Goodman and Gilman Manual of Pharmacology and Therapeutics
Chemotherapy of Microbial Diseases
Aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin, paromomycin, and neomycin) are used primarily to treat infections caused by aerobic gram-negative bacteria. Streptomycin is an important agent for the treatment of tuberculosis, and paromomycin is used orally for intestinal amebiasis and in the management of hepatic coma. Aminoglycosides are bactericidal inhibitors of protein synthesis. Mutations affecting proteins in the bacterial ribosome can confer marked resistance to their action. Most commonly resistance is due to acquisition of plasmids or transposon-encoding genes for aminoglycoside-metabolizing enzymes or from impaired transport of drug into the cell. Thus, there can be cross-resistance between members of the class.
Aminoglycosides are natural products or semisynthetic derivatives of compounds produced by a variety of soil actinomycetes. Amikacin, a derivative of kanamycin, and netilmicin, a derivative of sisomicin, are semisynthetic products. These agents contain amino sugars linked to an aminocyclitol ring by glycosidic bonds (Figure 54–1). They are polycations, and their polarity is responsible in part for pharmacokinetic properties shared by all members of the group. For example, none is absorbed adequately after oral administration, inadequate concentrations are found in cerebrospinal fluid (CSF), and all are excreted relatively rapidly by the normal kidney. All members of the group share the same spectrum of toxicity, most notably nephrotoxicity and ototoxicity, which can involve the auditory and vestibular functions of the eighth cranial nerve.
Figure 54–1 Sites of activity of various plasmid-mediated enzymes capable of inactivating aminoglycosides. The red X indicates regions of the molecules that are protected from the designated enzyme. In gentamicin C1, R1R2CH3; in gentamicin C2, R1CH3, R2H; in gentamicin C1a, R1R2H. (Reproduced with permission from Moellering RC Jr. Microbiological considerations in the use of tobramycin and related aninoglycosidic aminocyclitol antibiotics. Med J Aust, 1977;2S:4–8. Copyright 1977. The Medical Journal of Australia.)
MECHANISM OF ACTION. The aminoglycoside antibiotics are rapidly bactericidal. Bacterial killing is concentration dependent: the higher the concentration, the greater the rate of bacterial killing. The bactericidal activity persists after the serum concentration has fallen below the minimum inhibitory concentration (MIC). These properties probably account for the efficacy of high-dose, extended-interval dosing regimens.
Aminoglycosides diffuse through aqueous channels formed by porin proteins in the outer membrane of gram-negative bacteria to enter the periplasmic space. Transport of aminoglycosides across the cytoplasmic (inner) membrane depends on a transmembrane electrical gradient coupled to electron transport to drive permeation of these antibiotics. This energy-dependent phase is rate-limiting and can be blocked or inhibited by divalent cations (e.g., Ca2+ and Mg2+), hyperosmolarity, a reduction in pH, and anaerobic conditions. Thus, the antimicrobial activity of aminoglycosides is reduced markedly in the anaerobic environment of an abscess and in hyperosmolar acidic urine.
Once inside the cell, aminoglycosides bind to polysomes and interfere with protein synthesis by causing misreading and premature termination of mRNA translation (Figure 54–2). The primary intracellular site of action of the aminoglycosides is the 30S ribosomal subunit. At least 3 of these ribosomal proteins, and perhaps the 16S ribosomal RNA as well, contribute to the streptomycin-binding site. Aminoglycosides interfere with the initiation of protein synthesis, leading to the accumulation of abnormal initiation complexes; the drugs also can cause misreading of the mRNA template and incorporation of incorrect amino acids into the growing polypeptide chains. The resulting aberrant proteins may be inserted into the cell membrane, leading to altered permeability and further stimulation of aminoglycoside transport.
Figure 54–2 Effects of aminoglycosides on protein synthesis. A. Aminoglycoside (represented by red circles) binds to the 30S ribosomal subunit and interferes with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA. As 30S-50S complexes downstream complete translation of mRNA and detach, the abnormal initiation complexes, so-called streptomycin monosomes, accumulate, blocking further translation of the message. Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to B, premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein or C, incorporation of incorrect amino acids (indicated by the red X), resulting in the production of abnormal or nonfunctional proteins.
