CLINICAL PHARMACOLOGY OF ANTIBACTERIAL  AGENTS

(part II)(part II)

Clinical Use of Antimicrobial Agents

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

Antimicrobial Therapy

Choice of Antimicrobial Agent

Choice of Antimicrobial Agent• Selection from among several drugs depends on Selection from among several drugs depends on host host

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

• Contraindicated in Contraindicated in Renal ImpairmentRenal Impairment  

Dosage Adjustment Needed in Hepatic Impairment • Amprenavir, Amprenavir,

atazanavir, atazanavir, chloramphenicol, chloramphenicol, clindamycin, clindamycin, erythromycin, erythromycin, fosamprenavir, fosamprenavir, indinavir, indinavir, metronidazole, metronidazole, rimantadine, rimantadine, tigecycline tigecycline

Drug Concentrations in Body Fluids

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

Drug Concentrations in Body Fluids• Most antimicrobial agents are Most antimicrobial agents are

well distributed to most body well distributed to most body tissues and fluids. Penetration tissues and fluids. Penetration into the cerebrospinal fluid is into the cerebrospinal fluid is an exception. Most do not an exception. Most do not penetrate uninflamed meninges penetrate uninflamed meninges to an appreciable extent. In the to an appreciable extent. In the presence of meningitis, presence of meningitis, however, the cerebrospinal however, the cerebrospinal fluid concentrations of many fluid concentrations of many antimicrobials increase antimicrobials increase

Monitoring Serum Concentrations of Antimicrobial Agents

Antimicrobial Drug Combinations

Rationale for Combination Antimicrobial Therapy (cont’d)

Rationale for Combination Antimicrobial Therapy (cont’d)

Synergism & Antagonism

Synergistic Action

Antagonistic Action

ANTIMICROBIAL PROPHYLAXIS

ANTIMICROBIAL PROPHYLAXIS

General principles of antimicrobial surgical prophylaxis

• The antibiotic should be active against common surgical The antibiotic should be active against common surgical wound pathogens; unnecessarily broad coverage should be wound pathogens; unnecessarily broad coverage should be avoided.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 The antibiotic must achieve concentrations achieve concentrations greater than the MIC of greater than the MIC of suspected pathogens, and suspected pathogens, and these concentrations must these concentrations must be present at the time of be present at the time of incision.incision.

• The shortest possible The shortest possible course—ideally a single course—ideally a single dose—of the most dose—of the most effective and least toxic effective and least toxic antibiotic should be used.antibiotic should be used.