1 Department of Medicine, Division of Infectious Diseases, Columbia University College of Physicians and Surgeons, 630 W. 168th Street, PH 8W-876, New York, NY 10032; 2 Department of Medicine, Division of Infectious Diseases, University of Rochester Medical Center, New York, USA; 3 Clinical Microbiology Service, Department of Pathology, College of Physicians and Surgeons, New York, USA; 4 Department of Pharmacy, New York Presbyterian Hospital, Columbia University Medical Center, New York, USA
Received 22 March 2004; returned 4 May 2004; revised 14 June 2004; accepted 19 June 2004
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Abstract |
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Patients and methods: We retrospectively reviewed the clinical and microbiological efficacy, and safety profile of polymyxin B in the treatment of MDR Gram-negative bacterial infections of the respiratory tract. Twenty-five critically ill patients received a total of 29 courses of polymyxin B administered in combination with another antimicrobial agent.
Results: Patients were treated with intravenous, and/or aerosolized polymyxin B. Mean duration of polymyxin B therapy was 19 days (range 257 days). End of treatment mortality was 21%, and overall mortality at discharge was 48%. Nephrotoxicity was observed in three patients (10%) and did not result in discontinuation of therapy.
Conclusions: Polymyxin B in combination with other antimicrobials can be considered a reasonable and safe treatment option for MDR Gram-negative respiratory tract infections in the setting of limited therapeutic options.
Keywords: RTIs , multidrug resistance , polymyxins
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Introduction |
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According to the recently updated National Nosocomial Infections Surveillance data, in 2002 there was a documented 32% increase in resistance to imipenem and a 37% increase in resistance to quinolones in Pseudomonas aeruginosa when compared with the previous 5 years (19972001).2 The data for Acinetobacter species are equally concerning.3
With a diminishing armamentarium of effective new chemotherapeutic agents, there has been renewed interest in the polymyxins, which had fallen out of favour due to nephrotoxicity and neurotoxicity reported during their use in the 1960s.4 Much of the recent experience with the polymyxins, however, has pertained to the use of intravenous colistin (polymyxin E) where the reported nephrotoxicity has ranged from 14% to 58%, and neurotoxicity was minimal.46 Published experience with polymyxin B is limited.
We present results from our experience with the use of polymyxin B therapy during a 3.5 year period for the treatment of respiratory tract infections caused by MDR Gram-negative bacilli.
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Materials and methods |
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All patients were treated at New York-Presbyterian Hospital, Columbia University Medical Center, a 1200 bed tertiary care hospital in northern Manhattan. Patients who received one or more courses of intravenous or aerosolized polymyxin B therapy for the treatment of a respiratory tract infection during the period January 2000June 2003 were identified by the pharmacy database. Respiratory tract infections were evaluated and distinguished from colonization according to the Centers for Disease Control and Prevention definitions for nosocomial infections.7 Patients were excluded if they received <2 days of polymyxin B therapy or were under 18 years of age. Data retrospectively extracted from medical records and computer databases included: patient demographics, length of hospitalization, need for intensive care unit (ICU) stay, need for mechanical ventilation, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, underlying conditions, clinical status, details of polymyxin B administration, culture and susceptibility results, blood count and serum chemistry.
Efficacy and safety evaluations
The primary outcome measure was mortality at the end of therapy. Secondary outcomes included mortality at hospital discharge, a favourable clinical response (determined by the treating physician as improved or stable clinical status at the end of therapy), microbiological clearance and safety. Nephrotoxicity was defined as the doubling of serum creatinine during therapy. Neurotoxicity was defined as any neurological sign or symptom that was not present at the start of therapy.
Identification and susceptibility testing of microorganisms were performed using the MicroScan system (Dade Behring, Inc., Deerfield, IL, USA). Susceptibility to polymyxin B was evaluated through the use of 10 µg colistin discs (BD Microbiology Systems, Cockeysville, MD, USA) using the KirbyBauer disc diffusion method. The breakpoint for susceptibility was a zone of inhibition of 11 mm. All breakpoints for interpretation of antibiotic susceptibility were those of the NCCLS.8
Polymyxin B administration
Intravenous polymyxin B doses were based on body weight and estimated creatinine clearance (CLCR). All patients were loaded on day 1 of therapy with 2.53 mg/kg polymyxin B (1 mg = 10 000 U). Subsequent doses were determined by estimated CLCR and adjusted accordingly during therapy, as described previously.9 Aerosolized polymyxin B therapy was not standardized; the most frequently administered dose was 2.5 mg/kg/day divided into doses administered at 6 h intervals.
Statistical analysis
Quantitative variables are expressed as mean or median values with ranges. Categorical variables were compared using the 2 test or Student's t-test, as appropriate. All statistical analyses were performed with SPSS version 11.0.
