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JAC Advance Access originally published online on March 25, 2008
Journal of Antimicrobial Chemotherapy 2008 61(6):1369-1375; doi:10.1093/jac/dkn128
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Ampicillin/sulbactam compared with polymyxins for the treatment of infections caused by carbapenem-resistant Acinetobacter spp.

M. S. Oliveira1,*, G. V. B. Prado1, S. F. Costa1,2, R. S. Grinbaum3 and A. S. Levin1,2

1 Department of Infection Control of Hospital das Clínicas, Rua Dr Ovídio Pires de Campos, 225, Sala 629, São Paulo-SP 05403-010, Brazil 2 Department of Infectious Diseases and LIM-54, University of São Paulo, Av. Dr Enéas de Carvalho Aguiar, 470, São Paulo-SP 05403-000, Brazil 3 Department of Infection Control of Hospital do Servidor Público Estadual de São Paulo, Avenida Ibirapuera, 981, São Paulo-SP 04029-000, Brazil

* Corresponding author. Tel/Fax: +55-11-3069-7066; E-mail: gcih{at}hcnet.usp.br

Received 7 December 2007; returned 28 December 2007; revised 26 February 2008; accepted 28 February 2008


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Background: There has been an increase in worldwide infections caused by carbapenem-resistant Acinetobacter. This poses a therapeutic challenge as few treatment options are available.

Objectives: The aim of this study was to evaluate the efficacy and safety of polymyxins and ampicillin/sulbactam for treating infections caused by carbapenem-resistant Acinetobacter spp. and to evaluate prognostic factors.

Methods: This was a retrospective review of patients from two teaching hospitals who had nosocomial infections caused by carbapenem-resistant Acinetobacter spp. from 1996 to 2004. Diagnosis of infection was based on CDC criteria plus the isolation of Acinetobacter from a usually sterile site or from bronchoalveolar lavage. Urinary tract infections were not included. Data on demographic and clinical features and treatment were collected from medical records. Prognostic factors associated with two outcomes (mortality during treatment and in-hospital mortality) were evaluated.

Results: Eighty-two patients received polymyxins and 85 were treated with ampicillin/sulbactam. Multiple logistic regression analysis revealed that independent predictors of mortality during treatment were treatment with polymyxins, higher Acute Physiological and Chronic Health Evaluation II (APACHE II) score, septic shock, delay in starting treatment and renal failure. On multivariate analysis, prognostic factors for in-hospital mortality were older age, septic shock and higher APACHE II score.

Conclusions: This is the first study comparing current therapeutic options for infections due to carbapenem-resistant Acinetobacter. The most important finding of the present study is that ampicillin/sulbactam appears to be more efficacious than polymyxins, which was an independent factor associated with mortality during treatment.

Keywords: colistin , antibiotics , drug resistance


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Acinetobacter spp. is a cause of nosocomial pneumonia, bacteraemia, urinary tract infections and secondary meningitis. Antimicrobial drugs frequently reported as active against Acinetobacter spp. include carbapenems, polymyxins, ampicillin/sulbactam, amikacin, rifampicin and tetracyclines. Currently carbapenems are considered the treatment of choice.

Unfortunately, over the past several years, there has been a worldwide increase in infections caused by carbapenem-resistant Acinetobacter.1–3 This poses a therapeutic challenge as few treatment options are available.

To date, there are no randomized clinical trials published to evaluate the best antimicrobial regimen for treating these infections. In non-randomized clinical studies and case series, success has been reported with treatment with polymyxins and sulbactam.4–16

Polymyxin B and polymyxin E (colistin) are used in clinical practice. They have an in vitro activity against many Gram-negative bacilli, including Acinetobacter spp. and Pseudomonas. The major adverse effects are nephrotoxicity, neurotoxicity and neuromuscular blockade.17,18 Sulbactam, a β-lactamase inhibitor, has good in vitro activity against Acinetobacter spp.19 and has been used successfully for treating carbapenem-resistant Acinetobacter strains.4,5,14–16 Sulbactam is commercially available in combination with ampicillin in a fixed 2:1 ratio. In general, it is well tolerated and the most frequent adverse effects are pain at the injection site, diarrhoea and rash.

Our objective was to investigate the effectiveness and safety of intravenous polymyxins (colistin or polymyxin B) and ampicillin/sulbactam for treating infections caused by carbapenem-resistant Acinetobacter spp., and to evaluate prognostic factors.


