combination therapy for pseudomonas in ICU covers multiple resistance mechanisms

  • combination therapy for pseudomonas can cover different resistance mechanism
  • it does not improve synergy and does not prevent resistance development

The Infectious Diseases Society of America/American Thoracic Society guideline for management of ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) has recommendations for antimicrobial selection for patients suspected to have pneumonia due to Pseudomonas aeruginosa. VAP is defined as pneumonia that develops in patients receiving mechanical ventilation that occurs at least 48 h after endotracheal intubation. HAP is defined as pneumonia not associated with mechanical ventilation that occurs at least 48 h after admission in a patient who has not been intubated at the time of admission to the hospital.

Directed therapy for patients with VAP or HAP due to P aeruginosa should be based upon the results of antimicrobial susceptibility testing. The guidelines do not specify which antipseudomonal antibiotic is preferable, as there has been no definitive evidence to show that any one antipseudomonal agent is clearly superior to another. Aminoglycosides are not recommended as monotherapy due to a lack of studies evaluating this in patients with HAP or VAP. It is recommended to use two antimicrobial agents to which the isolate is susceptible for patients who are in septic shock or are at a high risk for death.

Multiple mechanisms create antibiotic resistance, and different mechanisms may coexist in a single pathogen. Combination therapy increases the probability of overcoming those mechanisms and provides broader coverage for potential multidrug-resistant organisms. This also increases the odds that at least one of the antibiotics will have effective activity against the causative organism.This is desirable, since early and appropriate antibiotics are demonstrated to have an important impact on sepsis mortality.

Combination therapy for P aeruginosa is frequently used in an attempt to reduce the development of antibiotic resistance. In a meta-analysis of eight randomized controlled clinical trials comparing β-lactam monotherapy to β-lactam plus aminoglycoside therapy, combination therapy did not impact the development of antimicrobial resistance in susceptible isolates. In another meta-analysis of 64 trials comparing β-lactam monotherapy and β-lactam plus aminoglycoside combination therapy in immunocompetent patients with sepsis, there was no difference in the rate of development of resistance. As such, no data are currently available that demonstrate that combination therapy prevents the emergence of Pseudomonas resistance. This meta-analysis also did not identify enhanced efficacy with combination therapy, as no improved survival was observed for the patients who had infection caused by P aeruginosa.

Synergy represents a situation in which clinical effectiveness of a combination of antimicrobials is greater than merely the additive effect of the antimicrobial agents. Synergy is often mentioned as a justification for combination therapy against Pseudomonas species. Although the goal of combination therapy may be to effect the beneficial effect of synergy, a combination regimen may instead result in the detrimental effect of antagonism. An example of such an effect was with the treatment of pneumococcal meningitis in the 1950s, in which the fatality rate among patients who received penicillin alone was 21%, in contrast with 79% among those who received both penicillin (a bactericidal agent) plus chlortetracycline (a bacteriostatic agent). This demonstrated a significantly worse clinical outcome with combination therapy as opposed to therapy with penicillin alone. Synergy has not been convincingly demonstrated with combination therapy for Pseudomonas.12345

Footnotes

  1. SEEK Questionnaires ↩

  2. Harbarth S, Nobre V, Pittet D. Does antibiotic selection impact patient outcome? Clin Infect Dis. 2007;44(1):87-93. PubMed ↩

  3. Kalil AC, Metersky ML, Klompas M, et al. Executive summary: management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):575-582. PubMed ↩

  4. O’Neal H, Thomas C, Karam G. Principles governing antimicrobial use in the intensive care unit. In: Parillo J, Dellinger R, eds. Critical Care Medicine: Principles of Diagnosis and Management in the Adult. New York, NY: Elsevier; 2019:788-806. ↩

  5. Paul M, Benuri-Silbiger I, Soares-Weiser K, et al. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ. 2004;328(7441):668. PubMed ↩