Ehrlich's ‘magic bullet’ notion of chemotherapy foresaw substances that when given as a single dose would localize in the sites of infection and destroy the organisms there. Despite the enormous advances made in the development of antimicrobial compounds, none exhibits the remarkable properties Ehrlich visualized. Most antimicrobial agents are widely distributed in the body in response to forces that have nothing to do with infection and may result in concentrations of the agent being least in the sites where they are most needed.
Basis for therapeutic action
Among the many properties that must be exhibited by therapeutically useful chemotherapeutic agents, the ability to achieve effective concentrations and act in the complex environment of the infected lesion is essential. When antibiotics are given systemically the delivery and maintenance of effective concentrations at the site of infection are determined by the concentrations achieved in the blood, which are in turn determined by the absorption, distribution, metabolism, and elimination of the drug, and by the way in which the blood-borne drug is distributed to the tissues. From serial measurements of the concentration of the agent in the serum—usually in healthy volunteers—it is possible to calculate both its rates of absorption and elimination and the volume in which the drug is distributed. The volume of distribution indicates whether it is largely confined within the vascular compartment or spreads out into the extracellular fluid—the site of most infections—or penetrates into cells where some organisms, for example mycobacteria and brucellae, multiply. The rates of transfer, volume of distribution, and other key properties can be given numerical values that provide succinct and quantitative statements of the drug pharmacokinetics. In this respect antimicrobials do not differ from other drugs. However, in comparison with other drugs, information about intestinal elimination and distribution into tissues has special relevance for antimicrobial agents. Intestinal elimination determines the amount of an antimicrobial drug that reaches the colon, the impact on the normal flora there and therefore the risk of adverse effects such as Clostridium difficile colitis. Infections can occur in any tissue in the body and some pathogens survive within mammalian cells; therefore, unlike other drugs the anatomical location of target receptors for antimicrobials is highly variable.
The time required for the concentration of drug in the plasma to fall by half is called the plasma half-life. Half-lives of different antibiotics vary considerably. That of benzylpenicillin, for example, is only 30 min, whereas that of the antimalarial mefloquine is about 3 weeks.
The concentration achieved in plasma while the drug is resident in the body can be measured relatively simply, but the calculation of the true half-life must take into account the distribution phase (sometimes called α-phase) during which the compound is migrating from the plasma to the tissues; this is clearly influenced by the route of administration, since absorption from intestinal or intramuscular sites is not instantaneous (Fig. 14.1).
The half-life of a drug that is usually cited is that which follows distribution to the tissues and is designated the β-phase. Any metabolism of the drug, binding to plasma proteins, or alteration in the functional integrity of the organs of excretion (usually the kidney or the liver, or both) will affect the elimination of the drug and hence the plasma half-life.
If large doses are given or the half-life of the drug is such that complete elimination has not occurred before the next dose is administered, the concentration of drug in the plasma will progressively rise. The excretion phase being logarithmic, the rate of elimination rises as the concentration of drug rises; eventually excretion proceeds as fast as the accumulation and the drug reaches a steady state (Fig. 14.2). In this example the first dose results in plasma concentration that exceeds the minimum inhibitory concentration for the organism being treated but not throughout the dosing interval. If it is essential to reach higher concentrations immediately then a loading dose should be given, which is usually two to three times the maintenance dose.
The possibility of accumulation and its consequences must be considered when an agent with a long half-life is administered or the patient's capacity to eliminate the agent is known or thought likely to be impaired and the agent has dose-related side effects.
Fig. 14.1 Mean plasma (•) and inflammatory fluid (▲) concentrations following a single 750-mg oral dose of ciprofloxacin. The distribution (or α) phase lasts for 2 h and is followed by the elimination (or β) phase. There is an even longer distribution phase in the inflammatory fluid where concentrations do not peak until about 3 h after administration. There is a lag in diffusion of drug back into the plasma so that from 3 h after administration tissue fluid concentrations are higher than plasma concentrations. Reproduced from C. Catchpole, J.M. Andrews, J. Woodcock, and R. Wise. The comparative pharmacokinetics and tissue penetration of single-dose ciprofloxacin 400mg i.v. and 750 mg po. J. Antimicrob Chemother 33(1): 103-110, 1994 by permission of Oxford University Press.
Many antibiotics do not produce adequate plasma levels when given by mouth and are available only as injectable preparations. In some countries injections are favoured over oral therapy, but this has more to do with cultural differences and traditions than with proven therapeutic benefit. In the UK antibiotics are usually given by mouth whenever possible, particularly in domiciliary practice, because of the convenience of the oral route. The need for properties such as stability in solution means that pharmaceutical preparations (injections, capsules, tablets, syrups, etc.) can contain different derivatives of the drug, sometimes with distinct properties.
