Nosocomial Infections Due to Multidrug-Resistant Pseudomonas Aeruginosa: Epidemiology and Treatment Options

Marilee D. Obritsch, PharmD; Douglas N. Fish, PharmD, FCCM; Robert MacLaren, PharmD; Rose Jung, PharmD

Disclosures

Pharmacotherapy. 2005;25(10):1353-1364. 

In This Article

Clinical Treatments and Recommendations

The intrinsic susceptibility of P. aeruginosa is already limited to only several antimicrobial classes, but emergence of multidrug resistance compromises most of the antipseudomonals except colistin and polymyxin B therapies and synergistic combinations of antibiotics to which MDRPA strains are resistant.

A case report described the treatment of a patient with a double-lung transplant who was admitted with MDRPA pneumonia 2 months after transplantation.[36] The patient initially received ciprofloxacin, which was changed to piperacillin-tazobactam on admission to the intensive care unit. After completing bronchoscopy, the culture susceptibilities revealed MDRPA sensitive only to meropenem and colistin. Because of the potential nephrotoxicity of colistin, continuous-infusion meropenem was chosen as treatment on day 5 of hospitalization. The patient was given meropenem 2 g followed by a continuous infusion of 8 g/day, with new bags prepared every 6 hours. On day 25, no evidence of residual infiltrates was seen on the chest radiograph. The patient was weaned from mechanical ventilation, and antibiotics were discontinued. The patient was discharged on day 33 with no evidence of infection.

Colistin and polymyxin B are older antipseudomonal agents that have reemerged due to the increasing frequency of multidrug resistance. In the United States, colistin in the form of the sodium salt of its methane sulfonate derivative (sodium colistimethate) has been used.[37] The sulfomethyl polymyxin is a prodrug that must be hydrolyzed to release the active free base, which occurs at body temperature and at physiologic pH in aqueous systems. The in vivo conversion of the parenteral agents to colistin occurs at an unknown rate[30] and may influence the pharmacodynamic effects of the drug. When this formulation was initially introduced, systemic toxicity appeared to be less than that observed for polymyxin B.[37] However, colistimethate is less active than polymyxin B against most strains of P. aeruginosa. In doses that result in equal antibacterial effectiveness, the toxicity of these two agents appears to be similar. An excellent review is available on the history, mechanism of action, spectrum of activity, dosing, and dosage adjustment in renal dysfunction of colistin and polymyxin B[30]; therefore, these topics will not be addressed in detail here. Instead, this discussion will focus on the reported safety and efficacy of colistin and polymyxin B in patients without cystic fibrosis who are infected with multidrug-resistant organisms.

Colistin has activity (minimum inhibitory concentration [MIC] ≤ 2 µg/ml) against almost all strains of P. aeruginosa.[30,37] Polymyxin B and colistin demonstrated a similar spectrum of activity with an MIC at which 90% of isolates are inhibited of 2 B5g/ml against pathogens collected from the SENTRY Antimicrobial Surveillance Program.[38] For the polymyxins, an MIC of 2 B5g/ml or less is the quality control range recently approved by the Clinical and Laboratory Standards Institute (formerly known as the National Committee for Clinical Laboratory Standards) for susceptibility against P. aeruginosa.[39]

Because of the adverse-effect profile,[40] polymyxins are usually reserved as a salvage therapy in patients infected with multidrug-resistant gram-negative pathogens such as P. aeruginosa or Acinetobacter baumanii. Therefore, the efficacy data are mainly limited to retrospective reviews of patients treated with these agents. Efficacy data of colistin and polymyxin B in patients without cystic fibrosis are summarized in Table 1 .[41,42,43,44,45] In these reports, colistin was used in critically ill patients with significant comorbidities, prolonged hospitalization, and protracted exposure to antimicrobial selective pressures.[41,42,43,44] Mean ages ranged from 42-61 years, and the mean Acute Physiology and Chronic Health Evaluation II scores ranged from 13-21 with more than two major organ system failures. Many of the patients were mechanically ventilated, and the mean length of hospital stay before the infection with a multidrug-resistant pathogen ranged from 27-28 days. In addition, they included patients with pneumonia, septicemia, pyelonephritis, urinary tract infections, meningitis, sinusitis, catheter-related infections, surgical-site infections, and wound infections. Patients received intravenous colistimethate or polymyxin B with dosage adjustment based on renal function. The median duration of therapy ranged from 14-17 days. Most patients (56-100%) received concomitant aminoglycoside or β-lactam antipseudomonal agents. Overall, the mortality rate ranged from 20-61%, with efficacy or eradication rates of 58-88%. These response and in-hospital mortality rates are well within the broad reported range of clinical response and mortality rates for serious gram-negative infections.[1,10,11,12,13]

