Antimicrobial Therapy of Infections with Known Etiology

ANTIMICROBIAL THERAPY OF INFECTIONS WITH KNOWN ETIOLOGY

INTERPRETATION OF CULTURE RESULTS

Properly obtained and processed specimens for culture frequently yield reliable information about the cause of infection. The lack of a confirmatory microbiologic diagnosis may be due to the following:

1. Sample error, eg, obtaining cultures after antimicrobial agents have been administered, or contamination of specimens sent for culture

2. Noncultivable or slow-growing organisms (Histoplasma capsula-tum, Bartonella or Brucella species), in which cultures are oftendiscarded before sufficient growth has occurred for detection

3. Requesting bacterial cultures when infection is due to other organisms

4. Not recognizing the need for special media or isolation tech-niques (eg, charcoal yeast extract agar for isolation of legion-ella species, shell-vial tissue culture system for rapid isolation of cytomegalovirus)

Even in the setting of a classic infectious disease for which isolation techniques have been established for decades (eg, pneu-mococcal pneumonia, pulmonary tuberculosis, streptococcal pharyngitis), the sensitivity of the culture technique may be inad-equate to identify all cases of the disease.

GUIDING ANTIMICROBIAL THERAPY OF ESTABLISHED INFECTIONS

Susceptibility Testing

Testing bacterial pathogens in vitro for their susceptibility to anti-microbial agents is extremely valuable in confirming susceptibility, ideally to a narrow-spectrum nontoxic antimicrobial drug. Tests measure the concentration of drug required to inhibit growth of the organism (minimal inhibitory concentration [MIC]) or to kill the organism (minimal bactericidal concentration [MBC]).

The results of these tests can then be correlated with known drug concentrations in various body compartments. Only MICs areroutinely measured in most infections, whereas in infections in which bactericidal therapy is required for eradication of infection (eg, meningitis, endocarditis, sepsis in the granulocytopenic host), MBC measurements occasionally may be useful.

Specialized Assay Methods

A. Beta-Lactamase Assay

For some bacteria (eg, Haemophilus species), the susceptibility pat-terns of strains are similar except for the production of β lacta-mase. In these cases, extensive susceptibility testing may not be required, and a direct test for β lactamase using a chromogenic β-lactam substrate (nitrocephin disk) may be substituted.

B. Synergy Studies

Synergy studies are in vitro tests that attempt to measure synergis-tic, additive, indifferent, or antagonistic drug interactions. In general, these tests have not been standardized and have not cor-related well with clinical outcome. (See section on Antimicrobial Drug Combinations for details.)

MONITORING THERAPEUTIC RESPONSE: DURATION OF THERAPY

The therapeutic response may be monitored microbiologically or clinically. Cultures of specimens taken from infected sites should eventually become sterile or demonstrate eradication of the patho-gen and are useful for documenting recurrence or relapse. Follow-up cultures may also be useful for detecting superinfec-tions or the development of resistance. Clinically, the patient’s systemic manifestations of infection (malaise, fever, leukocytosis) should abate, and the clinical findings should improve (eg, as shown by clearing of radiographic infiltrates or lessening hypox-emia in pneumonia).

The duration of definitive therapy required for cure depends on the pathogen, the site of infection, and host factors (immunocom-promised patients generally require longer courses of treatment). Precise data on duration of therapy exist for some infections (eg, streptococcal pharyngitis, syphilis, gonorrhea, tuberculosis, and cryptococcal meningitis). In many other situations, duration of therapy is determined empirically. For recurrent infections (eg, sinus-itis, urinary tract infections), longer courses of antimicrobial therapy or surgical intervention are frequently necessary for eradication.

Clinical Failure of Antimicrobial Therapy

When the patient has an inadequate clinical or microbiologic response to antimicrobial therapy selected by in vitro susceptibility testing, systematic investigation should be undertaken to deter-mine the cause of failure. Errors in susceptibility testing are rare, but the original results should be confirmed by repeat testing. Drug dosing and absorption should be scrutinized and tested directly using serum measurements, pill counting, or directly observed therapy.

The clinical data should be reviewed to determine whether the patient’s immune function is adequate and, if not, what can be done to maximize it. For example, are adequate numbers of granulocytes present and are HIV infection, malnutrition, or underlying malignancy present? The presence of abscesses or for-eign bodies should also be considered. Finally, culture and suscep-tibility testing should be repeated to determine whether superinfection has occurred with another organism or whether the original pathogen has developed drug resistance.

ANTIMICROBIAL PHARMACODYNAMICS

The time course of drug concentration is closely related to the anti-microbial effect at the site of infection and to any toxic effects. Pharmacodynamic factors include pathogen susceptibility testing, drug bactericidal versus bacteriostatic activity, drug synergism, antag-onism, and postantibiotic effects. Together with pharmacokinetics,pharmacodynamic information permits the selection of optimal anti-microbial dosage regimens.

Bacteriostatic versus Bactericidal Activity

Antibacterial agents may be classified as bacteriostatic or bacteri-cidal (Table 51–3). For agents that are primarily bacteriostatic, inhibitory drug concentrations are much lower than bactericidal drug concentrations. In general, cell wall-active agents are bacteri-cidal, and drugs that inhibit protein synthesis are bacteriostatic.

