The Patient–Drug–Pathogen Interaction

THE PATIENT–DRUG–PATHOGEN INTERACTION

In the laboratory the strain of pathogen, the number of infecting organisms, the culture medium, the antibiotic concentration, and the duration of antibiotic exposure can be precisely specified. This precision cannot be obtained in patients. In addition, chemotherapy of hu-man disease is complex, as it depends on a complex patient–drug–pathogen interaction. This interaction has six components:

·            Pharmacokinetics: What the patient does to the drug. For example, a patient with renal failure will have diminished renal clearance of gen-tamicin.

·            Pharmacodynamics: What the drug does to the patient. For example, erythromycin stimulates gut motilin receptors and may induce nausea. The patient may stop taking the erythromycin.

·            Immunity: What the patient does to the pathogen. For example, a patient with AIDS who is exposed to tuberculosis may develop the disease in spite of receiving a course of postex-posure prophylactic antituberculosis chemo-therapy, which would be effective in a patient with an intact immune system. Immunity in-cludes both nonspecific complement-mediated opsonization and specific antibody- and cell-mediated immunity.

·            Sepsis: What the pathogen does to the patient. For example, a patient with gram-negative bacillary pneumonia may receive a perfectly adequate course of antibiotic chemotherapy, only to succumb to systemic inflammatory re-sponse syndrome (SIRS), an exaggerated and counterproductive release of inflammatory cy-tokines.

·            Resistance: What the pathogen does to the drug. For example, some strains of Pseudomonas aeruginosa produce a plasmid-mediated adeny-lase that inactivates gentamicin by chemically altering its structure.

·            Selective toxicity: What the drug does to the pathogen. For example, acyclovir triphosphate, the phosphorylated derivative of acyclovir, lacks the 3 -hydroxy group necessary for adding the next nucleotide to the chain and ter-minates DNA elongation. This effect is selec-tive, since herpes simplex DNA elongation is inhibited by markedly lower concentrations than is mammalian DNA elongation.

Pharmacokinetics

To be clinically useful, a chemotherapeutic drug must have both selective toxicity against pathogens and fa- vorable pharmacokinetics. The processes of absorption, distribution, metabolism, and elimination compose a drug’s pharmacokinetics. The concentration of the drug in a patient’s body as a function of time is determined by the dose administered and the drug’s pharmacoki-netics in that patient.

Absorption from the gastrointestinal tract can be af-fected by other drugs and by food. Aluminum, calcium, and magnesium ions in antacids or dairy products form insoluble chelates with all tetracyclines and inhibit their absorption. Food inhibits tetracycline absorption but enhances doxycycline absorption; food delays but does not diminish metronidazole absorption; fatty food en-hances griseofulvin absorption.

The chemical structure of a drug determines which enzymes metabolize it; a drug that fails to cross the cell membrane because of its polarity or size will be unme-tabolized even if biochemically active degradative en-zymes are present in the cytosol. Systemic use of drugs that are poorly absorbed or are destroyed by the gas-trointestinal environment requires parenteral adminis-tration. Of course, if the goal is to attack pathogens in the gastrointestinal tract, then poor gastrointestinal ab-sorption may be an advantage.

An antibiotic drug that is itself nontoxic may have metabolites that are toxic, diminishing its usefulness. For example, imipenem is hydrolyzed by renal dipeptidase to a metabolite that is inactive against bacteria but is toxic to humans. Coadministration of cilastatin inhibits the renal dipeptidase, which both prevents the formation of the toxic metabolite and decreases imipenem clear-ance, prolonging the half-life of the drug.

Partitioning of some drugs into cells occurs. Red blood cells parasitized by malaria selectively take up chloroquine, which accounts in part for the efficacy of this antimalarial against intracellular malarial forms. The intrahepatocellular concentration of chloroquine is 500 times that of the blood plasma concentration. Macrolides and fluoroquinolones are also selectively partitioned into cells, which accounts in part for their ef-ficacy against mycoplasma and chlamydia, both intra-cellular pathogens.

Extensive protein binding of a drug decreases its free level and decreases the compound’s glomerular fil-tration. Because protein binding is reversible, bound drug and free drug are in dynamic equilibrium; thus protein binding determines the optimal dose and dosing interval of the drug. A drug’s pharmacokinetic proper-ties are an important source of variation in the clinical response of patients to chemotherapy.

As mentioned earlier, pharmacokinetics is not solely the property of a drug but instead is the consequence of interactions between the drug and the physiology of the patient. Thus, statements like “the half-life of gentam-icin is 2 hours” are not very useful, as the half-life is likely be longer or shorter in a given individual patient.

Individualization of dosing of chemotherapeutic drugs with a low therapeutic index is essential to effective, safe chemotherapy.

The concentrations of chemotherapeutic drugs in blood plasma, cerebrospinal fluid, urine, or ascites fluid can be measured to determine whether sufficient drug is present to inhibit or kill a given pathogen and to ensure that the concentration is not so high as to be toxic to the patient.

