Page 924 - Basic _ Clinical Pharmacology ( PDFDrive )

910 SECTION VIII Chemotherapeutic Drugs

ANTIMICROBIAL (eg, β-lactams and vancomycin). For drugs whose killing action is
PHARMACODYNAMICS concentration-dependent, the rate and extent of killing increase
with increasing drug concentrations. Concentration-dependent
The time course of drug concentration is closely related to the killing is one of the pharmacodynamic factors responsible for the
antimicrobial effect at the site of infection and to any toxic effects. efficacy of once-daily dosing of aminoglycosides. For drugs whose
Pharmacodynamic factors include pathogen susceptibility testing, killing action is time-dependent, bactericidal activity continues as
drug bactericidal versus bacteriostatic activity, drug synergism, long as serum concentrations are greater than the MBC.
antagonism, and postantibiotic effects. Together with pharmaco-
kinetics, pharmacodynamic information permits the selection of Postantibiotic Effect
optimal antimicrobial dosage regimens. Persistent suppression of bacterial growth after limited exposure to
an antimicrobial agent is known as the postantibiotic effect (PAE).
Bacteriostatic versus Bactericidal Activity The PAE can be expressed mathematically as follows:
Antibacterial agents may be classified as bacteriostatic or bacte-
ricidal (Table 51–3). For agents that are primarily bacteriostatic, PAE = T – C
inhibitory drug concentrations are much lower than bactericidal where T is the time required for the viable count in the test (in
drug concentrations. In general, cell wall-active agents are bacte- vitro) culture to increase tenfold above the count observed imme-
ricidal, and drugs that inhibit protein synthesis are bacteriostatic. diately before drug removal and C is the time required for the
The classification of antibacterial agents as bactericidal or bac- count in an untreated culture to increase tenfold above the count
teriostatic has limitations. Some agents that are considered to be observed immediately after completion of the same procedure
bacteriostatic may be bactericidal against selected organisms. On used on the test culture. The PAE reflects the time required for
the other hand, enterococci are inhibited but not killed by vanco- bacteria to return to logarithmic growth.
mycin, penicillin, or ampicillin used as single agents. Proposed mechanisms include (1) slow recovery after reversible
Bacteriostatic and bactericidal agents are equivalent for the nonlethal damage to cell structures; (2) persistence of the drug at
treatment of most infectious diseases in immunocompetent a binding site or within the periplasmic space; and (3) the need
hosts. Bactericidal agents should be selected over bacteriostatic to synthesize new enzymes before growth can resume. Most anti-
ones in circumstances in which local or systemic host defenses microbials possess significant in vitro PAEs (≥1.5 hours) against
are impaired. Bactericidal agents are required for treatment of susceptible Gram-positive cocci (Table 51–4). Antimicrobials
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 TABLE 51–4 Antibacterial agents with in vitro
and quinolones) and agents that exhibit time-dependent killing postantibiotic effects ≥1.5 hours.
Against Gram-Positive Cocci Against Gram-Negative Bacilli
Aminoglycosides Aminoglycosides
TABLE 51–3 Bactericidal and bacteriostatic
antibacterial agents. Carbapenems Carbapenems
Cephalosporins Chloramphenicol
Bactericidal Agents Bacteriostatic Agents Chloramphenicol Quinolones
Aminoglycosides Chloramphenicol Clindamycin Rifampin
Bacitracin Clindamycin Daptomycin Tetracyclines
β-Lactam antibiotics Ethambutol Glycopeptide antibiotics Tigecycline
Daptomycin Macrolides Ketolides
Fosfomycin Nitrofurantoin Macrolides
Glycopeptide antibiotics Novobiocin Oxazolidinones
Isoniazid Oxazolidinones Penicillins
Ketolides Sulfonamides Quinolones
Metronidazole Tetracyclines Rifampin
Polymyxins Tigecycline Streptogramins
Pyrazinamide Trimethoprim Sulfonamides
Quinolones Tetracyclines
Rifampin Tigecycline
Streptogramins Trimethoprim