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 is undiagnosed immunodeficiency, malignancy, or malnutrition present? The presence of abscesses or foreign bodies should also be considered. Finally, culture and susceptibility testing should be repeated to determine whether superinfection has occurred with another organism or whether the original pathogen has developed drug resistance.
The time course of drug concentration is closely related to the antimicrobial effect at the site of infection and to any toxic effects. Pharmacodynamic factors include pathogen susceptibility testing, drug bactericidal versus bacteriostatic activity, drug synergism, antagonism, and postantibiotic effects. Together with pharmacokinetics, pharmacodynamic information permits the selection of optimal antimicrobial dosage regimens.
Antibacterial agents may be classified as bacteriostatic or bactericidal (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 bactericidal, and drugs that inhibit protein synthesis are bacteriostatic.
The classification of antibacterial agents as bactericidal or bacteriostatic 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 vancomycin, 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 endocarditis and other endovascular infections, meningitis, and infections 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
TABLE 51–3 Bactericidal and bacteriostatic antibacterial agents.
(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.
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: where T is the time required for the viable count in the test (in vitro) culture to increase tenfold above the count observed immediately 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 antimicrobials possess significant in vitro PAEs (≥1.5 hours) against susceptible Gram-positive cocci (Table 51–4). Antimicrobials
TABLE 51–4 Antibacterial agents with in vitro postantibiotic effects ≥1.5 hours.
with significant PAEs against susceptible Gram-negative bacilli are limited to carbapenems and agents that inhibit protein or DNA synthesis.