The fraction of a dose of an oral drug that is absorbed unchanged and available to interact with the target is known as its bioavailability. The degree to which antimicrobial compounds are absorbed when given orally differs greatly (Table 14.1). Absorption is one factor that determines the effect that an antimicrobial has on the normal flora of the colon but intestinal elimination is also important.
Fig. 14.2 Illustration of a drug dosed twice daily that takes five doses to reach steady state. The shaded area shows the area under the concentration-time curve at steady state over 24 h. is the maximum (or peak) concentration at steady state and is the minimum (or trough) concentration at steady state. MIC is the minimum inhibitory concentration for a target pathogen. Reproduced from ‘Basis of Anti-Infective Therapy: Pharmacokinetic - Pharmacodynamic Criteria and Methodology for Dual Dosage Individualisation’ by A. Sanchez-Navarro and MM Sanchez Recio, Clinical Pharmacokinetics; 1999, 37(4): 289-304, with permission from Wolters Kluwer Health.
Antibiotic esters (pro-drugs)
Some drugs that can be given orally are nevertheless irregularly absorbed and often produce low plasma concentrations. Erythromycin is one example of this, and several derivatives have been produced in an attempt to overcome the difficulty, including erythromycin estolate, which is microbiologically inactive, but is much more lipid soluble than the parent drug and much better absorbed in the small intestine, where non-specific esterases liberate the active erythromycin into the portal vein. Esterification as the means of improving the oral absorption of drugs has been fairly widely used, other examples being the esters of ampicillin, such as pivampicillin, and aciclovir (valaciclovir). Such microbiologically inactive compounds that are converted to the active form are known as pro-drugs.
Esters such as cefuroxime axetil allow drugs that must otherwise be administered by injection to be given orally. Others, like the erythromycin and ampicillin esters, increase the poor absorption of the native compound.
Table 14.1 Bioavailability and intestinal elimination of some commonly prescribed antibacterial drugs after oral administration. Note that drugs that are well absorbed may still achieve high concentrations in the faeces because of secretion into bile or other enteral secretions. Similarly some drugs are eliminated in the intestine after parenteral administration (e.g. ceftriaxone)
The most direct way of ensuring adequate concentrations of antibiotic in the blood is by intravenous injection. The highest instantaneous concentrations are, of course, achieved by a single rapid intravenous injection, but any benefit of this may be offset by rapid excretion, and many agents are given by infusion over 15-20 min. Sometimes slow infusion is necessary in order to minimize side effects (as with vancomycin and the ‘red man syndrome’; p. 220) or local reaction at the injection site. Addition of antibiotics to drip infusions should be avoided if possible, since the slow rate of administration results in low plasma levels of the drug. Sometimes degradation of the drug in solution can occur over the prolonged period of administration, particularly if administration is combined with glucose. Certain combinations of β-lactam antibiotics and aminoglycosides mutually inactivate each other when mixed in intravenous solutions.
When all the drug is delivered directly into the plasma within a short time the plasma half-life is determined solely by the rate of elimination. When, however, uptake into the plasma is much slower then the persistence of the drug will depend not only on the rate at which it is eliminated but also on the rate at which it is added. Absorption from intramuscular sites is usually rapid, but to maintain inhibitory levels of penicillin, special depot preparations, such as procaine penicillin, have been developed (p. 17). These allow slow release from the injection site so that the plasma concentration is prolonged.
Compounds in the plasma generally reach the tissues by diffusion, although in some cases there is active secretion into, for example, saliva, bile, or urine. One important factor affecting the diffusibility of compounds is the degree to which they are bound to plasma proteins, mostly albumin. With some drugs, such as cloxacillin, ceftriaxone, fusidic acid, or teicoplanin more than 90% of the drug is bound and is antibacterially inactive. Only the diffusible fraction of the drug reaches the tissues and only this fraction exerts any antimicrobial effect. As the unbound fraction diffuses away, more of the plasma-bound drug dissociates and the equilibrium between the bound and the free compound is maintained. Because of this effect in limiting the activity and diffusibility of the drug, high degrees of protein binding might be perceived as disadvantageous.
However, two things have to be considered. The first is that, in order to be therapeutically effective, adequate concentrations of free drug must be achieved at the site of infection. That this occurs with the compounds mentioned, despite high degrees of protein binding, is clear from their clinical efficacy. The second is that bound drug will go wherever the protein goes and that includes the protein poured into the infected sites with inflammatory exudate. To this extent, protein-bound drug may be looked upon as a pro-drug with the valuable property of ‘homing in’ on to sites of inflammation. Once in the site, as far as is known, the concentration of free and active drug is still defined by the equilibrium between free and bound drug.