Colistin has been thought to be less effective in patients with osteomyelitis, biliary tract disease, endocarditis, and pneumonia, probably because of suboptimal concentrations at the local site of infection.[42] This is particularly alarming because many multidrug-resistant organisms cause pneumonia, especially in mechanically ventilated patients. In a retrospective study, 75% of patients with pneumonia failed colistin therapy.[41] Since then, other studies have shown that colistin has similar effectiveness as that of other anti-pseudomonal agents. In subgroup analyses, the effective rates in pneumonia or ventilator-associated pneumonia ranged from 56-73%.[42,44] However, eradication rates ranged from 33-53%.[42,43] Even in patients with favorable outcomes, persistence of organism at a respiratory site can be as high as 70%.[44] Inadequate duration of therapy or persistent risk factors for pneumonia may cause significant relapses or superinfection with such low eradication rates. This is supported by results of another study in which progression to bacteremia was significantly associated with an unfavorable response.[44]

Most patients treated with colistin received concomitant aminoglycosides or β-lactam antipseudomonal agents despite resistance to such agents in some cases.[41,42,43,44] Although the authors of one of the above-mentioned studies[44] found no difference in response rates between the 10 patients who received colistin monotherapy and 13 patients who received another concomi-tant antipseudomonal agent, drawing any conclusions is difficult due to the small number of patients and retrospective nature of the study. In addition, a case series described adjunctive use of aerosolized colistin for the treatment of nosocomial pneumonia and tracheobronchitis due to MDRPA in three patients.[46] Dosages of inhaled colistin were 100-150 mg twice/day for 11-14 days. The patients also received concomitant antibiotics that included ceftazidime and amikacin in patient 1, gentamicin in patient 2, and ceftazidime in patient 3. All patients improved clinically, and one patient had a documented microbiologic response with negative cultures at follow-up.

Another case series of patients with nosocomial pneumonia described the treatment of one patient with MDRPA with use of both nebulized and intravenous colistin.[47] The patient's treatment included 7 days of intravenous colistin therapy 75 mg every 8 hours, nebulized colistin 112.5 mg every 8 hours for 5 days, and 32 days of intravenous colistin 75 mg every 8 hours. The patient showed clinical improvement, but no follow-up cultures were available. The patient was eventually discharged after 234 days of hospitalization.

As the prevalence of MDRPA increases and treatment options become limited, various antimicrobial combinations have been proposed as an alternative in clinical practice despite resistance to one or both agents in the combination. Since interactions between antibiotics are difficult to explore in patients, especially when bacteria are resistant to both agents within the combination, investigations rely heavily on in vitro testing. In general, in vitro studies use four methods to assess synergistic activity: checker-board, Etest, time-kill, and in vitro pharmaco-dynamic models.[48] Unfortunately, there is discordance between the results of checkerboard titration and time-kill curve methods.[49,50] Compared with the checkerboard titration method, previous studies suggest that time-kill assays correlate better with cure in animal models, and thus, time-kill curves are the preferred method to evaluate antibiotic combinations. Although both time-kill and checkerboard methods are discussed, recommendations provided in this review rely more heavily on the results obtained with use of the time-kill methodology. In vitro synergy studies evaluating various antimicrobial combinations against MDRPA are summarized in Table 2 .[45,48,51,52,53,54,55,56,57,58,59,60]

Because of differences in antimicrobial combinations, concentrations of these agents, and strains tested, reported results vary significantly. The checkerboard evaluations indicate that rates of synergy range from 0-25%, 0-30%, 0-17%, and 0-33% for two β-lactams, β-lactam plus fluoroquinolone, β-lactam plus aminoglycoside, and fluoroquinolone plus aminoglycoside combinations, respectively.[51,52] Although only two studies examined triple combination therapies, they report higher rates of synergy if the combinations included two β-lactams.[53,54] For example, rates of synergy for β-lactam plus aminoglycoside combinations ranged from 0-71% in these studies. However, when two β-lactams were combined with an amino-glycoside, the rate of synergy improved to 43-100%.

