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Septic shock and Pseudomonas pneumonia: Is combination therapy necessary?
Pseudomonas aeruginosa is one of the most important pathogens considered when treating patients with hospital-acquired pneumonia or ventilator-associated pneumonia. Infections by P. aeruginosa are notoriously difficult to treat because of their intrinsic resistance to many antibiotics as well as their ability to acquire resistance.
When treating patients at risk for hospital-acquired (HAP) or ventilator-associated pneumonia (VAP) due to P. aeruginosa, every effort needs to be made to provide appropriate antibiotic coverage while respecting efforts to reduce antibiotic resistance. Recently, the Infectious Diseases Society of America and the American Thoracic Society released a new guideline for the management of adults with HAP or VAP. The guideline recommends using two antibiotics from different classes for empiric therapy for those with suspected VAP or HAP if the patient has risk factors for multidrug-resistant organisms (MDROs) or for patients residing in units where greater than 10% of gram-negatives are resistant to an agent being considered for monotherapy.
This guideline specifically addresses the question, “Should monotherapy or combination therapy be used to treat patients with HAP/VAP due to P. aeruginosa?” The guideline recommends that after P. aeruginosa has been identified and sensitivity is known, monotherapy, rather than combination therapy, should be utilized provided the patient is not in septic shock or at a high risk for death. However, if the results of antibiotic susceptibility testing are known for those patients in septic shock or at a high risk for death, the recommendation is for combination therapy utilizing two antibiotics to which the isolate is susceptible instead of monotherapy.
Rationale for combination therapy
There are several rationales for using combination therapy to treat serious infections. Combination therapy is used to expand the antimicrobial coverage to include all potential pathogens when the infecting organism is not known, or when the infection is polymicrobic in nature. Additionally, with increasing antimicrobial resistance, using combination therapy increases the likelihood that the initial therapy will be active against the infecting pathogens. Studies have shown lower mortality and improved patient outcomes when patients are treated with adequate initial therapy, and therefore treating with more than one agent decreases the odds of delaying adequate therapy. Patients infected with an MDRO are more likely to have a delay in adequate therapy, but using combination therapy can help reduce some risk for undertreatment. Lastly, combination therapy may lower the probability of developing resistant mutations, and perhaps even result in synergistic activity.
Evidence for combination therapy in septic shock
The evidence for monotherapy vs. combination therapy for P. aeruginosa HAP/VAP treatment is largely derived from observational trials. These trials have shown that combination therapy offers no mortality or treatment failure benefit compared with those receiving monotherapy, provided the pathogen was sensitive to the antimicrobial utilized. However, when specifically evaluating the evidence for patients with septic shock, there are conflicting results. A large, retrospective, propensity-matched study evaluated the outcome of patients with culture-positive bacterial septic shock treated with one or more antibiotics that were appropriately chosen for their primary pathogen. This study showed that combination therapy was associated with a decrease in mortality compared with monotherapy (35.3% vs. 29%; HR = 0.77; 95% CI, 0.67-0.88).
A meta-analysis of 64 randomized trials, including 7,586 patients, evaluated all-cause mortality rates for beta-lactam antibiotic monotherapy vs. beta-lactam/aminoglycoside combination therapy for sepsis patients. The types of infections included pneumonia, urinary tract, intra-abdominal, and skin and soft tissue, as well as infections with unknown origins. The outcome of this meta-analysis concluded that there was no difference in all-cause mortality and clinical failure with monotherapy. This held true for a subgroup analysis when looking specifically at patients with gram-negative and P. aeruginosa infections. The combination therapy group, however, did experience more nephrotoxicity, which is logical since aminoglycoside therapy was utilized.
A large prospective trial recently analyzed the mortality impact of adequate empirical and definitive combination therapy vs. adequate empirical and definitive monotherapy in patients with P. aeruginosa bacteremia. Empiric and definitive monotherapy was not associated with increased 30-day mortality compared with those who received combination therapy. However, the overall 30-day mortality rate was 30%, which underscores the high mortality rate associated with this infection.
Combination therapy and increased resistance
Although there are potential benefits of combination therapy, some negative effects include increased treatment costs and increased risks for adverse side effects. One potential benefit of combination therapy is a theoretical decrease in the development of resistance. However, a recent study called this into question. The study evaluated the evolution of resistance in P. aeruginosa during combination therapy utilizing ciprofloxacin combined with ceftazidime, and ceftazidime combined with tobramycin, compared with single-agent use or sequential exposure to the two agents. While the ceftazidime/tobramycin combination prevented the selection of resistant mutations, the ceftazidime/ciprofloxacin combination consistently selected for mutations that expressed broad-spectrum resistant mutations. This contrasts with what the researchers observed after a single-drug exposure, where they detected narrow-spectrum resistance induction. The authors suggest that antibiotic combinations should be analyzed for their ability to select for broad-spectrum resistance mechanisms before being implemented into clinical practice.
Stewardship point of view
Providing appropriate care to the critically ill, septic patient is a balancing act with respect to providing adequate antimicrobial therapy while minimizing untoward effects from that therapy. It is difficult to argue against using dual antibiotics aimed at P. aeruginosa in the patient who remains in septic shock. The mortality rate for these patients is high despite adequate antimicrobial therapy, even though the data supporting this are weak. Once patients clinically improve, de-escalation of therapy should be considered to reduce unnecessary antibiotic use to help minimize selective pressures that can lead to MDR pathogens and increased adverse events. We also need more data regarding how combination therapy may or may not increase the risks for mutations that select for broad-spectrum resistance mechanisms. The data suggesting an increased risk for inducing broad-spectrum resistance with the combination of ceftazidime and ciprofloxacin are concerning since this is a relatively common combination therapy approach to treating patients with HAP or VAP due to P. aeruginosa. There are few antimicrobials in the immediate pipeline to help us deal with MDR pathogens, so we must use our current antimicrobials judiciously to help preserve their utility.
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- For more information:
- Jeff Brock, PharmD, MBA, BCPS AQ-ID, is an infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at: JBrock@mercydesmoines.org.
Disclosure: Brock reports no relevant financial disclosures.