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  Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 4  |  Page : 592-594
 

Monotherapy versus combination therapy against carbapenem-resistant Gram-negative bacteria: A retrospective observational study


1 Department of Infectious Diseases, Apollo Speciality Hospital, Chennai, Tamil Nadu, India
2 Department of Oncology, Apollo Speciality Hospital, Chennai, Tamil Nadu, India
3 Department of Statistics, Apollo Speciality Hospital, Chennai, Tamil Nadu, India
4 Department of Intensive Care, Apollo Speciality Hospital, Chennai, Tamil Nadu, India

Date of Web Publication21-Apr-2017

Correspondence Address:
A Ghafur
Department of Infectious Diseases, Apollo Speciality Hospital, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.204767

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 » Abstract 

BACKGROUND: Colistin-based combination therapy (CCT) is extensively used to treat infections due to carbapenem-resistant Gram-negative bacteria (CRGNB). There are no data available from India on the usefulness of combination therapy, especially in the oncology setup. The aim of this study was to analyze the clinical effectiveness of CCT over monotherapy in patients with CRGNB. MATERIALS AND METHODS: We conducted a retrospective, observational study of patients with CRGNB bloodstream infections in our oncology and bone marrow transplant center. RESULTS: Over a 3-year study period (2011–2014), we could identify 91 patients satisfying study criteria. There was no statistically significant difference in the 28-day mortality between monotherapy and combination therapy arms (mono n = 26, mortality 10 (38.5%); combination n = 65, mortality 28 (40%); P = 0.886). Neutropenic patients with Enterobacteriaceae bloodstream infections performed better with combination therapy (mono n = 7, mortality 6 (85.7%); combination therapy n = 22, mortality 8 (36.4%); P = 0.035). There was no significant difference in the 28-day mortality between the two treatment arms in other subgroups. CONCLUSION: Our study did not find CCT superior to colistin monotherapy in patients with CRGNB blood stream infections; except in the subgroup of neutropenic patients with Enterobacteriaceae bloodstream infections, where combination therapy performed better.


Keywords: Colistin combination therapy, colistin monotherapy, extensive drug resistance Gram-negative bacteria, neutropenic fever, New Delhi metallo-β-lactamase


How to cite this article:
Ghafur A, Devarajan V, Raja T, Easow J, Raja M, Sreenivas S, Ramakrishnan B, Raman S, Devaprasad D, Venkatachalam B, Nimmagadda R. Monotherapy versus combination therapy against carbapenem-resistant Gram-negative bacteria: A retrospective observational study. Indian J Cancer 2016;53:592-4

How to cite this URL:
Ghafur A, Devarajan V, Raja T, Easow J, Raja M, Sreenivas S, Ramakrishnan B, Raman S, Devaprasad D, Venkatachalam B, Nimmagadda R. Monotherapy versus combination therapy against carbapenem-resistant Gram-negative bacteria: A retrospective observational study. Indian J Cancer [serial online] 2016 [cited 2019 Dec 12];53:592-4. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/592/204767



 » Introduction Top


Rising prevalence of carbapenem-resistant Gram-negative bacteria (CRGNB) is a serious global threat, with a resultant increase in morbidity and mortality of patients.[1],[2] Colistin-based combination therapy (CCT) can result in better clinical outcome of patients with CRGNB infections though this opinion is largely based on observational studies.[2] Combination therapy can also reduce the development of colistin heteroresistance as proven in in vitro studies; however, the argument is yet to be supported in clinical studies.[1]

There are inadequate data on the clinical outcome of CRGNB infections from India. The aim of this study was to analyze the clinical effectiveness of CCT over colistin monotherapy (CM) in patients with CRGNB.


 » Materials and Methods Top


Retrospective analysis of 91 patients who had carbapenem-resistant Gram-negative bacteremia (CRGNB) identified over a period of 3 years (January 2011–December 2014) was done by medical records review at Apollo Speciality Hospital, a 300-bedded Tertiary Care Oncology, Neurosurgical and Orthopedic Center in South India. Institutional Ethics Committee approved the study.

Bacterial identification and susceptibility were done using VITEK2 compact system (bioMérieux, France). Susceptibility results were interpreted according to the Clinical and Laboratory Standards Institute guideline. CRGNB was defined as resistant to imipenem and/or meropenem in vitro. Colistin susceptibility was done using VITEK2 compact for all isolates and some isolates minimum inhibitory concentration by E-test according to availability.