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Patients and definition of infection

We performed a retrospective review of the consecutive case records from two large teaching hospitals of all patients from 1996 to 2004 who had nosocomial infections caused by carbapenem-resistant Acinetobacter spp. Hospital das Clínicas has 2200 beds of which 1000 are in the main building where this study was conducted. Hospital do Servidor Público Estadual has 900 beds. Both are tertiary-care hospitals. The patients were identified by the databases of the infection control departments. These electronic databases have information on nosocomial infections and causative microorganisms, which are collected prospectively by the infection control teams as part the hospital infection surveillance systems. We used them only to retrieve patient's hospital records.

The study was approved by the Ethics Committee of both hospitals (approval number: 661/04) and all medical records were reviewed by a physician (M. S. O.).

Diagnosis of infection was based on CDC criteria20 plus the isolation of Acinetobacter from a usually sterile site or from quantitative bronchoalveolar lavage (≥10 000 cfu/mL). Only organ-space surgical site infections were included. Urinary tract infections were not included. This information was obtained from the databases of the infection control departments, thus had been collected prospectively by the infection control nurses.

Identification was performed using routine microbiological methods. Identification and susceptibility testing were performed by an automated broth microdilution method (Vitek, bioMérieux, Hazelwood, MO, USA). The breakpoints were those defined by the CLSI (formerly the NCCLS).21,22 Susceptibility to polymyxins was not performed as the methods for this were not standardized until 2005. We considered that all isolates were susceptible, because polymyxin B showed excellent in vitro activity against 2621 Acinetobacter isolates in a previous study.23

The following variables were collected from all available medical records for each patient: dates of admission to the hospital and to the unit in which the Acinetobacter infection occurred; gender; age; presence of co-morbidities; severity of illness according to Acute Physiological and Chronic Health Evaluation II (APACHE II) score at the time of patient's admission to the unit (both hospitals provided systematic documentation of variables included in APACHE II score as they have standardized forms for patients' daily evaluation)24; antibiotic use and invasive procedures during the 10 days previous to the diagnosis of infection; surgery during the 60 days previous to the diagnosis of infection; diagnosis of infection; diagnosis of septic shock; date and site of isolation of Acinetobacter.

Outcomes

Clinical outcomes of the treated patients were classified as: cure, improvement, failure or indeterminate. ‘Indeterminate’ was defined as death or change in treatment within 72 h of beginning the initial regimen. ‘Improvement’ was defined as eradication of all the signs and symptoms of infection (except fever), which allowed discontinuation of antimicrobial therapy defined by the assistant physician. ‘Cure’ required the same criteria of improvement plus the disappearance of fever and, when the patient was in an intensive care unit (ICU), either extubation or discharge from the ICU was required. ‘Failure’ was defined as death or persistent signs and symptoms of infection or persistent isolation of Acinetobacter; or change of antibiotic between 3 and 7 days after treatment initiation.

A cohort study to determine prognostic factors was performed. We excluded the untreated group and included only patients treated with ampicillin/sulbactam or polymyxins. The following data on the treatment regimen were obtained: dosage, route, duration of treatment and other simultaneous antibiotic treatments.

The outcomes for the cohort studies were: mortality during treatment and in-hospital mortality.

Adverse effects

Renal function during treatment was monitored by measuring the serum creatinine levels. Renal failure was defined as a 2-fold increase in serum creatinine at any time during the treatment compared with the level at the start of therapy or an increase by 1 mg/dL if initial creatinine was abnormal (>1.4 mg/dL).25 We evaluated the reporting of any neurological abnormalities, such as seizures, facial paresthesia and altered mental status. Neurotoxicity was defined as the presence of these signs or symptoms that were not related to another neurological diagnosis. We also monitored reports of skin rash and diarrhoea.

Data analysis

We described clinical characteristics of these infections, such as treatment and adverse effects, and evaluated two outcomes: death during treatment and death during hospitalization.

Continuous variables were presented as means ± SD, median and range, and for categorical variables, we calculated frequency. Groups of treated patients (polymyxin versus ampicillin/sulbactam) were compared with the two outcomes using the {chi}2 test for categorical variables and the Mann–Whitney test for continuous variables. Data were analysed using EpiInfo 6.04 software (CDC, Atlanta, USA). A P value of 0.05 was considered statistically significant.

Multivariate analysis using the logistic regression method was performed using Stata 7.0 (Statacorp, TX, USA) including all variables with a P value of 0.25 or lower in the univariate analysis. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated for each variable. Variables in which 95% CI did not include 1.0 were maintained in the final model.


