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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 3  |  Page : 87-94

Colistin monotherapy versus colistin-based combination therapy in the treatment of extensive drug-resistant Acinetobacter baumannii infections: A retrospective cohort study


1 Department of Critical Care, Dr. Sulaiman Al Habib Medical Group, Riyadh, KSA
2 McMaster University, Division of Critical Care, Hamilton, Canada
3 Department of Pharmacy, Security Forces Hospital, Riyadh, KSA
4 Department of Medicine, Infectious Diseases Division, Prince Mohamed Bin Abdulaziz Hospital, Ministry of Health, Riyadh, KSA
5 Department of Critical Care, Security Forces Hospital, Riyadh, KSA
6 Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
7 Internal Medicine Department, Medical student at King Abdul-Aziz University, Jeddah, KSA
8 Department of Internal Medicine, Security Forces Hospital, Riyadh, KSA
9 Department of Pathology, King Saud Medical City, Jeddah, KSA
10 Department of Internal Medicine, Dr. Sulaiman Al Habib Medical Group, Riyadh, KSA

Date of Web Publication16-Feb-2018

Correspondence Address:
Awad Al-Omari
Department of Critical Care, Dr. Sulaiman Al Habib Medical Group, Riyadh
KSA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sccj.sccj_18_17

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  Abstract 


Introduction: Acinetobacter baumannii is a Gram-negative Coccobacillus and is a frequent cause of hospital-acquired infections. Because some strains of A. baumannii are resistant to many antibiotics (i.e., extensively drug-resistant A. baumannii, or XDRAB), selecting antibiotics to treat infected patients is challenging. Clinical outcomes in critically ill patients with XDRAB infections are poor. In this study, we evaluated the clinical effectiveness of colistin as monotherapy and in combination with other antibiotics. Patients and Methods: A retrospective cohort study was performed on 94 critically ill patients (age ≥18 years) to assess the clinical effectiveness of treating XDRAB infections with colistin, either in monotherapy or combination with tigecycline, meropenem, or both. Clinical and microbiological data were obtained from patient records. We included patients suffering from XDRAB ventilation-associated pneumonia (VAP), or ventilator-associated tracheobronchitis (VAT), or VAT with bacteremia. Results: The mean age of the patients was 53.3 years (±23.7 years), and the mean Acute Physiology and Chronic Health Evaluation II score was 22.7 (standard deviation = 7.1). VAP and VAT with bacteremia were found in 84% and 16% of patients, respectively. Half (51%) of patients achieved microbiological clearance. The median Intensive Care Unit (ICU) stay was 29 days (interquartile range [IQR]: 17, 55) and the median mechanical ventilation (MV) duration was 21 days (IQR: 12, 42). MV duration and ICU length of stay were lower in the group of patients treated with colistin and meropenem than in those treated with colistin alone. Mortality was significantly lower in patients who received (colistin and tigecycline 30%) than in those who were treated with monotherapy (75%) with an odd ratio 0.03 (95% confidence interval: 0.00, 0.32; P < 0.01). Conclusions: Colistin-based combination treatment regimens mainly with tigecycline or with tigecycline and meropenem were associated with better treatment outcomes of XDRAB-induced VAP and VAT with bacteremia than colistin monotherapy.

Keywords: Acinetobacter baumannii, colistin, combination therapy, extensively drug-resistant Acinetobacter baumannii, tigecycline, ventilation-associated pneumonia


How to cite this article:
Al-Omari A, Alhazzani W, Al-Subaie MF, Memish Z, Abdelwahed H, Ma J, Alamri MA, Alenazi SS, Al-Shammari H, Aljomaah H, Salih S, Al-Obeid S. Colistin monotherapy versus colistin-based combination therapy in the treatment of extensive drug-resistant Acinetobacter baumannii infections: A retrospective cohort study. Saudi Crit Care J 2017;1:87-94