MICROBIAL RESISTANCE TO THE AMINOGLYCOSIDES. Bacteria may be resistant to aminoglycosides because of:
• Inactivation of the drug by microbial enzymes
• Failure of the antibiotic to penetrate intracellularly
• Low affinity of the drug for the bacterial ribosome
Clinically, drug inactivation is the most common mechanism for acquired microbial resistance. The genes encoding aminoglycoside-modifying enzymes are acquired primarily by conjugation and transfer of resistance plasmids (see Chapter 48). These enzymes phosphorylate, adenylate, or acetylate specific hydroxyl or amino groups (see Figure 54–1). Amikacin is a suitable substrate for only a few of these inactivating enzymes (see Figure 54–1); thus, strains that are resistant to multiple other aminoglycosides tend to be susceptible to amikacin. However, a significant percentage of clinical isolates ofEnterococcus faecalis and E. faecium are highly resistant to all aminoglycosides. Resistance to gentamicin indicates cross-resistance to tobramycin, amikacin, kanamycin, and netilmicin because the inactivating enzyme is bifunctional and can modify all these aminoglycosides. Owing to differences in the chemical structures of streptomycin and other aminoglycosides, this enzyme does not modify streptomycin, which is inactivated by another enzyme; consequently, gentamicin-resistant strains of enterococci may be susceptible to streptomycin. Intrinsic resistance to aminoglycosides may be caused by failure of the drug to penetrate the cytoplasmic (inner) membrane. Transport of aminoglycosides across the cytoplasmic membrane is an active process that depends on oxidative metabolism. Strictly anaerobic bacteria thus are resistant to these drugs because they lack the necessary transport system.
Missense mutations in Escherichia coli that substitute a single amino acid in a crucial ribosomal protein may prevent binding of streptomycin. Although highly resistant to streptomycin, these strains are not widespread in nature. Similarly, 5% of strains of Pseudomonas aeruginosa exhibit such ribosomal resistance to streptomycin. Because ribosomal resistance usually is specific for streptomycin, these strains of enterococci remain sensitive to a combination of penicillin and gentamicin in vitro.
ANTIBACTERIAL SPECTRUM OF THE AMINOGLYCOSIDES. The antibacterial activity of gentamicin, tobramycin, kanamycin, netilmicin, and amikacin is directed primarily against aerobic gram-negative bacilli. Kanamycin, like streptomycin, has a more limited spectrum. The aerobic gram-negative bacilli vary in their susceptibility to the aminoglycosides (see Table 54–1).
Typical Minimal Inhibitory Concentrations of Aminoglycosides That Will Inhibit 90% (MIC90) of Clinical Isolates for Several Species
Aminoglycosides have little activity against anaerobic microorganisms or facultative bacteria under anaerobic conditions. Their action against most gram-positive bacteria is limited, and they should not be used as single agents to treat infections caused by gram-positive bacteria. In combination with a cell wall–active agent, such as a penicillin or vancomycin, an aminoglycoside produces a synergistic bactericidal effect in vitro. Clinically, the superiority of aminoglycoside combination regimens over β-lactams alone is not proven except in relatively few infections (discussed later).
ADME AND DOSING
ABSORPTION. The aminoglycosides are polar cations and therefore are poorly absorbed from the GI tract. Less than 1% of a dose is absorbed after either oral or rectal administration. The drugs are eliminated quantitatively in the feces. Nonetheless, long-term oral or rectal administration of aminoglycosides may result in accumulation to toxic concentrations in patients with renal impairment. Absorption of gentamicin from the GI tract may be increased by GI disease (e.g., ulcers or inflammatory bowel disease). Instillation of these drugs into body cavities with serosal surfaces also may result in rapid absorption and unexpected toxicity (i.e., neuromuscular blockade). Intoxication may occur when aminoglycosides are applied topically for long periods to large wounds, burns, or cutaneous ulcers, particularly if there is renal insufficiency.
All the aminoglycosides are absorbed rapidly from intramuscular sites of injection. Peak concentrations in plasma occur after 30-90 min. These concentrations range from 4-12 μg/mL following a 1.5-2 mg/kg dose of gentamicin, tobramycin, or netilmicin and from 20-35 μg/mL following a 7.5 mg/kg dose of amikacin or kanamycin. There is increasing use of aminoglycosides administered via inhalation, primarily for the management of patients with cystic fibrosis who have chronic P. aeruginosa pulmonary infections. Amikacin and tobramycin solutions for injection have been used, as well as a commercial formulation of tobramycin designed for inhalation (TOBI, others).
DISTRIBUTION. Because of their polar nature, the aminoglycosides do not penetrate into most cells, the CNS, or the eye. Except for streptomycin, there is negligible binding of aminoglycosides to plasma albumin. The apparent volume of distribution of these drugs is 25% of lean body weight and approximates the volume of extracellular fluid. The aminoglycosides distribute poorly into adipose tissue, which must be considered when using weight-based dosing regimens in obese patients.