Another important aspect of protein binding is that drugs may compete for binding sites. It is possible for one drug to displace another of lower affinity, resulting in increased concentration and, possibly, toxicity of the liberated drug.
Infections occur in every tissue in the body, therefore information is required about distribution of antimicrobial drugs throughout the body.
Most bacteria are located in the extracellular fluid. However, some bacteria (e.g. Mycobacterium tuberculosis and Legionella pneumophila) survive within cells and drugs that are used to treat these infections must be capable of entering into and functioning within mammalian cells. Viruses, chlamydiae, and malaria parasites are essentially intracellular organisms.
Distribution in extracellular fluid of non-specialized tissues
Most tissues are supplied by fenestrated capillaries, which allow the free diffusion of antimicrobial drugs from plasma to the extracellular fluid. In this case the average drug concentration in plasma is the same as in the extracellular fluid.
Distribution of drugs into extracellular fluid of specialized tissues.
In contrast to other tissues, the capillaries supplying the central nervous system, the posterior chamber of the eye and the prostate are non-fenestrated. The tight junctions between the endothelial cells of these capillaries can only be crossed by lipid-soluble drugs that are capable of passage through the cells. Concentrations of antimicrobial agents within these specialized sites cannot be predicted from knowledge of plasma concentrations. In addition to these naturally occurring specialized sites, infection may occur in sites with impaired blood supply because of trauma or because of collection of fibrin as in the cardiac vegetations that result from bacterial endocarditis.
Penetration of drugs into intracellular fluid depends on the lipid solubility of the drug. β-Lactam antibiotics and aminoglycosides have poor lipid solubility and do not achieve high concentrations in cells. In contrast, lipid-soluble drugs such as macrolides and quinolones may achieve higher concentrations within cells than in the plasma or extracellular fluid.
Interpreting tissue distribution data
In most bacterial infections the organisms are contained in the extracellular fluid (Table 14.2). For these infections it can be assumed that the average concentration in the plasma is a reasonable indication of the average drug concentration at the site of infection (Fig. 14.1) and knowledge of plasma kinetics is all that is required.
A drug's volume of distribution is an indicator of its tissue distribution. If the volume of distribution is between 10 and 20 litres, the drug distributes into extracellular compartments. If the volume of distribution is of the order of 25-40 litres, intracellular distribution is implied. In rare circumstances, distribution volumes may be measured in hundreds or even thousands of litres. These large volumes suggest extensive binding to intracellular protein or organelles.
Table 14.2 Kinetic requirements for treatment of bacterial infections at different anatomical sites
Drug concentrations in tissue biopsies
Drug concentrations are measures in homogenized tissue samples; the result is therefore an average of the extracellular and intracellular concentrations. However, because cells make up about 70% of the volume of most tissue samples the intracellular concentration has a dominant influence so that the result is not a good indicator of drug concentration in extracellular fluid, which is where most pathogens are located. For example, β-lactam antibiotics do not penetrate eukaryotic cells. Suppose that the concentration of a β-lactam in extracellular fluid is 10 mg/l: the concentration in a homogenized tissue biopsy would be only 3 mg/l because extracellular fluid accounts for only 30% of the biopsy.
Most intracellular bacterial infections occur in the lung where distribution of antibacterial drugs has been relatively well characterized. This information is of direct relevance to the management of infections caused by the obligate intracellular pathogens that cause pneumonia (Legionella pneumophila, Chlamydophila pneumoniae, Mycobacterium tuberculosis). Ability to penetrate eukaryotic cells is a prerequisite for drugs aimed at infections caused by these organisms. However, high lung tissue concentrations are of less certain relevance in most lung infections, which are caused by extracellular pathogens.
Many antibiotics are modified in the body; the resulting metabolites are important for several reasons. First, they are generally, though not always, microbiologically less active than the parent compound. Some metabolites show not only different degrees, but also different spectra, of activity. In addition, metabolites may differ from the parent compounds in toxicity. If they are relatively inactive and more toxic, conventional microbiological assay of the drug will give very poor guidance as to the toxic hazard. This is particularly true of allergy, which can be triggered by tiny concentrations of minor metabolites rather than the parent compound. Finally, the metabolites may display altered pharmacokinetic characteristics, so that the period for which they are present in the body and able to achieve an antibacterial (or toxic) effect may be longer, or shorter than that of the parent compound.
