CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AGENTS (part II)

Clinical Use of Antimicrobial Agents The development of antimicrobial drugs represents one of the most important advances in therapeutics, both in the control or cure of serious infections and in the prevention and treatment of infectious complications of other therapeutic modalities such as cancer chemotherapy and surgery. However, evidence is overwhelming that antimicrobial agents are vastly overprescribed in outpatient settings, and the availability of antimicrobial agents without prescription in many developing countries has already severely limited therapeutic options in the treatment of life- threatening infections. Therefore, the clinician should first determine whether antimicrobial therapy is warranted for a given patient.The development of antimicrobial drugs represents one of the most important advances in therapeutics, both in the control or cure of serious infections and in the prevention and treatment of infectious complications of other therapeutic modalities such as cancer chemotherapy and surgery. However, evidence is overwhelming that antimicrobial agents are vastly overprescribed in outpatient settings, and the availability of antimicrobial agents without prescription in many developing countries has already severely limited therapeutic options in the treatment of life- threatening infections. Therefore, the clinician should first determine whether antimicrobial therapy is warranted for a given patient.

Antimicrobial Therapy

Choice of Antimicrobial Agent

Selection from among several drugs depends on host factors that include the following: (1) concomitant disease states (eg, AIDS, neutropenia due to the use of cytotoxic chemotherapy; severe chronic liver or kidney disease) or the use of immunosuppressive medications; (2) prior adverse drug effects; (3) impaired elimination or detoxification of the drug (may be genetically predetermined but more frequently is associated with impaired renal or hepatic function due to underlying disease); (4) age of the patient; (5) pregnancy status; and (6) epidemiologic exposure (eg, exposure to a sick family member or pet, recent hospitalization, recent travel, occupational exposure, or new sexual partner).Selection from among several drugs depends on host factors that include the following: (1) concomitant disease states (eg, AIDS, neutropenia due to the use of cytotoxic chemotherapy; severe chronic liver or kidney disease) or the use of immunosuppressive medications; (2) prior adverse drug effects; (3) impaired elimination or detoxification of the drug (may be genetically predetermined but more frequently is associated with impaired renal or hepatic function due to underlying disease); (4) age of the patient; (5) pregnancy status; and (6) epidemiologic exposure (eg, exposure to a sick family member or pet, recent hospitalization, recent travel, occupational exposure, or new sexual partner).

Guiding Antimicrobial Therapy of Established Infections

AmoxicillinAmoxicillin MoxifloxacinMoxifloxacin CotrimCotrim CefuroximeCefuroxime AzithromycinAzithromycin

Post-Antibiotic Effect

Bactericidal & Bacteriostatic Activity

Antimicrobial Agents that Require Dosage Adjustment or Are Contraindicated in Patients with Renal or Hepatic Impairment Dosage Adjustment Needed in Renal ImpairmentDosage Adjustment Needed in Renal Impairment Contraindicated in Renal ImpairmentContraindicated in Renal Impairment

Dosage Adjustment Needed in Hepatic Impairment Amprenavir, atazanavir, chloramphenicol, clindamycin, erythromycin, fosamprenavir, indinavir, metronidazole, rimantadine, tigecyclineAmprenavir, atazanavir, chloramphenicol, clindamycin, erythromycin, fosamprenavir, indinavir, metronidazole, rimantadine, tigecycline

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 increaseMost 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

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 increaseMost 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

Monitoring Serum Concentrations of Antimicrobial Agents

Antimicrobial Drug Combinations

Rationale for Combination Antimicrobial Therapy (cont’d)

Synergism & Antagonism

Synergistic Action

Antagonistic Action

ANTIMICROBIAL PROPHYLAXIS

General principles of antimicrobial surgical prophylaxis The antibiotic should be active against common surgical wound pathogens; unnecessarily broad coverage should be avoided.The antibiotic should be active against common surgical wound pathogens; unnecessarily broad coverage should be avoided. The antibiotic should have proved efficacy in clinical trials.The antibiotic should have proved efficacy in clinical trials.

General principles of antimicrobial surgical prophylaxis The antibiotic must achieve concentrations greater than the MIC of suspected pathogens, and these concentrations must be present at the time of incision.The antibiotic must achieve concentrations greater than the MIC of suspected pathogens, and these concentrations must be present at the time of incision. The shortest possible course—ideally a single dose—of the most effective and least toxic antibiotic should be used.The shortest possible course—ideally a single dose—of the most effective and least toxic antibiotic should be used.