Monotherapy or Combination Therapy?

The Pseudomonas aeruginosa Conundrum

Kristi A. Traugott, Pharm.D.; Kelly Echevarria, Pharm.D.; Pamela Maxwell, Pharm.D.; Kay Green, B.S.; James S. Lewis, II, Pharm.D.

Disclosures

Pharmacotherapy. 2011;31(6):598-608. 

In This Article

Abstract and Introduction

Abstract

The use of combination antibiotic therapy for severe pseudomonal infections is a standard practice in many hospitals; however, the data supporting its use are somewhat unclear. Possible benefits of combination therapy for Pseudomonas aeruginosa infections include in vitro antibiotic synergy, prevention of the emergence of bacterial resistance while receiving therapy, and improved adequacy of empiric therapy. Unfortunately, the potential disadvantages are also considerable, the most worrisome of which are drug toxicity and creation of multidrug-resistant organisms in the environment. Many in vitro and animal studies have attempted to shed light on this clinically challenging issue; however, these studies have often yielded conflicting results and used different study methods, which limits the clinical utility of the results. Clinical studies have also attempted to clarify this issue, particularly in patients with serious pseudomonal infections such as bacteremia and ventilator-associated pneumonia, but again, often resulted in conflicting conclusions. Thus, we performed a MEDLINE search (1950–May 2010) of clinical and in vitro studies evaluating the use of antibiotic combination therapy and monotherapy for bacteremia and pneumonia due to P. aeruginosa. Although a clear answer still eludes this controversy, combination therapy for seriously ill patients suspected of having pseudomonal infection has been shown, with considerable evidence, to improve the likelihood of an active agent being included in the initial antibiotic regimen of these patients. The clinical status of the patient and true likelihood of encountering a multidrug-resistant organism should be evaluated before deciding on empiric combination therapy. Future research may be able to better identify which patient populations might receive the most benefit from combination therapy rather than using combination therapy for everyone at risk for these infections.

Introduction

During the 1960s, Pseudomonas aeruginosa emerged as a major human pathogen, mainly causing infections in immunocompromised patients as well as those with burns or cystic fibrosis.[1] Since then, this pathogen has become the gram-negative bacteria most commonly associated with hospital-acquired infections.[2] With a mortality rate of 18–61%, these infections require optimal management, which remains the subject of considerable controversy.[3]

Pseudomonas aeruginosa causes a variety of infections, including bacteremia, urinary tract infections, hospital-acquired pneumonia, ventilator-associated pneumonia (VAP), skin and soft tissue infections, as well as ear, eye, and throat infections. Recent data from the National Healthcare Safety Network 2008 annual update revealed that P. aeruginosa caused 7.9% of all health care–associated infections from 2006–2007. When broken down by types of infection, P. aeruginosa caused 16.3% of VAPs (second only to Staphylococcus aureus), 10% of catheterassociated urinary tract infections (fourth most common cause), 5.6% of surgical site infections, and 3.1% of central line–associated bloodstream infections.[4]

The rapidity with which patients succumb to severe pseudomonal infections is disturbing, as up to 50% of patients with P. aeruginosa bacteremia die within the first 24–72 hours of diagnosis.[5,6] Further complicating the management of these patients is the limited number of drugs available for treatment of P. aeruginosa infections because of the inherent resistance of this bacteria to multiple antibiotics. In fact, before the release of doripenem in 2007, a new antipseudomonal antibiotic had not come to market in over 10 years. Current antipseudomonal treatment options are listed in Table 1. The ability of P. aeruginosa to use numerous mechanisms of antibacterial resistance and its ability to acquire additional determinants further compound the complexity of managing these patients.[7,8] Many studies have documented increasing resistance among P. aeruginosa isolates. One study identified a significant increase in P.aeruginosa isolates resistant to imipenem and ceftazidime,[9] and another study revealed an increase of multidrug resistance from 4% in 1993 to 14% in 2002.[10] In another study, 120 bacteremic strains of P. aeruginosa were examined, and 64% of strains were found to harbor at least one mechanism of resistance.[11]

This review focuses on the debate regarding antibiotic monotherapy versus combination therapy for two types of serious pseudomonal infections: bacteremia and VAP. Given the impressive mortality rates associated with these infections, as well as the resistance issues associated with P. aeruginosa, it is not difficult to understand why clinicians frequently use combination therapy for these infections. To review the data that support or refute the practice of combination therapy for these infections, we performed a MEDLINE search (1950–May 2010) of clinical and in vitro studies evaluating the use of antibiotic combination therapy and monotherapy for bacteremia and pneumonia due to P. aeruginosa; areas of remaining controversy are also discussed.

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