Hospital identification numbers of patients with CRGNB bacteremia were recovered from microbiology laboratory, and their medical records were tracked and analyzed. Data for variables such as age, sex, underlying immunocompromising condition, co-morbidities, Intensive Care Unit (ICU) stay, duration of the first isolate from admission, colistin administration within 24 h of index date of blood culture collection, colistin dose, duration and cumulative dose, presence of indwelling devices, and prior antibiotic exposure were looked into. Pitt bacteremia score and Charlson comorbidity index were calculated for all patients. Acute Physiology and Chronic Health Evaluation II (APACHE II) score was calculated for ICU patients. The outcome including 28-day mortality was analyzed. Antimicrobial therapy was considered appropriate if the regimen included antibiotics that were active in vitro. Only the first bacteremic episode from each patient was included in this study. Patients with polymicrobial bacteremia were excluded. Those patients who received colistin, carbapenem, or tigecycline for <72 h were excluded from the study. Neutropenia was defined as a neutrophil count lower than 1000/mm 3. Treatment given before obtaining susceptibility results was defined as empirical.


 » Results Top


Of 114 patients with CRGNB bloodstream infections, 91 satisfied study criteria; 10 (10.9%) patients with Escherichia coli, 45 (49.4%) patients with Klebsiella, 26 (28.5%) patients with Acinetobacter, and 10 (10.9%) patients with Pseudomonas. Majority of patients (67 out of 91; 73.6%) were diagnosed to have hematologic (n = 39) or solid organ malignancy (n = 28). There were 21 neurosurgical patients and 3 with other underlying diseases. Thirty-six (40%) patients were neutropenics. CM was administered in 26 (28.5%) patients and CCT (with meropenem and or tigecycline) in 65 (71.4%) patients. There was no statistically significant difference in the 28-day mortality between monotherapy and combination therapy arms (38.5% and 40%, respectively) (P = 0.886). Of 91 patients, 37 patients received colistin plus meropenem combination, 15 patients received triple combination of colistin plus meropenem plus tigecycline, 13 patients received colistin plus tigecycline combination, and 26 patients received colistin monotherapy.

The monotherapy and combination therapy arms were comparable in terms of all variables. Subgroup analysis of 36 (40%) neutropenic patients (both arms with similar Pitt bacteremia score) did not divulge any significant difference in the mortality between the two treatment arms (P = 0.463). The finding was similar in the nonneutropenic group as well (P = 0.236) [Table 1].
Table 1: Analysis of 91 patients with carbapenem-resistant Gram-negative bacteria bloodstream infections

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Of the 91 patients, 40 (44%) had received colistin on the day of blood sample collection, on empirical basis. Mean colistin dose administered was 8.5 ± 1.1 in combination therapy arm and 8.7 ± 0.8 in monotherapy arm (overall mean 8.6 ± 1.02 in n = 91 patients). Subgroup analysis of 55 patients with CR Enterobacteriaceae bacteremia (E. coli-10 [18.1%], Klebsiella 45 [81.9%]) also did not demonstrate any statistical significant difference in mortality between the two arms (mono n = 16, CCT n = 39, P = 0.332). Of the 55 patients in the Enterobacteriaceae group (ICU and non-ICU), subgroup analysis of neutropenics patients (n = 29) revealed a significant mortality difference favoring combination therapy (monotherapy n = 7, mortality 6 [85.7%]; combination therapy n = 22, mortality 8 [36.4%] P = 0.035) [Table 2]. Triple drug combination of colistin with carbapenem and tigecycline had the lowest mortality (colistin plus meropenem plus tigecycline 2 out of 10 died, colistin plus meropenem 5 out of 10 died, P = 0.041), with all groups having similar Pitt bacteremia score and Charlson comorbidity index. There was no significant mortality difference between the two treatment arms in patients with nonfermenter (Acinetobacter and Pseudomonas) bacteremia (n = 36) as well (P = 0.067), but combination arm had high Pitt score (P = 0.007).
Table 2: Subgroup analysis

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A subgroup analysis of patients in ICU (n = 70) also did not reveal any significant difference between the mono and combination arms. Combination arm had patients with higher severity of illness, having higher APACHE II (P = 0.042) and Pitt score (P = 0.036) compared to patients in monotherapy arm. As we did not have enough variables with significance, a multivariate analysis was not feasible. Therefore, a subgroup analysis of patients in ICU-based on APACHE II score was done. Patients with APACHE II score cutoff value of >20, denoting higher severity of illness were analyzed separately (n = 44), monotherapy (n = 10), combination therapy (n = 34), 28 day mortality was 7 (70%) in mono and 21 (61.8%) in combination (P = 0.724), and this analysis also did not reveal any difference in the mortality between the two arms. An analysis of alive (n = 35) and dead (n = 35) patients in the ICU did not disclose any statistically significant difference between the receipt of either mono or combination therapy in the two groups (P = 0.98).


