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.


Pharmacotherapy. 2011;31(6):598-608. 

In This Article

Summary and Limitations of the Clinical Data

Pseudomonas aeruginosa is an organism known to cause serious nosocomial infections with exceptionally high mortality rates. The difficulty in managing patients with these infections is due to the decreasing availability of reliable antipseudomonal antibiotics, numerous inherent and acquired mechanisms of resistance, and increasing rates of antibacterial resistance. These issues have resulted in the investigation of combination therapy for serious pseudomonal infections in an attempt to decrease morbidity and mortality. Available data suggest that the largest benefit of combination therapy stems from the improved likelihood of appropriate empiric therapy rather than in vitro synergy or prevention of emergence of resistance.

The use of combination therapy to improve appropriate empiric therapy has demonstrated significant decreases in mortality. When empiric combination therapy is used, the second agent chosen should be one likely to be active against an organism resistant to the primary agent. Although fluoroquinolones are commonly used for combination therapy, several investigations have shown little benefit in expansion of empiric therapy when adding these agents to β-lactams.[44,56] Conversely, studies suggest combination therapy with an aminoglycoside is associated with a greater risk of nephrotoxicity, with a NNH as low as 15 when aminoglycosides are used, as well as increased costs and the possibility of increased occurrence of superinfections and isolation of resistant organisms. Again, it must be stressed that the benefit of combination therapy will be only in patients who ultimately have the disease in question, whereas the harm will be applicable to all treated patients. Since less than 10% of nosocomial infections of all types are due to P.aeruginosa, this suggests a large number of patients will be exposed to the added harms, cost, and possible risk of resistance without deriving significant benefit. For this reason, it is critical that we develop better prediction tools to identify patients with P. aeruginosa infection.

Limitations of the clinical studies discussed include their retrospective design, variable patient populations, and small numbers of patients. Despite the notoriety of P. aeruginosa, pseudomonal bacteremia is not exceedingly common. As a result, large, randomized, prospective studies are difficult to perform. These issues have resulted in several of the aforementioned analyses spanning long periods of time during which medical advances may have influenced treatments. Unfortunately, none of the studies were statistically powered to detect a mortality difference between combination therapy and monotherapy.

Another issue with the retrospective design of these studies is selection bias. Because the majority of studies were retrospective, and those that were prospective were observational and not randomized, the choice of combination therapy versus monotherapy was based on the physician's discretion. This factor may have influenced the results by differences in prescriber habits and/or critically ill patients receiving combination therapy more often.

To compensate for the inadequate sample sizes in these studies, several meta-analyses have attempted to combine the data, resulting in conflicting conclusions. Significant heterogeneity and poor quality of the included studies severely limit these meta-analyses. Included studies have different study designs (prospective vs retrospective, randomized vs nonrandomized), inclusion criteria (monomicrobial vs polymicrobial), and patient populations, and they examined a wide variety of antibiotics. Also, different definitions of adequate therapy increase the difficulty of combining different trials. Finally, most studies did not define mortality as the primary outcome. Although pseudomonal VAP occurs more commonly than bacteremia, even fewer studies have attempted to examine combination therapy in this setting.