Concentrations of aminoglycosides in secretions and tissues are low. High concentrations are found only in the renal cortex and the endolymph and perilymph of the inner ear; the high concentration in these sites likely contribute to the nephrotoxicity and ototoxicity caused by these drugs. As a result of active hepatic secretion, concentrations in bile approach 30% of those found in plasma, but this represents a very minor excretory route for the aminoglycosides. Inflammation increases the penetration of aminoglycosides into peritoneal and pericardial cavities. Concentrations of aminoglycosides achieved in CSF with parenteral administration usually are subtherapeutic. Treatment of meningitis with intravenous administration is generally suboptimal. Intrathecal or intraventricular administration of aminoglycosides has been used to achieve therapeutic levels, but the availability of third- and fourth-generation cephalosporins has generally made this unnecessary.
Administration of aminoglycosides to women late in pregnancy may result in accumulation of drug in fetal plasma and amniotic fluid. Streptomycin and tobramycin can cause hearing loss in children born to women who receive the drug during pregnancy. Insufficient data are available regarding the other aminoglycosides; therefore, these agents should be used with caution during pregnancy and only for strong clinical indications in the absence of suitable alternatives.
ELIMINATION. The aminoglycosides are excreted almost entirely by glomerular filtration, achieving urine concentrations of 50-200 μg/mL. The half-lives of the aminoglycosides in plasma are 2-3 h in patients with normal renal function. Because the elimination of aminoglycosides depends almost entirely on the kidney, a linear relationship exists between the concentration of creatinine in plasma and thet1/2 of all aminoglycosides in patients with moderately compromised renal function. Because the incidence of nephrotoxicity and ototoxicity is likely related to the overall drug exposure to aminoglycosides, it is critical to reduce the maintenance dosage of these drugs in patients with impaired renal function.
Although excretion of aminoglycosides is similar in adults and children >6 months of age, half-lives of aminoglycosides may be prolonged significantly in the newborn: 8-11 h in the first week of life in newborns weighing <2 kg and ~5 h in those weighing >2 kg. Thus, it is critically important to monitor plasma concentrations of aminoglycosides during treatment of neonates. Aminoglycoside clearances are increased and half-lives are reduced in patients with cystic fibrosis. Larger doses of aminoglycosides may likewise be required in burn patients because of more rapid drug clearance, possibly because of drug loss through burn tissue. Aminoglycosides can be removed from the body by either hemodialysis or peritoneal dialysis.
Aminoglycosides can be inactivated by various penicillins in vitro and thus should not be admixed in solution. Some reports indicate that this inactivation may occur in vivo in patients with end-stage renal failure, making monitoring of aminoglycoside plasma concentrations even more necessary in such patients. Amikacin appears to be the aminoglycoside least affected by this interaction; penicillins with more nonrenal elimination (such as piperacillin) may be less prone to cause this interaction.
DOSING. High-dose, extended-interval administration of aminoglycosides is the preferred means of administering aminoglycosides for most indications and patient populations. Administering once daily higher doses at extended intervals is likely to be at least equally efficacious and potentially less toxic than administration of divided doses. Because of the post-antibiotic effect of aminoglycosides, good therapeutic response can be attained even when concentrations of amino-glycosides fall below inhibitory concentrations for a substantial fraction of the dosing interval. High-dose, extended-interval dosing schemes for aminoglycosides may also reduce the characteristic oto- and nephro-toxicity of these drugs. This diminished toxicity is probably due to a threshold effect from accumulation of drug in the inner ear or in the kidney. High-dose, extended-interval regimens, despite the higher peak concentration, provide a longer period when concentrations fall below the threshold for toxicity than does a multiple-dose regimen (compare the 2 dosage regimens shown in Figure 54–3).
Figure 54–3 Comparison of single dose and divided dose regimens for gentamicin. In a hypothetical patient, a dose of gentamicin (5.1 mg/kg) is administered intravenously as a single bolus (red line) or in 3 portions, a third of the dose every 8 h (purple line), such that the total drug administered is the same in the 2 cases. The threshold for toxicity (green dashed line) is the plasma concentration of 2 μg/mL, the maximum recommended for prolonged exposure. The single-dose regimen produces a higher plasma concentration than the every-8-h regimen; this higher peak provides efficacy that otherwise might be compromised due to prolonged sub-threshold concentrations later in the dosing interval or that is provided by the lower peak levels achieved with the every-8-h regimen. The once-daily regimen also provides a 13-h period during which plasma concentrations are below the threshold for toxicity. The every-8-h regimen, by contrast, provides only 3 short (~1 h) periods in 24 h during which plasma concentrations are below the threshold for toxicity. The single high-dose, extended interval is generally preferred for aminoglycosides, with a few exceptions (during pregnancy, in neonates, etc.), as noted in the text. On the other hand, a divided-dose regimen can be useful for maximizing the time above a threshold (e.g., MIC) for some antibiotics (see Figure 48–4).
