Page 927 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 51 Clinical Use of Antimicrobial Agents 913

a penicillin or vancomycin. When tested alone, penicillins and antagonize the action of bactericidal cell wall-active agents
vancomycin are only bacteriostatic against susceptible enterococ- because cell wall-active agents require that the bacteria be
cal isolates. When these agents are combined with an amino- actively growing and dividing.
glycoside, however, bactericidal activity results. The addition of 2. Induction of enzymatic inactivation: Some Gram-negative bacilli,
gentamicin or streptomycin to penicillin allows for a reduction in including Enterobacter species, P aeruginosa, Serratia marcescens,
the duration of therapy for selected patients with viridans strepto- and Citrobacter freundii, possess inducible β-lactamases. β-Lactam
coccal endocarditis. antibiotics such as imipenem, cefoxitin, and ampicillin are potent
Other synergistic antimicrobial combinations have been shown inducers of β-lactamase production. If an inducing agent is com-
to be more effective than monotherapy with individual compo- bined with an intrinsically active but hydrolyzable β-lactam such
nents. Trimethoprim-sulfamethoxazole has been successfully used as piperacillin, antagonism may result.
in the treatment of bacterial infections and P jiroveci (carinii)
*
pneumonia. β-Lactamase inhibitors restore the activity of intrin-
sically active but hydrolyzable β lactams against organisms such as ANTIMICROBIAL
Staphylococcus aureus and Bacteroides fragilis. Three major mecha- ■
nisms of antimicrobial synergism have been established: PROPHYLAXIS
1. Blockade of sequential steps in a metabolic sequence: Antimicrobial agents are effective in preventing infections in
Trimethoprim-sulfamethoxazole is the best-known example of many settings. Antimicrobial prophylaxis should be used in cir-
this mechanism of synergy (see Chapter 46). Blockade of the cumstances in which efficacy has been demonstrated and benefits
two sequential steps in the folic acid pathway by trimethoprim- outweigh the risks of prophylaxis. Antimicrobial prophylaxis may
sulfamethoxazole results in a much more complete inhibition be divided into surgical prophylaxis and nonsurgical prophylaxis.
of growth than achieved by either component alone.
2. Inhibition of enzymatic inactivation: Enzymatic inactivation Surgical Prophylaxis
of β-lactam antibiotics is a major mechanism of antibiotic
resistance. Inhibition of β lactamase by β-lactamase inhibitor Surgical wound infections are a major category of nosocomial
drugs (eg, sulbactam) results in synergism. infections. The estimated annual cost of surgical wound infections
3. Enhancement of antimicrobial agent uptake: Penicillins and in the USA is more than $1.5 billion.
other cell wall-active agents can increase the uptake of amino- The National Research Council (NRC) Wound Classification
glycosides by a number of bacteria, including staphylococci, Criteria have served as the basis for recommending antimicrobial
enterococci, streptococci, and P aeruginosa. Enterococci are prophylaxis. NRC criteria consist of four classes (see Box: National
thought to be intrinsically resistant to aminoglycosides because Research Council [NRC] Wound Classification Criteria).
of permeability barriers. Similarly, amphotericin B is thought The Study of the Efficacy of Nosocomial Infection Control
to enhance the uptake of flucytosine by fungi. (SENIC) identified four independent risk factors for postop-
erative wound infections: operations on the abdomen, operations
lasting more than 2 hours, contaminated or dirty wound classifi-
Mechanisms of Antagonistic Action cation, and at least three medical diagnoses. Patients with at least

There are few clinically relevant examples of antimicrobial two SENIC risk factors who undergo clean surgical procedures
antagonism. The most striking example was reported in a study of have an increased risk of developing surgical wound infections and
patients with pneumococcal meningitis. Patients who were treated should receive antimicrobial prophylaxis.
with the combination of penicillin and chlortetracycline had a Surgical procedures that necessitate the use of antimicrobial
mortality rate of 79% compared with a mortality rate of 21% in prophylaxis include contaminated and clean-contaminated opera-
patients who received penicillin monotherapy (illustrating the first tions, selected operations in which postoperative infection may
mechanism set forth below). be catastrophic such as open heart surgery, clean procedures that
The use of an antagonistic antimicrobial combination does involve placement of prosthetic materials, and any procedure
not preclude other potential beneficial interactions. For example, in an immunocompromised host. The operation should carry a
rifampin may antagonize the action of anti-staphylococcal penicil- significant risk of postoperative site infection or cause significant
lins or vancomycin against staphylococci. However, the aforemen- bacterial contamination.
tioned antimicrobials may prevent the emergence of resistance to General principles of antimicrobial surgical prophylaxis include
rifampin. the following:
Two major mechanisms of antimicrobial antagonism have been 1. The antibiotic should be active against common surgical
established: wound pathogens; unnecessarily broad coverage should be
1. Inhibition of cidal activity by static agents: Bacteriostatic avoided.
agents such as tetracyclines and chloramphenicol can 2. The antibiotic should have proved efficacy in clinical trials.
3. The antibiotic must achieve concentrations greater than the
* MIC of suspected pathogens, and these concentrations must be
Pneumocystis jiroveci is a fungal organism found in humans (P carinii
infects animals) that responds to antiprotozoal drugs. See Chapter 52. present at the time of incision.