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During the study period, there were 283 infections caused by carbapenem-resistant Acinetobacter spp., of which 9 were treated with both regimens and 8 received other antibiotics (4 patients were treated with ciprofloxacin, 3 with piperacillin/tazobactam and 1 with gentamicin). Ninety-nine patients did not receive adequate antimicrobial treatment.

Non-treated patients presented median age of 60 years (range: 1–87) and median APACHE II score of 18 points (range: 2–40). Most of them had been submitted to invasive procedures: 83% were under mechanical ventilation, 92% had a central venous catheter and 91% had a urinary catheter. Eighty-five per cent were in an ICU when the Acinetobacter infection occurred. Bloodstream infection was the most common infection site (62%), followed by pneumonia (20%) and surgical site infection (10%). In-hospital mortality was 91% and death occurred within the first 72 h after isolation in 75% of the cases.

These 116 patients (99 non-treated, 9 treated with both regimens and 8 treated with other antibiotics) were excluded.

Eighty-two patients received polymyxins and 85 were treated with ampicillin/sulbactam. The demographic and clinical characteristics of these 167 treated patients are summarized in Table 1.


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  		Table 1. Clinical and demographic characteristics of patients with severe carbapenem-resistant Acinetobacter spp. infections treated with ampicillin/sulbactam or polymyxins, in two large teaching hospitals, from 1996 to 2004

 
The median hospital stay before the diagnosis of the Acinetobacter spp. infection was 26 days (range: 1–275) for the polymyxin group and 23 days (range: 0–201) for the ampicillin/sulbactam group.

Median time between Acinetobacter isolation and treatment was 4 days (range: –8 to 23) for the polymyxin group and 4 days (range: –5 to 13) for the ampicillin/sulbactam group. Median daily dose was 5.1 million units (MU) for colistin (range: 1.0–9.0 MU), 1 MU for polymyxin B (range: 0.4–1.5 MU) and 9 g for ampicillin/sulbactam (range: 1.5–12 g). The treatment duration was 11.5 days (range: 0–50) and 14 days (range: 1–30) for polymyxins and ampicillin/sulbactam, respectively. Simultaneous antimicrobial use was common: 29% and 28% of patients using polymyxins and ampicillin/sulbactam received carbapenems, and 70% and 60% received vancomycin, respectively. Aminoglycoside use was infrequent: 2% in the polymyxin group and 4% in the ampicillin/sulbactam group.

The clinical outcomes for patients treated with ampicillin/sulbactam or polymyxins are summarized in Table 2.


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  		Table 2. Clinical outcomes of patients with severe carbapenem-resistant Acinetobacter spp. infections treated with ampicillin/sulbactam or polymyxins, in two large teaching hospitals, from 1996 to 2004

 
The onset of renal failure occurred in 18 of 69 patients (26%) in the polymyxin group and in 21 of 81 (26%) in the ampicillin/sulbactam group. No symptoms of neurotoxicity were observed. Skin rash was observed in 3 (4%) and 11 (13%) of the polymyxins and ampicillin/sulbactam groups, respectively.

Potential prognostic factors for mortality during treatment were evaluated by univariate analysis (Table 3). Older age, higher APACHE II score, septic shock, cancer and treatment with polymyxins were significantly associated with mortality during the treatment.


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  		Table 3. Univariate analysis of prognostic factors for mortality during treatment in patients with severe carbapenem-resistant Acinetobacter spp. infections treated with polymyxins or ampicillin/sulbactam in two large teaching hospitals from 1996 to 2004

 
Table 4 shows the univariate analysis of potential prognostic factors for in-hospital mortality. Significant factors were: older age, hospitalization in Hospital das Clínicas, higher APACHE II score, septic shock and mechanical ventilation on the first day of treatment.


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  		Table 4. Univariate analysis of prognostic factors for in-hospital mortality in patients with severe carbapenem-resistant Acinetobacter spp. infections treated with polymyxins or ampicillin/sulbactam in two large teaching hospitals from 1996 to 2004

 
The following variables were included in the multivariate analysis of prognostic factors associated with mortality during treatment: age (classified as ≥58 and <58 years, the median age of all patients), cancer, septic shock, APACHE II score (classified as ≥15 and <15 points), treatment (polymyxin or ampicillin/sulbactam), time elapsed before starting antibiotics (classified as ≤48 and >48 h) and hospital involved.

Variables included in the multivariate analysis to evaluate in-hospital mortality were: age (classified as ≥58 and <58 years), cancer, septic shock, mechanical ventilation, APACHE II score (classified as ≥15 and <15 points), treatment (polymyxin or ampicillin/sulbactam) and hospital involved.