In severe bacterial infections that are difficult to erad-icate, such as endocarditis or osteomyelitis, it may be im-portant to ensure that the patient’s serum remains bacte-ricidal at the lowest, or trough, concentration in the dosing interval. Dilutions of patient’s serum can be incu-bated with the organism isolated from the patient and the minimum bactericidal concentration determined through serial dilutions. Treatment is considered adequate if the serum remains bactericidal at a dilution of 1:8.

Pharmacodynamics

In the case of antibiotic chemotherapy, the ideal phar-macodynamic response is usually no pharmacodynamic response; the pharmacological target is not normal hu-man cells but rather a parasite, a virus-infected human cell, or a cancerous cell. The less selective the chemother-apeutic drug, the greater the severity of adverse effects. Cancer chemotherapy is often severely toxic, even life threatening. Suppression of a viral infection, such as oc-curs in the treatment of HIV with antiviral drugs, is of-ten complicated by serious drug-associated toxicity, such as hepatotoxicity or bone marrow suppression.

Compared with other pharmacological agents, anti-bacterial chemotherapeutic drugs are remarkably safe. Toxicity is common mainly in patients who are given in-appropriately high doses or who develop high drug lev-els because of decreased drug clearance. Most antibi-otics are renally cleared, so renal failure is a common cause of diminished antibiotic drug clearance.

The adverse reactions associated with the use of an-tibacterial chemotherapy include allergic reactions, toxic reactions resulting from inappropriately high drug doses, interactions with other drugs, reactions related to alterations in normal body flora, and idiosyncratic reac-tions. Several types of allergic responses occur, including immediate hypersensitivity reactions (hives, anaphy-laxis), delayed sensitivity reactions (interstitial nephri-tis), and hapten-mediated serum sickness. Allergic cross-reactions to structurally related antibiotics can occur. Although an alternative non–cross-reacting antibiotic is generally preferred, desensitization protocols are avail-able for situations in which there is no good alternative.

There is heterogeneity in human populations for the hepatic microsomal cytochrome P450 enzyme . Possession of an unfavorable phenotype may place a patient at risk for drug toxicity. For exam- ple, some patients who are slow acetylators of isoniazid may develop peripheral neuropathy with standard-dose isoniazid therapy.

Toxicity is most likely in tissues that interact with the drug. For example, gentamicin is polycationic and binds to anionic phospholipids in the cell membranes of renal proximal tubular cells, where it inhibits phospho-lipases and damages intracellular organelles.

Some adverse reactions are unrelated to either al-lergy or overdose; these are termed idiosyncratic. For instance, sulfonamides may precipitate acute hemolysis in some people having a glucose-6-phosphate dehydro-genase deficiency.

Many antibiotics alter the enteric microbial flora, particularly if high concentrations reach the colon. Antibiotic-sensitive bacteria are suppressed or killed, thereby removing their inhibitory effects on potentially pathogenic organisms. Overgrowth of pathogenic mi-crobes can then occur. Unlike anaerobes, Clostridium difficile is resistant to clindamycin and some β-lactams. Use of such an antibiotic permits the proliferation of C. difficile, which then elaborates its toxin in high concen-tration. This toxin can cause pseudomembranous colitis, which can be fatal if not recognized and treated.

The effectiveness of chemotherapy is enhanced by adequate immune function; however, some antibiotics suppress immune function. For example, tetracyclines can decrease leukocyte chemotaxis and complement activation. Rifampin decreases the number of T lym-phocytes and depresses cutaneous hypersensitivity. Antibiotics such as the sulfonamides may induce granu-locytopenia or bone marrow aplasia. These effects are not well understood but may be due to enteric bacterial metabolic byproducts of these antibiotics.

Immunity

In the absence of antibiotic therapy, many patients survive infection, even infection by highly virulent pathogens. Thus, immunity may be due to factors such as a high func-tional reserve of organs or to an enhanced nonspecific op-sonization of pathogens by complement. In other cases, specific partial immunoglobulin (Ig) G–mediated immu-nity was produced during prior exposure to the pathogen or a new IgM-mediated immunity develops during the course of the infection. Specific immunity can be either cell mediated or antibody mediated and may be enhanced by endogenously produced cytokines. Exogenously ad-ministered cytokines also may prove clinically useful as adjuncts to antibiotic chemotherapy.

Sepsis

Sepsis, or SIRS, is a maladaptive reaction to severe in-fection in which a variety of inflammatory mediators are released. Some of these mediators are bacterial metabolic products, while others are cytokines pro-duced by humans during infection or other inflamma-tory disease. These mediators can induce failure of sev-eral organ systems. Cardiac function can be suppressed; acute respiratory distress syndrome can occur; renal failure is common; and disseminated intravascular co-agulation can occur.