How to cite this URL:
Al-Omari A, Alhazzani W, Al-Subaie MF, Memish Z, Abdelwahed H, Ma J, Alamri MA, Alenazi SS, Al-Shammari H, Aljomaah H, Salih S, Al-Obeid S. Colistin monotherapy versus colistin-based combination therapy in the treatment of extensive drug-resistant Acinetobacter baumannii infections: A retrospective cohort study. Saudi Crit Care J [serial online] 2017 [cited 2018 Jun 23];1:87-94. Available from: http://www.sccj-sa.org/text.asp?2017/1/3/87/225728




  Introduction Top


Acinetobacter baumannii is a Gram-negative, round, rod-shaped Coccobacillus that acts as an opportunistic human pathogen. Numerous reports of infection in soldiers serving in Iraq and Afghanistan led to an increased interest in A. baumannii.[1]A. baumannii primarily affects critically ill Intensive Care Unit (ICU) and immunocompromised patients.[2] Several mechanisms of drug resistance have been acquired by A. baumannii, and these have led to an increased the prevalence of multidrug-resistant (MDR) strains.[3] Drug resistance mechanisms include the production of antimicrobial inactivation enzymes, efflux pumps, and altered porins.[3] Recently, A. baumannii has emerged as one of the most problematic pathogens that causes nosocomial infections, such as ventilation-associated pneumonia (VAP), bacteremia, surgical site infection, and urinary tract infection. Infections are particularly problematic in ICU patients,[2] in whom mortality rates approach 34%–43%.[4] Treatments for A. baumannii include sulbactam, carbapenems, amikacin, and some tetracyclines (doxycycline and minocycline).[5],[6] Polymyxin-class agents such as colistin and polymyxin B gained popularity after the emergence of carbapenem-resistant strains, and although these agents were clinically effective,[7] nephrotoxicity induced by colistin was observed in 27%–58% of patients.[8] Clinical outcomes in critically ill patients with MD A. baumannii (MDRAB) and extensively drug-resistant A. baumannii (XDRAB) infections are poor, and existing studies regarding treatment options are limited. In addition, research using newer anti-infective agents, such as tigecycline for the treatment of ICU patients with VAP, is lacking.[9] Treatment of patients with XDRAB infection is hampered by the lack of evidence supporting effective treatments, and clinical controversies and challenges remain. In this study, we evaluated the association of colistin as monotherapy and in combination with tigecycline or meropenem or both on treatment outcomes of critically ill patients with XDRAB infection.


  Patients and Methods Top


Study design

A retrospective cohort study was conducted on 94 adult patients with XDRAB VAP and ventilator-associated tracheobronchitis (VAT) with bacteremia at a tertiary hospital ICU in Saudi Arabia between January 1 and December 31, 2012. This tertiary care hospital receives approximately 18,000–19,000 admissions annually and has 29 ICU beds. For this study, we identified adult patients (age ≥18 years) who received any of the following regimens: colistin alone, colistin, and meropenem, colistin and tigecycline, or colistin, meropenem, and tigecycline. Pregnant patients and patients who received colistin therapy for <72 h were excluded from the study. For polymicrobial infections, patients were included only if antibiotic treatment was determined based on the presence of XDRAB. This study was approved by the research ethics board at our institution. We did not take consent for participation in the study because it is a retrospective study and was accepted by the ethics committee in our hospital.

Data extraction

XDRAB infections were diagnosed through positive cultures in 94 ICU patients with VAP or VAP with bacteremia. Data were collected for each patient as follows: patient demographics, microbiological variables (site of infection, with bacterial culture identification and sensitivity), current antibiotics, antibiotic treatment duration, renal replacement therapy, and outcomes of interest (ICU length of stay, duration of mechanical ventilation [MV], and mortality). Disease severity was assessed using Acute Physiology and Chronic Health Evaluation II (APACHE II) scores at ICU admission and on day 1 of antibiotic therapy. All-cause mortality was recorded 30 days from the onset of antibiotic treatment. Death caused by primary infection (attributable to A. baumannii infection) was defined as death occurring without resolution of signs and symptoms of infection and with no other cause of death identified.