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Results |
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A total of 25 patients received 29 courses of polymyxin B. The demographic and clinical features of the study cohort are summarized in Table 1. The mean age of the patients was 55 years; the median length of hospitalization was 64 days. The majority of patients were critically ill: the mean APACHE II score was 21 at the time of polymyxin B therapy and 23 patients (92%) required ICU care. All patients received combination therapy with another antibiotic.
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Acinetobacter baumannii was the most frequently isolated organism (55%). All isolates were found to be susceptible to polymyxin B (Table 2). Seven isolates of A. baumannii and five isolates of P. aeruginosa were reported resistant to all available antibiotics except polymyxin B.
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End-of-treatment mortality based on each course of polymyxin B was 21%, while overall discharge mortality was 48%. There were no deaths at the end of therapy in patients treated for P. aeruginosa infections compared with other Gram-negative organisms (0% versus 35%, P=0.028), but 25% of them did not survive to hospital discharge. Patients with. P. aeruginosa infections tended to have lower mean APACHE scores of 17 versus 24 (P=0.007). Of those patients who died, 67% died of infectious causes. A favourable clinical status was reported at the end of 22 courses of polymyxin B therapy (76%). One patient who had a favourable response to polymyxin B experienced a relapse and required an additional course of therapy; one patient received four courses over 1 year for recurrent infections. No difference in outcome was observed between patients who received intravenous or aerosolized polymyxin B for the treatment of pulmonary infections.
Follow-up cultures were available in 22 cases. Of these patients, 41% achieved microbiological clearance and this was associated with a longer duration of polymyxin B therapy (24 versus 16 days, P=0.058). Patients who cleared their cultures tended to have a lower overall discharge mortality (22% versus 62%, P=0.099). Resistance to polymyxin B was not observed during the 3.5 year time period evaluated.
Adverse events
Polymyxin B therapy was well tolerated. Nine courses (31%) were initiated in patients with pre-existing renal disease or receiving acute dialysis (mean baseline creatinine of 2.2 mg/dL). Overall, nephrotoxicity occurred during three courses (10%); however, two received only aerosolized therapy and one of them received concomitant tobramycin. After excluding patients on chronic haemodialysis, only one course of intravenous polymyxin B was associated with nephrotoxicity (6%). None of the patients had pre-existing renal disease and none of the increases in serum creatinine resulted in discontinuation of therapy. Neurotoxicity, manifesting as onset of seizures and neuromuscular weakness, possibly related to polymyxin B therapy, was observed during two courses (7%).
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Discussion |
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Previous studies demonstrated lower efficacy of the polymyxins for the treatment of pulmonary infections, ascribed to their large molecular structure and poor penetration into the pleura. Unique to some of our patients is the use of aerosolized polymyxin B alone or in combination with another systemic antibiotic or intravenous polymyxin B. Interestingly, we did not observe any difference in favourable clinical outcome for patients who received aerosolized therapy compared with those who received intravenous polymyxin B for pulmonary infections (67% versus 76%, P=0.63); however, numbers were small so firm conclusions cannot be made.
Our experience was notable for remarkably low rates of adverse effects. Only three patients doubled their creatinine during treatment. Given that two of these patients received aerosolized polymyxin B, which is not expected to be systemically absorbed, and all three died of multi-organ failure, it is probable that the nephrotoxicity observed was more likely due to the patients' clinical status and concomitant use of nephrotoxic agents than to polymyxin B alone.9 Neurotoxicity, while difficult to assess in severely ill ICU patients, appeared minimal.
One limitation of our study was the use of the disc diffusion method for testing in vitro susceptibility to colistin, an unreliable method of determining susceptibility.10 The NCCLS does not provide interpretive criteria for testing of the polymyxins. Gales and colleagues10 have shown that even with modified zone criteria for colistin and polymyxin B, some degree of error persisted. However, the majority of false-susceptible errors were noted among Stenotrophomonas maltophilia isolates and not in Acinetobacter or Pseudomonas strains.10
The lack of a control group in our study limits us from drawing firm conclusions about the clinical effectiveness of polymyxin B. We do not propose that it should be a first-line drug, particularly since there is a scarcity of well-designed, controlled trials investigating this agent. It is unlikely, however, that such studies will be forthcoming and few, if any, antimicrobials targeting these organisms appear on the horizon. Our series, reassessing the safety of the drug, confirms that it can be used in combination with additional antimicrobials to safely and adequately treat MDR Gram-negative respiratory tract infections.
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Acknowledgements |
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This work was presented in part at the Interscience Conference for Antimicrobial Agents and Chemotherapy, Chicago, September 1417, 2003
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Footnotes |
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References |
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8 . National Committee for Clinical Laboratory Standards. (2003). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallySixth edition. NCCLS, Villanova, PA, USA.
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Evans, M. E., Feola, D. J. & Rapp, R. P. (1999). Polymyxin B sulfate and colistin: old antibiotics for emerging multiresistant Gram-negative bacteria. Annals of Pharmacotherapy 33, 9607.
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Gales, A. C., Reis, A. O. & Jones, R. N. (2001). Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. Journal of Clinical Microbiology 39, 18390.