Propranolol, chlorpromazine and diclofenac restore susceptibility of extensively drug-resistant (XDR)-Acinetobacter baumannii to fluoroquinolones

Abstract

Nosocomial infections caused by extensively drug-resistant (XDR) or Pan-Drug resistant (PDR) Acinetobacter (A.) baumannii have recently increased dramatically creating a medical challenge as therapeutic options became very limited. The aim of our study was to investigate the antibiotic-resistance profiles and evaluate the various combinations of ciprofloxacin (CIP) or levofloxacin (LEV) with antimicrobial agents and non-antimicrobial agents to combat antimicrobial resistance of XDR A. baumannii. A total of 100 (6.25%) A. baumannii clinical isolates were recovered from 1600 clinical specimens collected from hospitalized patients of two major university hospitals in Upper Egypt. Antimicrobial susceptibility tests were carried out according to CLSI guidelines. Antimicrobial susceptibility testing of the respective isolates showed a high percentage of bacterial resistance to 19 antimicrobial agents ranging from 76 to99%. However, a lower percentage of resistance was observed for only colistin (5%) and doxycycline (57%). The isolates were categorized as PDR (2; 2%), XDR (68; 68%), and multi-drug resistant (MDR) (30; 30%). Genotypic analysis using ERIC-PCR on 2 PDR and 32 selected XDR isolates showed that they were not clonal. Combinations of CIP or LEV with antibiotics (including, ampicillin, ceftriaxone, amikacin, or doxycycline) were tested on these A. baumannii non-clonal isolates using standard protocols where fractional inhibitory concentrations (∑FICs) were calculated. Results of the respective combinations showed synergism in 23.5%, 17.65%, 32.35%, 17.65% and 26.47%, 8.28%, 14.71%, 26.47%, of the tested isolates, respectively. CIP or LEV combinations with either chlorpromazine (CPZ) 200 μg/ml, propranolol (PR) in two concentrations, 0.5 mg/ml and 1.0 mg/ml or diclofenac (DIC) 4 mg/ml were carried out and the MIC decrease factor (MDF) of each isolate was calculated and results showed synergism in 44%, 50%, 100%, 100% and 94%, 85%, 100%, 100%, of the tested isolates, respectively. In conclusion, combinations of CIP or LEV with CPZ, PR, or DIC showed synergism in most of the selected PDR and XDR A. baumannii clinical isolates. However, these combinations have to be re-evaluated in vivo using appropriate animal models infected by XDR-or PDR-A. baumannii.

Impact of target site mutations and plasmid associated resistance genes acquisition on resistance of Acinetobacter baumannii to fluoroquinolones

“…Antimicrobial agents use strategies are known to significantly reduce the frequency of bacterial infections in patients 27 . Among which fluoroquinolones (FQs) have the widest use and are currently recommended by different physicians as they have multiple applications and different advanced generations 4 . Nevertheless the emergence and spread of bacterial resistance to FQs among Gram-negative bacteria generally and A. baumannii specifically is becoming increasingly serious with their extensive use.…”

“…A. baumannii infection is difficult to remedy, as of its everlasting fullness to acquire antimicrobial resistance due to the suppleness of its genome 30 . Many acquired resistance mechanisms have been reported for this pathogen and therefore, render it able to express MDR, XDR, or PDR phenotypes that were associated with significant morbidities and mortalities 4 . Therefore, this study aimed to determine the mechanisms behind A. baumannii resistance to FQs.…”

“…FQs in the last four decades had shown good activity against A. baumannii isolates, however, resistance to these drugs has quickly been rised 15 . FQs are a widely prescribed medication in Egypt, and FQs resistance has jumped up sharply 4 , 5 , 35 . Our findings emphasize that most A. baumannii isolates (71%) were recovered from patients treated for long period with FQs, while the rest (29%) of A. baumannii isolates were recovered from patients treated with other antimicrobial agents such as cephalosporins, imipenem, and the penicillin derivative (amoxicillin) or combination (amoxicillin-clavulanic acid).…”

“…Different acquired resistance mechanisms as a result of overuse by physicians or misuse of antibiotics by patients have been reported for this pathogen and therefore, causing it to be able to express PDR or extensively drug-resistant (XDR) phenotypes particularly among critically ill patients 4 . Fluoroquinolones (FQs) in the last four decades had shown good activity against A. baumannii isolates.…”

“…Fluoroquinolones (FQs) in the last four decades had shown good activity against A. baumannii isolates. However, resistance to these drugs has rapidly emerged 4 . FQs are a widely prescribed medication in Egypt, and quinolone resistance has jumped up sharply 5 .…”