Monotherapy versus combination therapy against

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Original Article

Monotherapy versus combination therapy against carbapenem‑resistant Gram‑negative bacteria: A retrospective observational study Ghafur A, Devarajan V, Raja T1, Easow J1, Raja MA1, Sreenivas S1, Ramakrishnan B2, Raman SG1, Devaprasad D3, Venkatachalam B3, Nimmagadda R1 Departments of Infectious Diseases, 1Oncology, 2Statistics and 3Intensive Care, Apollo Speciality Hospital, Chennai, Tamil Nadu, India Correspondence to: Dr. Abdul Ghafur, E‑mail: [email protected]

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. Key Words: Colistin combination therapy, colistin monotherapy, extensive drug resistance Gram‑negative bacteria, neutropenic fever, New Delhi metallo‑β‑lactamase

Introduction 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 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. Access this article online Quick Response Code:

Website: www.indianjcancer.com DOI: 10.4103/0019-509X.204767 PMID: *******

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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 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 The current practice of using combination therapy to treat CRGNB infections is due to reported survival benefit based on small retrospective case series.[1‑6] 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 593

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Table 2: Subgroup analysis Characteristics Neutropenic (n=36) out of 91 CRGNB Mortality Nonneutropenic (n=55) out of 91 CRGNB Mortality Pitts score Enterobacteriaceae (n=55) Mortality Enterobacteriaceae in neutropenics (n=29) Mortality Nonfermenters (n=36) out of 91 Mortality Pitts score ICU (n=70) Mortality Apache II score Pitts score ICU patients with APACHE II >20 (n=44) Mortality ICU patients with APACHE II