Exceptions to the high-dose/extended-interval dosing include pregnancy, neonates, and in pediatric infections, and combination therapy for endocarditis. In these infections, multiple daily doses (with a lower total daily dose) are preferred because data documenting equivalent safety and efficacy of extended-interval dosing are inadequate. Extended-interval dosing should also be avoided in patients with significant renal dysfunction (i.e., creatinine clearance <25 mL/min). Aminoglycoside doses must be adjusted for patients with creatinine clearances of <80 mL/min (Table 54–2), and plasma concentrations must be monitored. Concentrations of aminoglycosides achieved in plasma after a given dose vary widely among patients.
Dose Reduction of Aminoglycosides Based on Calculated Creatinine Clearance
For twice- or thrice-daily dosing regimens, both peak and trough plasma concentrations are determined. The peak concentration documents that the dose produces therapeutic concentrations, while the trough concentration is used to avoid toxicity. Trough concentrations should be <1-2 μg/mL for gentamicin, netilmicin, and tobramycin and <10 μg/mL for amikacin and streptomycin. Monitoring of aminoglycoside plasma concentrations also is important when using an extended-interval dosing regimen. The most accurate method for monitoring plasma levels for dose adjustment is to measure the concentration in 2 plasma samples drawn several hours apart (e.g., at 2 and 12 h after a dose). The clearance then can be calculated and the dose adjusted to achieve the desired target range.
UNTOWARD EFFECTS. All aminoglycosides have the potential to produce reversible and irreversible vestibular, cochlear, and renal toxicity.
OTOTOXICITY. Vestibular and auditory dysfunction can follow the administration of any of the aminoglycosides, and ototoxicity may become a dose-limiting adverse effect. Aminoglycoside-induced ototoxicity results in irreversible, bilateral high-frequency hearing loss and temporary vestibular hypofunction. Degeneration of hair cells and neurons in the cochlea correlates with the loss of hearing. Accumulation within the perilymph and endolymph occurs predominantly when aminoglycoside concentrations in plasma are high. Diffusion back into the bloodstream is slow; the half-lives of the aminoglycosides are 5 to 6 times longer in the otic fluids than in plasma. Drugs such as ethacrynic acid andfurosemide potentiate the ototoxic effects of the aminoglycosides in animals, but data from humans implicating furosemide are less convincing.
Streptomycin and gentamicin produce predominantly vestibular effects, whereas amikacin, kanamycin, and neomycin primarily affect auditory function; tobramycin affects both equally. The incidence of ototoxicity is difficult to determine. Audiometric data suggest that the incidence could be as high as 25%. The incidence of vestibular toxicity is particularly high in patients receiving streptomycin; nearly 20% of individuals who received 500 mg twice daily for 4 weeks for enterococcal endocarditis developed clinically detectable irreversible vestibular damage. Because the initial symptoms may be reversible, patients receiving high doses and/or prolonged courses of aminoglycosides should be monitored carefully for ototoxicity; however, deafness may occur several weeks after therapy is discontinued.
Clinical Symptoms of Cochlear Toxicity. A high-pitched tinnitus often is the first symptom of toxicity. If the drug is not discontinued, auditory impairment may develop after a few days. The tinnitus may persist for several days to 2 weeks after therapy is stopped. Because perception of sound in the high-frequency range (outside the conversational range) is lost first, the affected individual is not always aware of the difficulty, and it will not be detected except by careful audiometric examination. If the hearing loss progresses, the lower sound ranges are affected.
Clinical Symptoms of Vestibular Toxicity. Moderately intense headache lasting 1-2 days may precede the onset of labyrinthine dysfunction. This is followed immediately by an acute stage in which nausea, vomiting, and difficulty with equilibrium develop and persist for 1-2 weeks. Prominent symptoms include vertigo in the upright position, inability to perceive termination of movement (“mental past-pointing”), and difficulty in sitting or standing without visual cues. The acute stage ends suddenly and is followed by chronic labyrinthitis, in which, the patient has difficulty when attempting to walk or make sudden movements; ataxia is the most prominent feature. The chronic phase persists for ~2 months. Recovery from this phase may require 12-18 months, and most patients have some permanent residual damage. Early discontinuation of the drug may permit recovery before irreversible damage of the hair cells.