Bacterial identification and antimicrobial susceptibility testing

Bacterial identification and antibiotic susceptibility were determined using a microdilution method with a commercial dehydrate panel (Siemens Healthcare Diagnostic Ltd. MicroScan, Sacramento, CA, USA), according to the manufacturer's instructions, and using the Kirby-Bauer disk diffusion test on Mueller-Hinton agar (Bio-Rad, Marnes-la-Coquette, France) according to the Clinical and Laboratory Standards Institute (formerly NCCLS). MDRAB strains were detected using CHROMagar Acinetobacter (CHROMagar, Paris, France), which is a recently developed selective agar that contains agents for inhibiting the growth of the most Gram-positive organisms as well as carbapenem-susceptible Gram-negative Bacilli. Screening of carbapenemase activity to analyze the production of Class B and D carbapenemase-resistant isolates was first performed by a modified Hodge test (MHT).[10]

Study outcomes

Retrospective data were collected on the length of stay in the ICU or death in the ICU. Clinical and microbiological responses were evaluated on the 5th day of treatment and at the end of the treatment. Evaluations were based on pre-specified definitions as described in the Definitions section below.

Definitions

According to the criteria of the European Committee on antimicrobial susceptibility testing and the United States Food and Drug Administration

Multidrug-resistant Acinetobacter baumannii

Defined as A. baumannii isolates which show nonsusceptibility to one or more agents in at least three antimicrobial categories. The antimicrobial categories of concern include aminoglycosides, antipseudomonal penicillins, antipseudomonal carbapenems, antipseudomonal cephalosporins, antipseudomonal fluoroquinolones, polymyxins, penicillin plus beta-lactamase inhibitors, trimethoprim-sulfamethoxazole, and tetracyclines.[11]

Extensively drug-resistant Acinetobacter baumannii

Defined as A. baumannii isolates which show nonsusceptibility to one or more agents in all antimicrobial categories but show susceptibility to one or two categories only. The antimicrobial categories of concern includes aminoglycosides, antipseudomonal penicillins, antipseudomonal carbapenems, antipseudomonal cephalosporins, antipseudomonal fluoroquinolones, polymyxins, penicillin plus beta-lactamase inhibitors, trimethoprim-sulfamethoxazole, and tetracyclines.[11]

Clinical cure

Clinical cure was defined as the resolution of clinical signs and symptoms of pneumonia or bacteremia in comparison with the baseline clinical status, improvement or absence of progression in chest radiographic findings, and additional antibacterial treatment is not required.[12]

Clinical failure

Clinical failure was defined as the persistence or worsening of baseline signs and symptoms of pneumonia or bacteremia after 2 or more days of treatment, progression of baseline imaging abnormalities, or development of new pulmonary or extra-pulmonary clinical findings (such as fever, chills, and hypotension) consistent with active infection.[12]

Microbiological eradication

Microbiological eradication was defined as the absence of A. baumannii from cultures obtained from the primary infection site.[12]

Microbiological persistence

Microbiological persistence was defined as the continued presence of A. baumannii in cultures obtained from the primary infection site despite antibiotics therapy.[12]

Length of stay

ICU length of stay was defined as the number of days spent in the ICU.[13]

Ventilator-associated pneumonia

VAP was defined as pneumonia (Clinical Pulmonary Infection Score >6) in patients requiring MV for more than 48 h.[14]

Ventilator-associated tracheobronchitis

VAT was diagnosed if all of the following criteria were present: (a) fever (>38°C) with no other recognizable cause, (b) purulent sputum production, (c) positive (≥106 colony-forming units [cfu] per milliliter) endotracheal aspirate culture containing novel A. baumannii (not present at intubation), and (d) no radiographic signs of new pneumonia.[15]

Nosocomial bloodstream infections

Patients were considered to have nosocomial bloodstream infection if they showed clinical signs of infection (such as fever, chills, and hypotension) and also provided at least one A. baumannii positive blood culture drawn at least 72 h after hospital admission.[16]

Ventilator-free days

Ventilator-free days were defined as days alive and off MV.[17]

Nephrotoxicity

Colistin-related nephrotoxicity was assessed using risk, injury, failure, loss, and end-stage kidney disease criteria.[18] Nephrotoxicity was evaluated in patients who received colistin therapy for 5 or more days.

