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Principles of antimicrobial therapy of Pseudomonas aeruginosa infections

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SUMMARY AND RECOMMENDATIONS

 

The following general principles apply to the management of serious Pseudomonas aeruginosa infections

  1. Antibiotic resistance, both intrinsic and acquired, is important to consider when selecting empiric or directed therapy.
  2. Combination therapy may be indicated in certain high-risk patients and in severe infections.
  3. Antimicrobial therapy should be promptly initiated, as delayed therapy correlates with increased mortality.
  4. Source control is important. All infected catheters should be removed, and abscesses should be drained and obstructions relieved, whenever possible.

P. aeruginosa is intrinsically resistant to a number of antibiotics and can acquire resistance during therapy. These features limit the choices of antibiotics for P. aeruginosa

 

A limited number of antimicrobial agents have reliable activity against P. aeruginosa isolates that have not acquired additional resistance mechanisms. Additionally, certain agents require higher dosing when used for presumptive or known P. aeruginosa infections.

Fluoroquinolones are the only class of antibiotics which has an oral formulation that is reliably active against P. aeruginosa.

Aminoglycosides (gentamicin, tobramycin, amikacin) are active against P. aeruginosa but are generally not used as single agents because of inadequate clinical efficacy at most sites.

 

The use of combination antimicrobial therapy in patients with serious P. aeruginosa infections remains controversial, largely because of the paucity of well controlled comparison trials using clinically important end points. There is no convincing clinical evidence that using two active agents instead of one leads to improved outcomes despite theoretical synergistic activity or decreases the risk of emergent resistance. However, using two agents for empiric therapy may increase the likelihood that an active agent will be used for a potentially resistant organism, and this, in turn, is associated with better outcomes for serious infections. 

 

We typically reserve combination therapy for empiric treatment of serious infections known or suspected to be caused by P. aeruginosa that are associated with high mortality or when the risk of resistance is high. 

 

Thus, for patients who have sepsis or septic shock, have neutropenia and bacteremia, have severe burns, or are in a setting where the incidence of resistance to the chosen antibiotic class is high (eg, >10 to 15 percent), we suggest empiric therapy with a combination of two antipseudomonal agents. (Grade 2C). The two agents should be from different antibiotic classes, eg, a beta-lactam with an aminoglycoside or a quinolone.

 

For patients without any of these additional risk factors for mortality or resistant organisms, we recommend empiric treatment with a single antipseudomonal agent .

(Grade 2B)

 

Once antimicrobial susceptibility data are available, we typically use a single active antipseudomonal agent. The rare exceptions when a combination regimen may be warranted include neutropenia and bacteremia, endocarditis, failure to improve on therapy, and multidrug resistance. 

 

Multidrug resistance in many organisms, including P. aeruginosa, is a growing clinical problem, and often treatment with alternative antibiotics, such as colistin, is necessary. Certain strategies for treatment of resistant P. aeruginosa include the use of alternative drug combinations, and, for pneumonia, inhaled antibiotics as adjunctive therapy. However, the clinical data for some of these strategies are limited. Multidrug-resistant P. aeruginosa should be managed with the assistance of an expert in the treatment of such infections.

 

The general principles of antipseudomonal therapy in children are similar to those in adults with the main exception that antimicrobial dosing is weight-based. Use of a fluoroquinolone is a consideration for gram-negative infections caused by isolates susceptible to these agents, including infections caused by P. aeruginosa. No compelling published evidence supports the occurrence of sustained injury to developing bones or joints in children treated with available fluoroquinolone agents. 

 

Combination therapy for highly resistant infections 

 

The difficulty in treating P. aeruginosa infections caused by strains that are resistant to all or all but one antibiotic has led investigators to use novel combinations of drugs that separately have little or no activity against the isolate. There are minimal clinical data to support such combination therapy, and most clinical studies did not analyze patient outcomes stratified by susceptibility profile. However, if combination therapy is used for treatment of organisms with extreme or unusual multidrug resistance patterns, it should be done in consultation with an expert in treating such infections whenever possible.

In a single clinical series of 64 patients with nosocomial pulmonary infections due to a highly resistant P. aeruginosa susceptible only to colistin, treatment with the combination of cefepime and amikacin was associated with survival in 44 (69 percent). These agents were the least inactive antibiotics by MIC determination and had demonstrated synergy in vitro.

Other combination regimens have been found to have enhanced activity against multidrug-resistant P. aeruginosa in vitro, but there are scarce in vivo data to support their use. Such combinations include:

Ticarcillin plus tobramycin plus rifampin

Polymyxin B plus rifampin

A fluoroquinolone plus either ceftazidime or cefepime

Ceftazidime plus colistin

Clarithromycin plus tobramycin 

Azithromycin plus one of the following: tobramycindoxycyclinetrimethoprim, or rifampin

Colistin plus rifampin

Fosfomycin plus a carbapenem– one study suggested that a prolonged infusion of fosfomycin (16 to 24 g) in combination with a carbapenem would optimize drug exposure.

The mechanisms for the enhanced activity are unknown for most combinations.