Multiple logistic regression analysis revealed that treatment with polymyxins, higher APACHE II score, septic shock, delay in starting treatment and onset of renal failure were independent predictors of mortality during treatment. Older age, septic shock and higher APACHE II score were prognostic factors for in-hospital mortality (Table 5).


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  		Table 5. Multivariate analysis of risk factors associated with mortality during treatment and in-hospital mortality in patients with severe carbapenem-resistant Acinetobacter spp. infections treated with polymyxins or ampicillin/sulbactam in two large teaching hospitals from 1996 to 2004

 

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Despite the increasing frequency of infections caused by multidrug-resistant Acinetobacter, studies evaluating therapeutic options against these infections are scarce. Our objective was to investigate the efficacy and safety of polymyxins and ampicillin/sulbactam for the treatment of these infections and prognostic factors for mortality.

There were three major groups: patients who did not receive adequate treatment, those treated with ampicillin/sulbactam and those treated with polymyxins, of which half of them received colistin and half received polymyxin B. The polymyxin group contained significantly older patients, more frequently submitted to surgical procedures and had more patients with cancer. However, we believe that multivariate analysis adjusted for these differences.

Seventy-five per cent of the non-treated patients died within 72 h of specimen collection, suggesting lack of time to identify the aetiological agent and start treatment. The fact that these patients presented a slightly higher APACHE II score than the other two groups suggests that they had a worse underlying clinical condition.

Among treated patients, we analysed two outcomes: mortality during treatment and in-hospital mortality.

The main finding of our study is that treatment with polymyxins was independently associated with death during treatment when compared with treatment with ampicillin/sulbactam. We also demonstrated, in agreement with the findings of other studies,26–28 that the time to start the antibiotic regimen is an important factor in determining outcome. Other variables independently associated with mortality during treatment of patients with severe carbapenem-resistant Acinetobacter spp. were: severity of clinical condition (especially septic shock) and renal failure during treatment. These variables reflecting patients' underlying disease and clinical condition have been found to be the predictors of mortality in patients with Acinetobacter infections in previous studies.29,30

The choice of the antibiotic was not significantly associated with in-hospital mortality. A possible explanation for this observation is the severity of the illness of our population. In general, it may be difficult to distinguish mortality attributable to Acinetobacter baumannii infection from that attributable to the co-morbidities in severely ill patients. Thus, in this scenario, antibiotic treatment may not be a major determinant of survival. Infections by Acinetobacter may even be considered markers of severity of the patient's clinical condition and high risk of death during hospitalization.

Another interesting finding in our analysis was that renal failure during treatment occurred in the same proportion (26%) in both groups. However, the ampicillin/sulbactam group had more patients with baseline renal dysfunction, which may have influenced the treatment choice of the physician to use ampicillin/sulbactam. Neurotoxicity was not observed, but this may have been underestimated as most patients were sedated and under mechanical ventilation. A recent review, however, suggested that polymyxins are less toxic than previously reported.31

The main limitation of our study is that it is retrospective. Nevertheless, we used strict diagnostic criteria for infections and found that medical records provided adequate information. Clinical prospective randomized drug trials are very expensive and have been financed almost exclusively by pharmaceutical companies. Badly needed drugs that lack commercial interest, such as polymyxins, have low chances of being studied in prospective trials financed by the pharmaceutical industry. Funding will have to be obtained through non-profit organizations.

To our knowledge, this is the first study comparing current therapeutic options for infections due to carbapenem-resistant Acinetobacter. The most important finding of the present study is that ampicillin/sulbactam appears to be a more efficacious therapy than polymyxins.


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None to declare.


   Acknowledgements
 
We thank Cilmara P. Garcia, Marjorie Shafferman and Maria Beatriz Souza Dias for their review of the manuscript.


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1 Van Looveren M, Goossens H, the ARPAC Steering Group. Antimicrobial resistance of Acinetobacter spp. in Europe. Clin Microbiol Infect (2004) 10:684–704.[CrossRef][Web of Science][Medline]

2 Falagas ME, Kasiakou SK, Nikita D, et al. Secular trends of antimicrobial resistance of blood isolates in a newly founded Greek hospital. BMC (2006) 6:9.[CrossRef]

3 Guzmán-Blanco M, Casellas JM, Sader HS. Bacterial resistance to antimicrobial agents in Latin America. Infect Dis Clin North Am (2000) 14:67–81.[CrossRef][Web of Science][Medline]

4 Wood GC, Hanes SD, Croce MA, et al. Comparison of ampicillin-sulbactam and imipenem-cilastatin for the treatment of Acinetobacter ventilator-associated pneumonia. Clin Infect Dis (2002) 34:1425–30.[CrossRef][Web of Science][Medline]