NEPHROTOXICITY. Approximately 8-26% of patients who receive an aminoglycoside for several days develop mild renal impairment that is almost always reversible. The toxicity results from accumulation and retention of aminoglycoside in the proximal tubular cells. The initial manifestation of damage at this site is excretion of enzymes of the renal tubular brush border followed by mild proteinuria, and the appearance of hyaline and granular casts. The glomerular filtration rate is reduced after several additional days. The non-oliguric phase of renal insufficiency is thought to be due to the effects of aminoglycosides on the distal portion of the nephron with a reduced sensitivity of the collecting-duct epithelium to vasopressin. Although severe acute tubular necrosis may occur rarely, the most common significant finding is a mild rise in plasma creatinine. The impairment in renal function is almost always reversible because the proximal tubular cells have the capacity to regenerate. Toxicity correlates with the total amount of drug administered and with longer courses of therapy. High-dose, extended-interval dosing approaches lead to less nephrotoxicity at the same level of total drug exposure (as measured by area under the curve) than divided-dose approaches (see Figure 54–3). Neomycin, which concentrates to the greatest degree, is highly nephrotoxic in human beings and should not be administered systemically. Streptomycin does not concentrate in the renal cortex and is the least nephrotoxic. Drugs such as amphotericin B, vancomycin, angiotensin-converting enzyme inhibitors, cisplatin, and cyclosporine may potentiate aminoglycoside-induced nephrotoxicity.
NEUROMUSCULAR BLOCKADE. Acute neuromuscular blockade and apnea have been attributed to the aminoglycosides; patients with myasthenia gravis are particularly susceptible. In humans, neuromuscular blockade generally has occurred after intrapleural or intraperitoneal instillation of large doses of an aminoglycoside; however, the reaction can follow intravenous, intramuscular, and even oral administration of these agents. Neuromuscular blockade may be reversed by intravenous administration of a Ca+ salt.
OTHER UNTOWARD EFFECTS. In general, the aminoglycosides have little allergenic potential. Rare hypersensitivity reactions—including skin rashes, eosinophilia, fever, blood dyscrasias, angioedema, exfoliative dermatitis, stomatitis, and anaphylactic shock—have been reported as cross-hypersensitivity among drugs in this class.
THERAPEUTIC USES OF AMINOGLYCOSIDES
Gentamicin is an important agent for the treatment of many serious gram-negative bacillary infections. It is the aminoglycoside of first choice because of its lower cost and reliable activity against all but the most resistant gram-negative aerobes. Gentamicin preparations are available for parenteral, ophthalmic, and topical administration. Gentamicin, tobramycin, amikacin, and netilmicin can be used interchangeably for the treatment of most of the following infections. For most indications, gentamicin is preferred because of long experience with its use and its lower cost. Many different types of infections can be treated successfully with these aminoglycosides; however, owing to their toxicities, prolonged use should be restricted to the therapy of life-threatening infections and those for which a less toxic agent is contraindicated or less effective.
Aminoglycosides frequently are used in combination with a cell wall–active agent (β-lactam or glycopeptide) for the therapy of serious proven or suspected bacterial infections. The 3 rationales for this approach are: to expand the empiric spectrum of activity of the antimicrobial regimen; to provide synergistic bacterial killing; and to prevent the emergence of resistance to the individual agents. Combination therapy is used in infections such as healthcare-associated pneumonia or sepsis, where multidrug-resistant gram-negative organisms such as P. aeruginosa, Enterobacter, Klebsiella, and Serratia may be causative and the consequences of failing to provide initially active therapy are dire. The use of aminoglycosides to achieve synergistic bacterial killing and improve clinical response is most well established for the treatment of endocarditis due to gram-positive organisms, most importantlyEnterococcus. Clinical data do not support the use of combination therapy for synergistic killing of gram-negative organisms, with the possible exceptions of serious P. aeruginosainfections.