Statistical analysis

Data from 94 patients were assessed in this retrospective study. This sample size was sufficient to allow the assessment of more than five variables when using a linear regression model with continuous outcomes (e.g., the duration of MV and ICU length of stay) with statistical power of 80% at a significance level of 0.05, assuming a medium effect size corresponding to R2 = 0.13.[19] Baseline clinical characteristics and outcomes were summarized by means of descriptive statistics such as mean and standard deviation [20] in case of normally distributed continuous variables, median and IQR for nonnormally distributed continuous variables, and count and percentage for categorical variables. Multiple linear regression models, with adjustment for age and sex, were used to assess the effect of synergistic therapies on MV duration and ICU length of stay. Model assumptions and goodness-of-fit were evaluated using the residuals plot and the R2. Where appropriate, outcome variables were logarithmically transformed to achieve a better goodness of fit. For logarithmically transformed outcomes, estimated coefficients were exponentiated and reported as changes in the ratio of expected mean of the outcome variables. Logistic regression was used to investigate the association between synergistic therapies and mortality. Results from logistic regression analysis were reported as odds ratios (OR) and corresponding 95% confidence intervals (CI). The above analyses were also conducted separately for subgroups of patients with VAP and VAT to assess the effect of synergistic therapies in different subgroups. All analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA).


  Results Top


Clinical and statistical analysis

Ninety-four patients were included in the study (mean age ± standard deviation [SD] = 53.3 ± 23.7 years). The mean APACHE II score was 22.7 ± 7.1. Respiratory infection (VAP and VAT) was more prevalent (84.0% of patients) than bloodstream infection (16.0% of patients). The number of patients that received colistin alone, colistin + meropenem, colistin + tigecycline, or colistin + meropenem + tigecycline were 12, 36, 13, and 33 respectively. Approximately, 28.6% of patients had end-stage renal disease (ESRD) and received hemodialysis and overall, 35.1% of patients developed acute kidney injury that required hemodialysis. The overall microbiological clearance was achieved in 48/94 (51.06%) of patients receiving colistin either as monotherapy or in combination, in colistin monotherapy, the clearance was achieved in 7/12 (58.3%) patients while in combination of colistin with meropenem or tigecycline or meropenem plus tigecycline the clearance were 19/36 (52.8%), 7/13 (53.8%), and 15/33 (45.5%) patients, respectively. Patient characteristics are summarized in [Table 1]. Median MV duration was 21.0 days (IQR: 12.0, 42.0) and median ICU stay length was 29.0 days (IQR: 17.0, 55.0). The mortality rate was 47.9% (45/94 patients). Summary of these outcomes for patients receiving different antibiotic therapies are presented in [Table 2]. Results from linear regression analysis showed that MV duration for patients receiving colistin alone was 2.33-fold longer compared to patients treated with colistin + meropenem therapy (ratio of colistin + meropenem therapy to colistin alone, 0.43; 95% CI: 0.22, 0.85; P = 0.02). However, MV duration was not significantly lower for patients treated with any of the combined regimens compared to patients receiving colistin alone [Table 3]. Similarly, the ICU length of stay increased 96% for patients treated with colistin alone compared to patients receiving colistin + meropenem therapy (ratio of colistin + meropenem therapy to colistin alone, 0.51; 95% CI: 0.28, 0.93; P = 0.03), but ICU stay was not significantly lower for patients with combined treatments compared to patients receiving colistin alone [Table 3]. Risk of death was significantly lower in patients treated with colistin and meropenem (OR = 0.12; 95% CI: 0.02, 0.79; P = 0.03), colistin and tigecycline (OR = 0.03; 95% CI: 0.00, 0.32; P < 0.01), and colistin, meropenem and tigecycline (OR = 0.07; 95% CI: 0.01, 0.50; P < 0.01) compared to patients receiving colistin alone. Patients with VAP and VAT were analyzed separately [Table 1], [Table 2], [Table 3]. Forty-four patients were diagnosed with VAP (mean age ± SD = 62.0 ± 21.6 years). In this subgroup, the duration of MV was 4 times longer (ratio of colistin + meropenem therapy to colistin alone, 0.25; 95% CI: 0.09, 0.68; P = 0.01) and the ICU length of stay was 5 times longer (ratio of colistin + meropenem therapy to colistin alone, 0.20; 95% CI: 0.08, 0.54; P < 0.01) for patients receiving colistin alone compared to patients treated with colistin + meropenem. In addition, the ICU length of stay was 2.94 times longer for patients receiving colistin therapy alone compared to patients treated with the triple therapy (ratio of colistin + tigecycline + meropenem therapy to colistin alone, 0.34; 95% CI: 0.13, 0.89; P = 0.03). By contrast, MV duration and ICU length of stay for the 36 patients diagnosed with VAT (mean age ± SD = 41.1 ± 19.7 years) did not differ significantly for patients receiving different treatments.
Table 1: Summary of patient characteristics