Through their ability to cause cell lysis, antibiotics such as the β-lactams or aminoglycosides may increase the release of bacterial inflammatory mediators (e.g., gram-negative bacillary endotoxin). Antibiotics also may induce the release of endogenous cytokines, such as interleukin (IL) 1- , IL-6, and tumor necrosis factor (TNF-α ) from monocytes and IL-4 and IFN- from lymphocytes. These cytokines are important in inflam-matory and immunological responses and may con-tribute to the development of SIRS. Alternatively, these cytokines also may enhance immune function and en-hance antimicrobial activity. Although many drugs have been examined for their ability to reverse SIRS, no clin-ical studies of interventions in sepsis have yet been shown to significantly lessen mortality.

Resistance

Some pathogens are naturally resistant to certain chemotherapeutic drugs. Resistance can occur through mutation, adaptation, or gene transfer. The mechanisms accounting for innate and acquired resistance are es-sentially the same. Spontaneous mutation in bacterial cells occurs at a frequency of approximately one per million cells. Such mutations may confer resistance to the chemotherapeutic drug. Spontaneous mutation is not a major concern unless the use of the drug results in selection and proliferation of resistant mutant pathogens in the patient.

Resistance to an antibiotic can be the result of one or more mechanisms. Alterations in the lipopolysaccha-ride structure of gram-negative bacilli can affect the up-take of lipophilic drugs. Similarly, changes in porins can affect the uptake of hydrophilic drugs. Once the drug enters the cell, it may be enzymatically inactivated. Some bacteria possess pumps that remove drugs from the bacterial cytosol. The antibiotic also may be ineffec-tive as a result of mutation of genes coding for the tar-get site (e.g., penicillin-binding proteins, DNA gyrase, or ribosomal proteins).

It is clinically important to understand the nature of the mechanism of resistance to an antibiotic drug. For example, the β-lactam resistance of Streptococcus pneu-moniae is due to the appearance of altered penicillin-binding proteins. Thus, the use of a combination of a β-lactam and a penicillinase inhibitor, such as clavulanate, will not overcome streptococcal β-lactam resistance, be-cause the mechanism of resistance is not due to the production of a penicillinase.

Multiple resistance may occur. Such resistance is rec-ognized as a major problem in controlling bacterial in-fections and may be either chromosome or plasmid me-diated. Plasmids (extrachromosomal genetic elements), which code for enzymes that inactivate antimicrobials, can be transferred by conjugation and transduction from resistant bacteria to previously sensitive bacteria. Such a transfer can also occur between unrelated species of bacteria. Enzymes coded by plasmids (e.g., penicillinase, cephalosporinase, and acetylases) that are specific for a given antimicrobial inactivate the drug either by re-moval or addition of a chemical group from the mole-cule or by breaking a chemical bond. Transposons are segments of genetic material with insertion sequences at the end of the gene; these sequences allow genes from one organism to be easily inserted into the genetic ma-terial of another organism. Some of these transposons code for antibiotic resistance.

In vitro laboratory tests of sensitivity of a microor-ganism to specific antimicrobial agents are used to pre-dict efficacy in vivo. Often, it is enough to identify the causative pathogen in culture; the general resistance pattern of the pathogen and local patterns of resistance of the pathogen may then allow proper choice of chemotherapy. It is sometimes helpful to measure the antibiotic sensitivity of the specific isolated pathogen. Generally, a battery of tests against a selection of possi-ble antibiotic drugs is employed.

Some organisms, such as Staphylococcus aureus, Neisseria gonorrhoeae, and Haemophilus influenzae, may produce β-lactamase and therefore be resistant to penicillin and its congeners. Testing for β-lactamase pro-duction by isolates enables an early decision on the use of penicillin and congeners in treatment of the disease.

Lethal Versus Inhibitory Effects

Antibiotics can be classified according to their effects on the biochemistry or molecular biology of pathogens. There are ribosomal inhibitors (macrolides), cell wall disrupters ( β-lactams), DNA disturbers (fluoroquino-lones), and metabolic poisons (trimethoprim-sulfa-methoxazole). Antibiotics also can be classified accord-ing to whether they are static (inhibitory) or cidal (lethal). The classification of drugs as either static or cidal is based on laboratory assessment of the interac-tion of pathogen and antibiotic drug.

Cidal effects can be a result of the disruption of the cell wall or membrane. Cell lysis may occur when water diffuses into the high-osmolarity bacterial cytosol through the antibiotic-induced holes in the membrane, causing the bacteria to swell and burst. Cidal effects also can occur as a consequence of inhibition of bacterial DNA replication or transcription.

Static effects occur when the toxic effects of a chemotherapeutic drug are reversible. For example, inhibition of folate synthesis interferes with methylation, an important biochemical synthetic process. Reversal of this static effect can occur when the antibiotic concentration falls or if a compensatory increase in the synthesis of the inhibited enzymes occurs. The static versus cidal designa-tion is a false dichotomy, since there is a continuous spec-trum of activity between the two categories. The place of a drug along this spectrum will depend on both the phar-macological properties of the drug and such clinical fac-tors as immune system function, inoculum size, drug concentration in tissue, and duration of therapy. A cidal drug may prove to be merely static if an inappropriately low dose or short treatment course is prescribed. A static drug may be cidal if given in high doses for prolonged courses to exquisitely sensitive pathogens.