DOSING. The typical recommended intramuscular or intravenous dose of gentamicin sulfate when used for the treatment of known or suspected gram-negative organisms as a single agent or in combination therapy for adults with normal renal function is 5-7 mg/kg daily given over 30-60 min. For patients with renal dysfunction, the interval may be extended. For patients who are not candidates for extended-interval dosing, a loading dose of 2 mg/kg and then 3-5 mg/kg per day, one-third given every 8 h is recommended. Dosages at the upper end of this range may be required to achieve therapeutic levels for trauma or burn patients, those with septic shock, patients with cystic fibrosis, and others in whom drug clearance is more rapid or volume of distribution is larger than normal. Several dosage schedules have been suggested for newborns and infants: 3 mg/kg once daily for preterm newborns <35 weeks of gestation; 4 mg/kg once daily for newborns >35 weeks of gestation; 5 mg/kg daily in 2 divided doses for neonates with severe infections; and 2-2.5 mg/kg every 8 h for children up to 2 years of age. Peak plasma concentrations range from 4-10 μg/mL (dosing: 1.7 mg/kg every 8 h) and 16-24 μg/mL (dosing: 5.1 mg/kg once daily). It should be emphasized that the recommended doses of gentamicin do not always yield desired concentrations. Periodic determinations of the plasma concentration of aminoglycosides are recommended strongly.
Urinary Tract Infections. Aminoglycosides usually are not indicated for the treatment of uncomplicated urinary tract infections, although a single intramuscular dose of gentamicin (5 mg/kg) has been effective in uncomplicated infections of the lower urinary tract. However, as strains of E. coli have acquired resistance to β-lactams, trimethoprim-sulfamethoxazole, and fluoroquinolones, use of aminoglycosides may increase. Once the microorganism is isolated and its sensitivities to antibiotics are determined, the aminoglycoside should be discontinued if the infecting microorganism is sensitive to less toxic antibiotics.
Pneumonia. The organisms that cause community-acquired pneumonia are susceptible to broad-spectrum β-lactam antibiotics, macrolides, or a fluoroquinolone, and usually it is not necessary to add an aminoglycoside. Aminoglycosides are ineffective for the treatment of pneumonia due to anaerobes or S. pneumoniae, which are common causes of community-acquired pneumonia. They should not be considered as effective single-drug therapy for any aerobic gram-positive cocci (including Staphylococcus aureus or streptococci), the microorganisms commonly responsible for suppurative pneumonia or lung abscess. An amino-glycoside in combination with a β-lactam antibiotic is recommended as standard therapy for hospital-acquired pneumonia in which a multiple-drug-resistant gram-negative aerobe is a likely causative agent. Once it is established that the β-lactam is active against the causative agent, there is generally no benefit from continuing the aminoglycoside.
Meningitis. Availability of third-generation cephalosporins, especially cefotaxime and ceftriaxone, has reduced the need for treatment with aminoglycosides in most cases of meningitis, except for infections caused by gram-negative organisms resistant to β-lactam antibiotics (e.g., species of Pseudomonas and Acinetobacter). If an aminoglycoside is necessary, in adults, 5 mg of a preservative-free formulation of gentamicin (or equivalent dose of another aminoglycoside) is administered directly intrathecally or intraventricularly once daily.
Peritonitis Associated with Peritoneal Dialysis. Patients who develop peritonitis as a result of peritoneal dialysis may be treated with aminoglycoside diluted into the dialysis fluid to a concentration of 4-8 mg/L for gentamicin, netilmicin, or tobramycin or 6-12 mg/L for amikacin. Intravenous or intramuscular administration of drug is unnecessary because serum and peritoneal fluid will equilibrate rapidly.
Bacterial Endocarditis. “Synergistic” or low-dose gentamicin (3 mg/kg/day in 3 divided doses) in combination with a penicillin or vancomycin has been recommended in certain circumstances for treatment of infections due to gram-positive organisms, primarily bacterial endocarditis. Penicillin and gentamicin in combination are effective as a short-course (i.e., 2-week) regimen for uncomplicated native-valve streptococcal endocarditis. In cases of enterococcal endocarditis, concomitant administration of penicillin and gentamicin for 4-6 weeks is recommended. A 2-week regimen of gentamicin or tobramycin in combination with nafcillin is effective for the treatment of selected cases of staphylococcal tricuspid native-valve endocarditis. For patients with native mitral or aortic valve staphylococcal endocarditis, the risks of aminoglycoside administration likely outweigh the benefits.
Sepsis. Inclusion of an aminoglycoside in an empirical regimen is commonly recommended for the febrile patient with granulocytopenia and for sepsis when P. aeruginosa is a potential pathogen. More recent studies using potent broad-spectrum β-lactams (e.g., carbapenems and anti-pseudomonal cephalosporins) have demonstrated no benefit from adding an aminoglycoside to the regimen unless there is concern that an infection may be caused by a multiple-drug-resistant organism.