The classification of antibacterial agents as bactericidal or bac-teriostatic has limitations. Some agents that are considered to be bacteriostatic may be bactericidal against selected organisms. On the other hand, enterococci are inhibited but not killed by vanco-mycin, penicillin, or ampicillin used as single agents.

Bacteriostatic and bactericidal agents are equivalent for the treatment of most infectious diseases in immunocompetent hosts. Bactericidal agents should be selected over bacteriostatic ones in circumstances in which local or systemic host defenses are impaired. Bactericidal agents are required for treatment of endo-carditis and other endovascular infections, meningitis, and infec-tions in neutropenic cancer patients.

Bactericidal agents can be divided into two groups: agents that exhibit concentration-dependent killing (eg, aminoglycosides and quinolones) and agents that exhibit time-dependent killing (eg, β lactams and vancomycin). For drugs whose killing action is concentration-dependent, the rate and extent of killing increase with increasing drug concentrations. Concentration-dependent killing is one of the pharmacodynamic factors responsible for the efficacy of once-daily dosing of aminoglycosides.

For drugs whose killing action is time-dependent, bactericidal activity continues as long as serum concentrations are greater than the MBC. Drug concentrations of time-dependent killing agents that lack a postantibiotic effect should be maintained above the MIC for the entire interval between doses.

Postantibiotic Effect

Persistent suppression of bacterial growth after limited exposure to an antimicrobial agent is known as the postantibiotic effect (PAE). The PAE can be expressed mathematically as follows:

PAE = T – C

where T is the time required for the viable count in the test (in vitro) culture to increase tenfold above the count observed imme-diately before drug removal and C is the time required for the count in an untreated culture to increase tenfold above the count observed immediately after completion of the same procedure used on the test culture. The PAE reflects the time required for bacteria to return to logarithmic growth.

Proposed mechanisms include (1) slow recovery after reversible nonlethal damage to cell structures; (2) persistence of the drug at a binding site or within the periplasmic space; and (3) the need to synthesize new enzymes before growth can resume. Most antimi-crobials possess significant in vitro PAEs (≥ 1.5 hours) against susceptible gram-positive cocci (Table 51–4). Antimicrobials with significant PAEs against susceptible gram-negative bacilli are lim-ited to carbapenems and agents that inhibit protein or DNA synthesis.

In vivo PAEs are usually much longer than in vitro PAEs. This is thought to be due to postantibiotic leukocyte enhancement(PALE) and exposure of bacteria to subinhibitory antibiotic con-centrations. The efficacy of once-daily dosing regimens is in part due to the PAE. Aminoglycosides and quinolones possess concen-tration-dependent PAEs; thus, high doses of aminoglycosides given once daily result in enhanced bactericidal activity and extended PAEs. This combination of pharmacodynamic effects allows aminoglycoside serum concentrations that are below the MICs of target organisms to remain effective for extended periods of time.

PHARMACOKINETIC CONSIDERATIONS

Route of Administration

Many antimicrobial agents have similar pharmacokinetic proper-ties when given orally or parenterally (ie, tetracyclines, trimetho-prim-sulfamethoxazole, quinolones, chloramphenicol, metronid-azole, clindamycin, rifampin, linezolid, and fluconazole). In most cases, oral therapy with these drugs is equally effective, is less costly, and results in fewer complications than parenteral therapy.

The intravenous route is preferred in the following situations: (1) for critically ill patients; (2) for patients with bacterial menin-gitis or endocarditis; (3) for patients with nausea, vomiting, gast-rectomy, or diseases that may impair oral absorption; and (4) when giving antimicrobials that are poorly absorbed following oral administration.

Conditions That Alter Antimicrobial Pharmacokinetics

Various diseases and physiologic states alter the pharmacokinetics of antimicrobial agents. Impairment of renal or hepatic function may result in decreased elimination. Table 51–5 lists drugs that require dosage reduction in patients with renal or hepatic insuffi-ciency. Failure to reduce antimicrobial agent dosage in such patients may cause toxic effects. Conversely, patients with burns, cystic fibrosis, or trauma may have increased dosage requirements for selected agents. The pharmacokinetics of antimicrobials is also altered in the elderly, in neonates, and in pregnancy.

Drug Concentrations in Body Fluids

Most antimicrobial agents are well distributed to most body tissues and fluids. Penetration into the cerebrospinal fluid is an exception. Most do not penetrate uninflamed meninges to an appreciable extent. In the presence of meningitis, however, the cerebrospinal fluid concentrations of many antimicrobials increase (Table 51–6).

Monitoring Serum Concentrations of Antimicrobial Agents

For most antimicrobial agents, the relation between dose and therapeutic outcome is well established, and serum concentration monitoring is unnecessary for these drugs. To justify routine serum concentration monitoring, it should be established (1) that a direct relationship exists between drug concentrations and effi-cacy or toxicity; (2) that substantial interpatient variability exists in serum concentrations on standard doses; (3) that a small differ-ence exists between therapeutic and toxic serum concentrations;that the clinical efficacy or toxicity of the drug is delayed or difficult to measure; and (5) that an accurate assay is available.

In clinical practice, serum concentration monitoring is routinely performed on patients receiving aminoglycosides. Despite the lack of supporting evidence for its usefulness or need, serum vancomycin concentration monitoring is also widespread. Flucytosine serum concentration monitoring has been shown to reduce toxicity when doses are adjusted to maintain peak concen-trations below 100 mcg/mL.