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Table 2: Summary of patient outcomes

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Table 3: Regression analysis with combination as a predictor

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Microbiological analysis

In 2012, more than 90% of A. baumannii isolates from our hospital were XDRAB and were attributed as causing hospital-acquired infections. Twelve unique A. baumannii strains were isolated and were susceptible to colistin. Four of these unique strains were susceptible to gentamycin, one was susceptible to tigecycline and two were susceptible to ampicillin/sulbactam. Culture on CHROMagar Acinetobacter medium and modified CHROMagar supplemented with an antimicrobial (France) confirmed that all 12 strains studied were MDRAB. The inhibition of Pseudomonas aeruginosa growth confirmed the medium was specific medium for Acinetobacter. All of these 12 isolates were XDRAB. A MHT was used for detection of carbapenemases other than metallo-beta-lactamases. Overall, carbapenemase activity was detected in all clinical isolates (12/12) of XDRAB. Class-OXA-type enzymes (oxa-23 and oxa-24/40) was found to be the mediator of carbapenem resistance mechanism as revealed by molecular studies.[10]


  Discussion Top


In ICUs, MDRAB Pneumonia is the most common type of infection with a mortality rate of up to 43%.[2] Colistin is usually combined with sulbactam, cephalosporins, carbapenems, piperacillin-tazobactam, monobactams, aminoglycosides, fluoroquinolones, rifampin, tetracyclines, and tigecycline.[21] In this study, we investigated several treatment regimens for effectiveness against XDRAB infections. A. baumannii is resistant to a wide range of antibiotics and several studies found that antibiotics belonging to older classes are used preferentially for the treatment of the different infections caused by these strains, including colistin, polymyxin E, and polymyxin B. Despite the nephrotoxicity and neurotoxicity that often occurs when using these agents,[22] colistin remains the antibiotic of choice for treating XDRAB infections, and has a cure rate of 55%–80% as observed by some studies.[22] In recent years, A. baumannii isolates have become increasingly carbapenem-resistant as a result of the activity of OXA-type carbapenemases; however, Al-Obeid et al. detected the carbapenemase activity in all clinical isolates of XDRAB described in his study from Saudi Arabia, and found that OXA-23 was detected in11 out of 12 isolates and OXA-24/40 was detected in only one isolate.[10] The use of carbapenem therefore may increase the carbapenemase-producing A. baumannii and increases the risk of the emergence of multidrug-resistant strains.[23] Correspondingly, a significant decrease in the prevalence of MDRAB infections was achieved through restriction of carbapenem use in the ICU.[24],[25] Despite the lack of strong clinical evidence supporting the use of combination therapy over colistin monotherapy, combination therapy is frequently used as a therapeutic approach. Combination therapy is used due to its enhanced efficacy, and also to combat colistin-induced heteroresistance development,[26] rapid resistance selection, and drug toxicity. In vitro, Al-Obeid et al. detected good synergy between colistin and tigecycline against 25% of the isolates studied; this synergy was moderate for other antibiotics tested (carbapenem or piperacillin-tazobactam) (34). However, in this retrospective study, our results showed that the combination antibiotic therapies (especially colistin with tigecycline or with meropenem) were associated with better clinical outcomes (reduced mortality, ICU length of stay, and MV duration), than treatment with colistin alone, for patients with VAP and VAT, [Table 2].