Topical Applications. Gentamicin is absorbed slowly when it is applied topically in an ointment and somewhat more rapidly when it is applied as a cream. When the antibiotic is applied to large areas of denuded body surface, as may be the case in burn patients, plasma concentrations can reach 4 μg/mL, and 2-5% of the drug may appear in the urine.
UNTOWARD EFFECTS. The most important and serious side effects of the use of gentamicin are nephrotoxicity and irreversible ototoxicity. Intrathecal or intraventricular administration is used rarely because it may cause local inflammation.
The antimicrobial activity, pharmacokinetic properties, and toxicity profile of tobramycin are similar to those of gentamicin. Tobramycin may be given either intramuscularly, intravenously, or by inhalation. Tobramycin (TOBREX, others) also is available in ophthalmic ointments and solutions. Indications for the use of tobramycin are the same as those for gentamicin. The superior activity of tobramycin against P. aeruginosa makes it the preferred aminoglycoside for treatment of serious infections known or suspected to be caused by this organism. Tobramycin usually is used with an anti-pseudomonal β-lactam antibiotic. In contrast to gentamicin, tobramycin shows poor activity in combination with penicillin against many strains of enterococci. Most strains of E. faecium are highly resistant. Tobramycin is ineffective against mycobacteria. Dosages and serum concentrations are identical to those for gentamicin.
The spectrum of antimicrobial activity of amikacin is the broadest of the group. Because of its resistance to many of the aminoglycoside-inactivating enzymes, amikacin has a special role for the initial treatment of serious nosocomial gram-negative bacillary infections in hospitals where resistance to gentamicin and tobramycin has become a significant problem. Amikacin is active against most strains of Serratia, Proteus, and P. aeruginosa as well as most strains of Klebsiella, Enterobacter, and E. coli that are resistant to gentamicin and tobramycin. Most resistance to amikacin is found among strains of Acinetobacter, Providencia, and Flavobacterium and strains of Pseudomonas other than P. aeruginosa; these all are unusual pathogens. Amikacin is less active than gentamicin against enterococci and should not be used for this organism. Amikacin is not active against the majority of gram-positive anaerobic bacteria. It is active against Mycobacterium tuberculosis, including streptomycin-resistant strains and atypical mycobacteria.
The recommended dose of amikacin is 15 mg/kg/day as a single daily dose or divided into 2 or 3 equal portions, which must be reduced for patients with renal failure. The drug is absorbed rapidly after intramuscular injection, and peak concentrations in plasma approximate 20 μg/mL after injection of 7.5 mg/kg, The concentration 12 h after a 7.5 mg/kg dose is 5-10 μg/mL. A 15 mg/kg once-daily dose produces peak concentrations 50-60 μg/mL and a trough of <1 μg/mL. For treatment of mycobacterial infections, thrice-weekly dosing schedules are used, with doses up to 25 mg/kg. As with the other aminoglycosides, amikacin causes ototoxicity, hearing loss, and nephrotoxicity.
Netilmicin is similar to gentamicin and tobramycin in its pharmacokinetic properties and dosage. Its antibacterial activity is broad against aerobic gram-negative bacilli. Like amikacin, it is not metabolized by most of the aminoglycoside-inactivating enzymes; thus, it may be active against certain bacteria that are resistant to gentamicin (with the exception of resistant enterococci). Netilmicin is useful for the treatment of serious infections owing to susceptible Enterobacteriaceae and other aerobic gram-negative bacilli. The recommended dose of netilmicin for complicated urinary tract infections in adults is 1.5-2 mg/kg every 12 h. For other serious systemic infections, a total daily dose of 4-7 mg/kg is administered as a single dose or 2 to 3 divided doses. Children should receive 3-7 mg/kg/day in 2 to 3 divided doses; neonates receive 3.5-5 mg/kg/day as a single daily dose. The t1/2for elimination is usually 2–2.5 h in adults and increases with renal insufficiency. Netilmicin may produce ototoxicity and nephrotoxicity.
Streptomycin is used for the treatment of certain unusual infections generally in combination with other antimicrobial agents. It generally is less active than other members of the class against aerobic gram-negative rods.
Bacterial Endocarditis. The combination of penicillin G (bacteriostatic against enterococci) and streptomycin is effective as bactericidal therapy for enterococcal endocarditis. Gentamicin is generally preferred for its lesser toxicity; also, gentamicin should be used when the strain of enterococcus is resistant to streptomycin (MIC >2 mg/mL). Streptomycin should be used instead of gentamicin when the strain is resistant to the latter and has demonstrable susceptibility to streptomycin, which may occur because the enzymes that inactivate these 2 aminoglycosides are different.
