.

654.  Yamada Y, Ikawa K, Nakamura K, et al. Penetration of doripenem into prostatic tissue following intravenous administration in prostatectomy patients. Int J Antimicrob Agents 2010;35:504–506.

655.  Smith RP, Wilbur H, Sutphen NT, et al. Moxalactam concentrations in human prostatic tissue. Antimicrob Agents Chemother 1983;24:15–17.

656.  Klotz T, Braun M, Bin Saleh A, et al. Penetration of a single infusion of ampicillin and sulbactam into prostatic tissue during transurethral prostatectomy. Int Urol Nephrol 1999;31:203–209.

657.  Smith R, Wilbur H, Bassey C, et al. Azlocillin and mezolocillin concentration in human prostatic tissue. Chemotherapy 1988;34:267–271.

658.  Hoogkamp-Korstanje JAA, van Oort HJ, Schipper JJ, et al. Intraprostatic concentration of ciprofloxacin and its activity against urinary pathogens. J Antimicrob Chemother 1984;14:641–645.

659.  Drusano GL, Preston SL, Van Guilder M, et al. A population pharmacokinetic analysis of the penetration of the prostate by levofloxacin. Antimicrab Agents Chemother 2000;44(8):2046–2051.

660.  Kovarik JM, De Hond JAPM, Hoepelman IM, et al. Intraprostatic distribution of lomefloxacin following multiple-dose administration. Antimicrob Agents Chemother 1990;34:2398–2401.

661.  Bergeron MG, Thabet M, Toy R, et al. Norfloxacin penetration into human renal and prostatic tissues. Antimicrob Agents Chemother 1985;28:349–350.

662.  Giannopoulos A, Koratzanis G, Giamarellos-Bourboulis EJ. Pharmacokinetics of intravenously administered pefloxacin in the prostate; perspectives for its application in surgical prophylaxis. Int J Antimicrob Agents 2001;17:221–224.

663.  Foulds G, Madsen P, Cox C, et al. Concentration of azithromycin in human prostatic tissue. Eur J Clin Microbiol Infect Dis 1991;10:868–871.

664.  Giannopoulos A, Koratzanis G, Giamarellos-Bourboulis EJ, et al. Pharmacokinetics of clarithromycin in the prostate: implications for the treatment of chronic abacterial prostatitis. J Urol 2001;165:97–99.

665.  Baumueller A, Hoyme U, Madsen PO. Rosamicin: a new drug for the treatment of bacterial prostatitis. Antimicrob Agents Chemother 1977;12:240–242.

666.  Fraschini F, Scaglione F, Falchi M, et al. Miokamycin penetration into oral cavity tissues and crevicular fluid. Int J Clin Pharmacol Res 1989;9:293–296.

667.  Macfarlane JA, Walsh JM, Mitchell AAB, et al. Spiramycin in the prevention of postoperative staphylococcal infection. Lancet 1968;1:1–4.

668.  Oosterlinck W, Defoort R, Renders G. The concentration of sulphamethoxazole and trimethoprim in human prostate gland. Br J Urol 1975;47:301–304.

669.  Plomp TA, Mattelaer JJ, Maes RAA. The concentration of thiamphenicol in seminal fluid and prostatic tissue. J Antimicrob Chemother 1978;4:65–71.