Is Double Coverage of Gram-Negative Organisms Necessary?
Is Double Coverage of Gram-Negative Organisms Necessary?
Purpose. The appropriateness of combination therapy for infections caused by gram-negative organisms is examined.
Summary. Mortality from Pseudomonas aeruginosa infection is particularly high; therefore, empirical regimens are often selected to ensure coverage for this organism. The initial use of combination antimicrobial therapy for gram-negative infections is usually justified by one of three reasons: the potential for synergistic activity between two classes of antimicrobial agents, the broad empirical coverage provided by two antimicrobial agents with differing spectra of activity and resistance patterns, or the prevention of resistance development during antimicrobial therapy. Disadvantages of using combination therapy are increased drug toxicity, increased costs, and increased risk of superinfection with more-resistant bacteria or fungi. There are no clinical data that suggest that the combination of a β-lactam plus a fluoroquinolone results in improved patient outcomes compared with a β-lactam alone or a β-lactam plus an aminoglycoside. Results from studies that evaluate combination therapy versus monotherapy for gram-negative bacilli conflict with the common practice of use of double coverage. Strong evidence to support the administration of antimicrobials for double coverage of gram-negative organisms is lacking. Antimicrobial overuse may lead to antibiotic resistance, unnecessary adverse effects, and increased costs.
Conclusion. The available clinical evidence does not support the routine use of combination antimicrobial therapy for treatment of gram-negative infections. Patients with shock or neutropenia may benefit from combination therapy that includes an aminoglycoside.
Infections caused by gram-negative bacilli typically occur in the lungs, in the urinary tract, at surgical sites, and in the bloodstream and are a significant cause of morbidity and mortality. The gram-negative bacilli most commonly responsible for infection in humans are Enterobacter species, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Acinetobacter species, and Serratia marcescens. Depending on the site of infection and a patient's comorbid conditions, mortality related to infections caused by gram-negative bacilli ranges from 20% to 60%. Inappropriate initial antimicrobial therapy and a delay in drug administration are associated with poorer patient outcomes.
When a patient is suspected of having a gram-negative infection, initial antimicrobial coverage is often directed at P. aeruginosa, because this pathogen has been associated with higher mortality rates compared with other gram-negative organisms. Initial antimicrobial regimens often include two agents that are active against P. aeruginosa. The rationale for prescribing two antimicrobial agents originates from a 1989 study that found significantly lower mortality rates among patients who received combination therapy versus monotherapy (27% versus 47%, p < 0.02); however, most of the patients receiving monotherapy were treated with an aminoglycoside. This study was published when aminoglycosides and β-lactam antibiotics were the primary agents available to treat infections caused by P. aeruginosa. The results of the study are not pertinent to current practice for several reasons: (1) aminoglycosides are now dosed based on their pharmacokinetic and pharmacodynamic parameters, (2) fluoroquinolones have largely replaced aminoglycosides as the agents used in combination with β-lactam antibiotics, and (3) susceptibilities of the targeted microorganisms have changed over the years. Regardless of these factors, clinicians often prescribe two antibiotics for coverage of infections caused by P. aeruginosa. The usual regimens consist of a β-lactam antibiotic (i.e., antipseudomonal penicillin, third- or fourth-generation antipseudomonal cephalosporin, carbapenem, or aztreonam), plus an aminoglycoside or a fluoroquinolone. All of these agents have activity against P. aeruginosa; however, resistance mechanisms have been identified for these antipseudomonal antibiotics, and resistance to all of these agents is increasing.
The use of combination therapy to treat gram-negative infections remains controversial. Results from studies that compared the efficacy of combination therapy with that of monotherapy against gram-negative bacilli conflict. Strong evidence to support the use of two antimicrobials to treat gram-negative organisms is lacking. Unnecessary antimicrobial use may lead to antimicrobial resistance, increased adverse effects, and increased costs. No guidelines exist regarding double coverage of extended-spectrum β-lactamase-producing gram-negative organisms, and guidelines issued by the Infectious Diseases Society of America (IDSA) for the treatment of febrile neutropenic patients do not recommend combination therapy as first-line treatment. Similarly, the IDSA–American Thoracic Society guidelines for the treatment of hospital-acquired pneumonia recommend empirical combination therapy for late-onset pneumonia only or in patients at risk for multidrug-resistant pathogens. This article examines the appropriateness of combination therapy for gram-negative infections.