Streptomycin may be administered by deep intramuscular injection or intravenously. Intramuscular injection may be painful, with a hot tender mass developing at the site of injection. The dose of streptomycin is 15 mg/kg/day for patients with creatinine clearances >80 mL/min. It typically is administered as a 1000-mg single daily dose for tuberculosis or 500 mg twice daily, resulting in peak serum concentrations of ~50-60 and 15-30 μg/mL and trough concentrations of <1 and 5-10 μg/mL, respectively. The total daily dose should be reduced in direct proportion to the reduction in creatinine clearance for creatinine clearances >30 mL/min (see Table 54–2).
Tularemia. Streptomycin (or gentamicin) is the drug of choice for the treatment of tularemia. Most cases respond to the administration of 1-2 g (15-25 mg/kg) streptomycin per day (in divided doses) for 10-14 days.
Plague. Streptomycin is effective agent for the treatment of all forms of plague. The recommended dose is 2 g/day in 2 divided doses for 10 days. Gentamicin is probably as efficacious.
Tuberculosis. Streptomycin is a second-line agent for the treatment of active tuberculosis, and streptomycin always should be used in combination with at least 1 or 2 other drugs to which the causative strain is susceptible. The dose for patients with normal renal function is 15 mg/kg/day as a single intramuscular injection for 2-3 months and then 2 or 3 times a week thereafter.
UNTOWARD EFFECTS. Streptomycin has been replaced by gentamicin for most indications because the toxicity of gentamicin is primarily renal and reversible, whereas that of streptomycin is vestibular and irreversible. The administration of streptomycin may produce dysfunction of the optic nerve, including scotomas, presenting as enlargement of the blind spot. Among the less common toxic reactions to streptomycin is peripheral neuritis.
Neomycin is a broad-spectrum antibiotic. Susceptible microorganisms usually are inhibited by concentrations of ≤10 μg/mL. Gram-negative species that are highly sensitive are E. coli, Enterobacter aerogenes, Klebsiella pneumoniae, and Proteus vulgaris. Gram-positive microorganisms that are inhibited include S. aureus and E. faecalis. M. tuberculosis also is sensitive to neomycin. Strains of P. aeruginosa are resistant to neomycin. Neomycin sulfate is available for topical and oral administration. Neomycin currently is available in many brands of creams, ointments, and other products alone and in combination with polymyxin, bacitracin, other antibiotics, and a variety of corticosteroids. There is no evidence that these topical preparations shorten the time required for wound healing or that those containing a steroid are more effective.
THERAPEUTIC USES. Neomycin is used widely for topical application in a variety of infections of the skin and mucous. The oral administration of neomycin (usually in combination with erythromycin base) has been employed primarily for “preparation” of the bowel for surgery. Neomycin and polymyxin B have been used for irrigation of the bladder to prevent bacteriuria and bacteremia associated with indwelling catheters. For this purpose, 1 mL of a preparation (NEOSPORIN G.U. IRRIGANT) containing 40 mg neomycin and 200,000 units polymyxin B per milliliter is diluted in 1 L of 0.9% sodium chloride solution and is used for continuous irrigation of the urinary bladder through appropriate catheter systems. The bladder is irrigated at the rate of 1 L every 24 h.
ABSORPTION AND EXCRETION. Neomycin is poorly absorbed from the GI tract and is excreted by the kidney. A total daily intake of 10 g for 3 days yields a blood concentration below that associated with systemic toxicity if renal function is normal. About 97% of an oral dose of neomycin is not absorbed and is eliminated unchanged in the feces.
UNTOWARD EFFECTS. Hypersensitivity reactions, primarily skin rashes, occur in 6-8% of patients when neomycin is applied topically. The most important toxic effects of neomycin are ototoxicity and nephrotoxicity; as a consequence, the drug is no longer available for parenteral administration. Neuromuscular blockade with respiratory paralysis also has occurred after irrigation of wounds or serosal cavities. Individuals treated with 4-6 g/day of the drug by mouth sometimes develop a sprue-like syndrome with diarrhea, steatorrhea, and azotorrhea. Overgrowth of yeasts in the intestine also may occur.
Kanamycin is among the most toxic aminoglycosides and there are few indications for its use. It has no therapeutic advantage over streptomycin or amikacin and probably is more toxic; either should be used instead, depending on susceptibility of the isolate.