5 Jellison TK, Mckinnon PS, Rybak MJ. Epidemiology resistance outcomes of Acinetobacter baumannii bacteremia treated with imipenem-cilastatin or ampicillin-sulbactam. Pharmacotherapy (2001) 21:142–8.[CrossRef][Web of Science][Medline]

6 Garnacho-Montero J, Ortiz-Leyba C, Jimenez-Jimenez FJ, et al. Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-susceptible VAP. Clin Infect Dis (2003) 36:1111–8.[CrossRef][Web of Science][Medline]

7 Reina R, Estenssoro E, Saenz G, et al. Safety and efficacy of colistin in Acinetobacter and Pseudomonas infections: a prospective cohort study. Intensive Care Med (2005) 31:1058–65.[CrossRef][Web of Science][Medline]

8 Levin AS, Barone AA, Penco J, et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis (1999) 28:1008–11.[Web of Science][Medline]

9 Michalopoulos AS, Tsiodras S, Rellos K, et al. Colistin treatment in patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria: the renaissance of an old antibiotic. Clin Microbiol Infect (2005) 11:115–21.[CrossRef][Web of Science][Medline]

10 Markou N, Apostolakos H, Koumoudiou C, et al. Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients. Crit Care (2003) 7:R78–83.[CrossRef][Web of Science][Medline]

11 Kasiakou SK, Michalopoulos A, Soteriades ES, et al. Combination therapy with intravenous colistin for management of infections due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis. Antimicrob Agents Chemother (2005) 49:3136–46.[Abstract/Free Full Text]

12 Berlana D, Llop JM, Fort E, et al. Use of colistin in the treatment of multiple-drug-resistant Gram-negative infections. Am J Health Syst Pharm (2005) 62:39–47.[Abstract/Free Full Text]

13 Falagas ME, Bliziotis IA, Kasiakou SK, et al. Outcome of infections due to pandrug-resistant (PDR) Gram-negative bacteria. BMC Infect Dis (2005) 5:24.[CrossRef][Medline]

14 Corbella X, Ariza J, Ardanuy C, et al. Efficacy of sulbactam alone and in combination with ampicillin in nosocomial infections caused by multiresistant Acinetobacter baumannii. J Antimicrob Chemother (1998) 42:793–802.[Abstract/Free Full Text]

15 Levin AS, Levy CE, Manrique AE, et al. Severe nosocomial infections with imipenem-resistant Acinetobacter baumannii treated with ampicillin/sulbactam. Int J Antimicrob Agents (2003) 21:58–62.[CrossRef][Web of Science][Medline]

16 Cisneros JM, Reyes MJ, Pachón J, et al. Bacteremia due to Acinetobacter baumannii: epidemiology, clinical findings, and prognostic features. Clin Infect Dis (1996) 22:1026–32.[Web of Science][Medline]

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21 National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fourth Edition: Approved Standard M7-A4. (1996) Wayne, PA, USA: NCCLS.

22 National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing: M100-S5. (1996) Wayne, PA, USA: NCCLS.

23 Gales AC, Jones RN, Sader HS. Global assessment of the antimicrobial activity of polymyxin B against 54731 clinical isolates of Gram-negative bacilli: report from the SENTRY antimicrobial surveillance programme (2001–04). Clin Microbiol Infect (2006) 12:315–21.[CrossRef][Web of Science][Medline]

24 Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med (1985) 13:818–29.[Web of Science][Medline]

25 Bellomo R, Ronco C, Kellum JA, et al. Acute Dialysis Quality Initiative workgroup. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care (2004) 4:R204–12.

26 Kollef MH, Sherman G, Ward S, et al. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest (1999) 115:462–74.[CrossRef][Web of Science][Medline]

27 Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcome in the ICU setting. Chest (2000) 118:146–55.[CrossRef][Web of Science][Medline]

28 Iregui M, Ward S, Sherman G, et al. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest (2002) 122:262–8.[CrossRef][Web of Science][Medline]

29 Choi JY, Park YS, Kim CO, et al. Mortality risk factors of Acinetobacter baumannii bacteraemia. Intern Med J (2005) 35:599–603.[CrossRef][Web of Science][Medline]

30 Chen HP, Chen TL, Lai CH, et al. Predictors of mortality in Acinetobacter baumannii bacteremia. J Microbiol Immunol Infect (2005) 38:127–36.[Medline]

31 Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care (2006) 10:R27.[CrossRef][Medline]


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