Abstract and Introduction
Abstract
Purpose. The appropriateness of combination therapy for infections caused by gram-negative organisms is examined.
Summary. Mortality from Pseudomonas aeruginosa infection is particularly high; therefore, empirical regimens are often selected to ensure coverage for this organism. The initial use of combination antimicrobial therapy for gram-negative infections is usually justified by one of three reasons: the potential for synergistic activity between two classes of antimicrobial agents, the broad empirical coverage provided by two antimicrobial agents with differing spectra of activity and resistance patterns, or the prevention of resistance development during antimicrobial therapy. Disadvantages of using combination therapy are increased drug toxicity, increased costs, and increased risk of superinfection with more-resistant bacteria or fungi. There are no clinical data that suggest that the combination of a β-lactam plus a fluoroquinolone results in improved patient outcomes compared with a β-lactam alone or a β-lactam plus an aminoglycoside. Results from studies that evaluate combination therapy versus monotherapy for gram-negative bacilli conflict with the common practice of use of double coverage. Strong evidence to support the administration of antimicrobials for double coverage of gram-negative organisms is lacking. Antimicrobial overuse may lead to antibiotic resistance, unnecessary adverse effects, and increased costs.
Conclusion. The available clinical evidence does not support the routine use of combination antimicrobial therapy for treatment of gram-negative infections. Patients with shock or neutropenia may benefit from combination therapy that includes an aminoglycoside.
Introduction
Infections caused by gram-negative bacilli typically occur in the lungs, in the urinary tract, at surgical sites, and in the bloodstream and are a significant cause of morbidity and mortality. The gram-negative bacilli most commonly responsible for infection in humans are Enterobacter species, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Acinetobacter species, and Serratia marcescens. Depending on the site of infection and a patient's comorbid conditions, mortality related to infections caused by gram-negative bacilli ranges from 20% to 60%. Inappropriate initial antimicrobial therapy and a delay in drug administration are associated with poorer patient outcomes.
When a patient is suspected of having a gram-negative infection, initial antimicrobial coverage is often directed at P. aeruginosa, because this pathogen has been associated with higher mortality rates compared with other gram-negative organisms. Initial antimicrobial regimens often include two agents that are active against P. aeruginosa. The rationale for prescribing two antimicrobial agents originates from a 1989 study that found significantly lower mortality rates among patients who received combination therapy versus monotherapy (27% versus 47%, p < 0.02); however, most of the patients receiving monotherapy were treated with an aminoglycoside. This study was published when aminoglycosides and β-lactam antibiotics were the primary agents available to treat infections caused by P. aeruginosa. The results of the study are not pertinent to current practice for several reasons: (1) aminoglycosides are now dosed based on their pharmacokinetic and pharmacodynamic parameters, (2) fluoroquinolones have largely replaced aminoglycosides as the agents used in combination with β-lactam antibiotics, and (3) susceptibilities of the targeted microorganisms have changed over the years. Regardless of these factors, clinicians often prescribe two antibiotics for coverage of infections caused by P. aeruginosa. The usual regimens consist of a β-lactam antibiotic (i.e., antipseudomonal penicillin, third- or fourth-generation antipseudomonal cephalosporin, carbapenem, or aztreonam), plus an aminoglycoside or a fluoroquinolone. All of these agents have activity against P. aeruginosa; however, resistance mechanisms have been identified for these antipseudomonal antibiotics, and resistance to all of these agents is increasing.
The use of combination therapy to treat gram-negative infections remains controversial. Results from studies that compared the efficacy of combination therapy with that of monotherapy against gram-negative bacilli conflict. Strong evidence to support the use of two antimicrobials to treat gram-negative organisms is lacking. Unnecessary antimicrobial use may lead to antimicrobial resistance, increased adverse effects, and increased costs. No guidelines exist regarding double coverage of extended-spectrum β-lactamase-producing gram-negative organisms, and guidelines issued by the Infectious Diseases Society of America (IDSA) for the treatment of febrile neutropenic patients do not recommend combination therapy as first-line treatment. Similarly, the IDSA–American Thoracic Society guidelines for the treatment of hospital-acquired pneumonia recommend empirical combination therapy for late-onset pneumonia only or in patients at risk for multidrug-resistant pathogens. This article examines the appropriateness of combination therapy for gram-negative infections.