Occasionally, it is necessary to prevent metabolism from occurring. The carbapenem antibiotic imipenem is susceptible to a renal dehydropeptidase that opens the β-lactam ring. Consequently, imipenem is formulated with a dehydropeptidase inhibitor, cilastatin, which protects it from inactivation.
Antimicrobial agents that are metabolized are particularly liable to interact with other drugs. This is most likely to be a problem in intensive care, where patients are critically ill and receiving multiple drugs. Antimicrobial compounds that inhibit the metabolism of other drugs in the liver include macrolides, fluoroquinolones, and antifungal azoles. On the other hand, rifampicin is a non-specific inducer of hepatic metabolism and may therefore cause therapeutic failure of other co-administered drugs by increasing their clearance. Drugs frequently used in intensive care that are at risk of clinically relevant pharmacokinetic interactions with anti-infective agents include some benzodiazepines (especially midazolam and triazolam), immunosuppressive agents (cyclosporin, tacrolimus), anti-asthmatic agents (theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin, carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine), and anticoagulants (warfarin).
The human body harbours a large number of bacteria that have important functions, particularly in the gut. The adverse effects of antibiotics on the normal flora include emergence of resistant strains from among the normal flora and replacement of the normal flora by more harmful organisms, such as pathogenic fungi or Clostridium difficile. Bioavailability of commonly prescribed antimicrobial drugs varies quite widely (Table 14.1). In general, poorly absorbed oral compounds have a more profound effect on the normal flora of the colon. However, after absorption from the gut drugs may be eliminated from the body by secretion into bile or by secretion by enterocytes. Thus even intravenously administered antimicrobial agents may reach the gut in sufficient quantities to cause harmful effects on the normal flora.
Most antibiotics are eliminated by the kidneys, so that very high concentrations may be achieved in urine. Excretion is by glomerular filtration or tubular secretion, and sometimes both. The principal compounds excreted in the urine by active tubular secretion are the penicillins and cephalosporins. This process is so effective as to clear the blood of most of the drug during its passage through the kidney, and these compounds generally have a very short half-life of 2h or less. Increasing the frequency of administration can increase the period for which inhibitory levels of rapidly excreted agents are present in the blood. Alternatively, an agent that competes for the active transport mechanism may be used. The oral uricosuric agent probenecid shares the tubular route of excretion of penicillins and can be used to prolong the plasma half-life of these antibiotics.
Influence of infection
The vast majority of information about the pharmacokinetics of antimicrobial drugs comes from studies in normal volunteers. Infection is likely to change absorption, distribution, and elimination so plasma concentrations in patients may be profoundly different from those found in normal volunteers (Fig. 14.3).
Fig. 14.3 Plasma concentrations of quinine in healthy subjects compared with patients with uncomplicated and severe malaria following administration of a loading dose of 20mg (salt)/kg. Reproduced from J. White. Antimalarial pharmacokinetics and treatment regimens.British Journal of Clinical Pharmacology 1992; 34: 1-10 with permission from Blackwell Publishing.
In contrast to pharmacokinetics, which describes the way a drug is handled in the body, pharmacodynamics specifies the way the drug interacts with the microbial target in the conditions imposed by pharmacokinetic fluctuations. This aspect of drug action is much more speculative, since it is not normally susceptible to direct measurement in situ, but is valuable insofar as it tries to define the dosing pattern likely to lead to the most efficient eradication of the offending microbe.
Among the factors to be considered are: whether the area under the concentration-time curve is more important than the peak level achieved; whether the regular replenishment of an inhibitory concentration for a short period is more, or less, efficacious than a continuously maintained inhibitory level; and whether antimicrobial activity is prolonged beyond the time for which an inhibitory concentration is achieved—the so-called post-antibiotic effect (p. 31).
Such judgements rely heavily on knowledge of how the micro-organism responds in laboratory controlled conditions in vitro and models of varying degrees of elaboration are sometimes constructed to try to approximate more closely to the dynamic circumstances that exist in life. Extrapolation of these observations to the in-vivo situation depends on the assumption that similar behaviour can be expected to occur in the complex, fluctuating conditions within an infected lesion and, indeed, on whether concentrations at the site of infection can be reliably predicted given individual variation.
Perhaps the most extraordinary feature of antimicrobial pharmacokinetics is that, after more than 50 years of intensive clinical and experimental study, the shape of drug concentration-time curve that is needed at the site of infection to secure optimum antimicrobial effects is still not known. If we knew that, we would be one step (of several required) towards more rationally based dosage schedules.
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