Similar to VAP, VAT was associated with a high mortality rate;[27] however, little is known regarding disease management and optimal treatments. In this study, we used retrospective data to compare the effects of colistin monotherapy and various combination therapies in patients with VAT and VAP. However, numerous confounding factors are present in ICU patients, such as comorbid conditions, severity of underlying diseases, and variations in antibiotic treatment onset; therefore, our results must be interpreted accordingly. A randomized controlled trial is necessary to confirm or dispute the initial findings of this study. The mean APACHE II score in our study population was 22.7. Prior studies suggested that high APACHE II scores in patients with MDRAB infection are associated with higher 14–30 days mortalities. The mortality rate in our study population was 47.9%, which was similar to that reported in other studies.

[28] A recent Turkish study examined 214 patients from more than 27 locations and found that the cure rate and 14-day survival rate were higher in the colistin-based combination treatment group than in the colistin monotherapy group.[29] This was accompanied by a higher microbiological eradication rate in the combination group than in the single therapy group.[29] Our results also showed that the microbiological eradication rate was higher under combination therapy than in therapy with colistin alone. Lee et al. noted that combination carbapenem-sulbactam therapy was associated with better clinical outcomes in critically ill patients with MDRAB bacteremia.[30] Moreover, multiple in vitro studies found that antibiotic combination therapy was more effective than monotherapy in treating A. baumannii infection.[9],[30],[31],[32],[33] Several studies, including the present, showed that tigecycline, which is active against most carbapenemase-producing strains, may be used as an alternative to, or in combination with, polymyxin for the treatment of A. baumannii infection. Tigecycline has nevertheless been approved for the treatment of complicated intra-abdominal infections and complicated skin and soft tissue infections.[34] To the best of our knowledge, this is the first study with sufficient numbers of ICU patients to compare monotherapy with combination therapy in critically ill patients with XDRAB infections. However, a number of study limitations should be considered. First, the number of patients receiving colistin monotherapy was small (12 patients). Moreover, the results were limited by imprecision, despite having an overall significant effect. Second, retrospective studies are associated with higher risks of bias and greater difficulty in adjusting for confounding factors than randomized controlled trials. Third, the varied colistin dosages used in different patients may have produced variable clinical responses: recent studies suggested that standard doses of colistin might be insufficient for the treatment of Gram-negative MDR infection.[21] Finally, we observed in a number of ICU patients that all-cause mortality was lower with adjuvant inhaled colistin, falling from 45% to 18.75%, with colistin-IV and to 7% with colistin-IV + Tigecycline intravenous (unpublished observation).


  Conclusions Top


We propose that colistin-based combination treatment regimens (mainly with tigecycline or with tigecycline and meropenem) were associated with better treatment outcomes of XDRAB induced VAP and VAT than colistin monotherapy. However, the limitations of the study in terms of design and number of participants indicate that our conclusions must be viewed with caution and that a large randomized controlled trial is needed to confirm these initial findings.

Acknowledgment

We would like to thank Dr. Patrice Francoise (service of Infectious Diseases, Genomic Research Laboratory, CH-1211 Geneva 14, Switzerland) for help with the corrections of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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