 » Discussion Top


The current practice of using combination therapy to treat CRGNB infections is due to reported survival benefit based on small retrospective case series.[1],[2],[3],[4],[5],[6] Systematic review by Falagas suggested that combination antibiotic treatment may offer a comparative advantage over monotherapy with regard to the mortality of critically ill patients with severe infections due to carbapenemase-producing Klebsiella spp.[2] A meta-analysis by Paul et al. concluded that none of the individual studies or their pooled result showed a difference in mortality between colistin alone and colistin/carbapenem combination therapy for CR Gram-negative bacterial infections.[1] A very recent paper by Tumbarello et al. including multicenter retrospective data of 447 bacteremic episodes found combination therapy including carbapenem having a significant survival benefit, in those cases where meropenem MIC of the isolates were <8.[7] There are no published clinical data from India on combination therapy, especially with an oncology setup.

The current study did not find significant overall mortality difference between colistin mono and combination therapy groups. Subgroup analysis of neutropenics with Enterobacteriaceae bacteremia did demonstrate a mortality benefit, with the colistin-based combination, especially the triple combination of colistin, tigecycline, and meropenem but not among nonneutropenics with Enterobacteriaceae bloodstream infections. A large case series by Tumbrello et al.[3] had earlier reported mortality benefit with the triple combination against CR Klebsiella bacteremia while we could replicate this finding only in our neutropenic patients with Enterobacteriaceae bloodstream infection group and not among nonneutropenics. Though patients with nonfermenter bacteremia had similar mortality in both treatment arms, patients in combination arm had higher Pitt bacteremia score; hence, we cannot comment whether the combination arm could have had a survival benefit if both arms had similar Pitt scores. There was no significant mortality difference between the mono and combination arms in the ICU patients, including the subgroup with higher APACHE II score. However, it is difficult to confidently rule out any potential survival benefit of combination in sicker patients.

The overall mean daily dose of colistin used in the study patients was 8.6 million units. This could be one of the reasons why there was no statistically significant mortality difference between the two arms. In many earlier studies, dose of colistin was less than the current recommended 9 million, biasing results against CM.[1]

The retrospective nature and single center data were the main limitations of our study. The number of patients included in our study is indeed is not small, in comparison to many other single center studies on the subject with similar or smaller number of patients.[3],[4],[5],[6] However, only prospective randomized trials can have adequate number of patients to achieve power to solve the combination therapy conundrum.


 » Conclusion Top


Our study did not find CCT superior to CM in patients with CRGNB bloodstream infections; except in the subgroup of neutropenic patients with Enterobacteriaceae bloodstream infections, where combination therapy performed better. Randomized controlled trials are the need of the hour in India to prove or disprove the benefit of CCT, especially in patients with severe sepsis.

Acknowledgment

We express our gratitude to Mr. Karthik and Ms. Veena for assisting us in data collection. The study was carried out with the research grant from AstraZeneca as an investigator-initiated study. The design or data collection of the study and the content of the paper are in no way influenced by the grant provider.

Financial support and sponsorship

The study was carried out with the research grant from AstraZeneca, as an investigator-initiated study. The design or data collection of the study and the content of the paper are in no way influenced by the grant provider.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Paul M, Carmeli Y, Durante-Mangoni E, Mouton JW, Tacconelli E, Theuretzbacher U, et al. Combination therapy for carbapenem-resistant Gram-negative bacteria. J Antimicrob Chemother 2014;69:2305-9.  Back to cited text no. 1
    
2.
Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: Systematic evaluation of the available evidence. Antimicrob Agents Chemother 2014;58:654-63.  Back to cited text no. 2
    
3.
Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: Importance of combination therapy. Clin Infect Dis 2012;55:943-50.  Back to cited text no. 3
    
4.
Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: Superiority of combination antimicrobial regimens. Antimicrob Agents Chemother 2012;56:2108-13.  Back to cited text no. 4
    
5.
Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: Lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 2014;58:2322-8.  Back to cited text no. 5
    
6.
Zarkotou O, Pournaras S, Tselioti P, Dragoumanos V, Pitiriga V, Ranellou K, et al. Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect 2011;17:1798-803.  Back to cited text no. 6
    
7.
Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M, et al. Infections caused by KPC-producing Klebsiella pneumoniae: Differences in therapy and mortality in a multicentre study. J Antimicrob Chemother 2015;70:2133-43.  Back to cited text no. 7
    



 
 
    Tables

  [Table 1], [Table 2]

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