The studies using time-kill assays encompassed smaller numbers of strains than those reported for the checkerboard techniques, but more studies used the time-kill assay. These studies reported 0-27% synergy for aminoglycoside plus fluoroquinolone, 14-50% for β-lactam plus aminoglycoside, and 0-50% for β-lactam plus fluoroquinolone combinations.[52,54,55,56,57,58] Synergy obtained with combination of fluoroquinolone and β-lactam was shown to be no different for either ciprofloxacin or levofloxacin in several MDRPA isolates.[52] Similar to the studies involving checkerboard titrations, rates of synergy between β-lactam plus aminoglycoside and β-lactam plus fluoroquinolone were comparable.[52,54,55,56,57,58] One study examined triple combinations, and similar to checkerboard titrations, these combinations resulted in higher synergy rates (ceftazidime plus aztreonam and amikacin 43% vs aztreonam and amikacin 14%).[54]

Time-kill studies have shown synergism when colistin was combined with β-lactams, ciprofloxacin, or rifampin against MDRPA. Colistin and rifampin resulted in synergy in 23.5% (4/17) of genetically distinct isolates of P. aeruginosa at 2 hours, 35.3% (6/17) at 4 hours, 41.2% (7/17) at 6 hours, and 11.8% (2/17) at 24 hours.[59] When two strains of MDRPA were tested against colistin given alone or in combination with either ciprofloxacin or ceftazidime in time-kill curve experiments, colony counts at 24 hours were lowest when colistin was given to achieve a peak of 18 mg/L every 12 hours.[48] Combination of colistin (maximum concentration 6 or 18 mg/L) and continuous-infusion ceftazidime (steady-state concentration 50 mg/L) showed synergistic activity at 24 hours against one strain of P. aeruginosa. In comparison, colistin alone was more active at 24 hours than the combination of colistin and ciprofloxacin.

Studies that correlate results of in vitro synergy testing with clinical outcome are rare. However, two studies used in vitro synergy testing to guide therapy despite resistance to both agents used. A hospital in France reported an outbreak of an MDRPA resistant to virtually all antimicrobials with the exception of colistin in 67 patients.[60] In vitro testing found the cefepime and amikacin combination to be highly synergistic. All patients were treated with cefepime 6 g/day and amikacin 15 mg/kg/day as these were the most active antibiotics (modal MIC 32 mg/L and 64 mg/L, respectively). For pulmonary infections, duration of treatment was 14-20 days. Patients with positive stool cultures for the organisms were treated with oral colistin and neomycin for 6 days. For the 64 patients in the intensive care unit who were treated, 44 recovered and 20 died (31% mortality). Infection was judged to be unrelated to death in 12 patients, an aggravating factor in 7, and responsible for death in 1 patient.

The second study involved in vitro synergy testing with rifampin and colistin against five MDRPA strains with colistin MICs of 4 B5g/ml and resistant to rifampin.[45] The checkerboard method demonstrated full synergy against one multidrug-resistant isolate and partial synergy against the remaining four isolates. The time-kill curves with the colistin and rifampin combination demonstrated bactericidal activity, whereas colistin alone had no bactericidal effect in the two MDRPA strains tested. Four of the patients with these MDRPA strains were subsequently treated with a parenteral colistin 150 mg/day intravenously in one to two divided doses and rifampin 600 mg given intravenously or orally, with two patients receiving adjunctive nebulized colistin 75 mg twice/day and one patient receiving amikacin (1 g/day). Three of the patients had pneumonia and one had a central venous catheter-related bacteremia. Duration of treatment ranged from 10-28 days. All patients had microbiologic eradication of the MDRPA strain and clinical improvement.

In vitro data from checkerboard and time-kill assays indicate similar results when β-lactams are combined with aminoglycosides or fluoro-quinolones for synergy against MDRPA isolates. There are few data supporting the use of fluoroquinolones in combination with amino-glycosides in MDRPA. Although use of double β-lactam combinations has been discouraged in clinical practice, the results from synergy testing indicate frequent synergy without antagonism.[53,54] Triple combinations show good results in the aforementioned studies, but more data are needed for appropriate recommendations.[53,54,55] Finally, small observational studies demonstrate that a synergistic combination in vitro may be able to guide treatment of MDRPA infections.[45,60] Additional studies are needed to confirm reliability of using synergistic combinations in treating MDRPA infections. However, in vitro evaluations provide evidence of combining otherwise resistant antipseudomonals as therapy in patients without any alternatives.

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