Study On Doripenem In The Treatment Of Acute Bacterial Respiratory And Urinary Tract Infections

Part I Efficiacy of doripenem in acute bacterial respiratory and urinarytract infections:A multicenter,prospective,single-blind randomized andparallel-controlled clinical studyBACKGROUNDSCarbapenems are a class of atypical β-lactam antibiotics which have strongantibacterial activity and broad antimicrobial spectrum. Carbapenems are effective inhospital-acquired infections and have strong antibacterial effect on gram-positive andgram-negative aerobic and anaerobic bacteria, including producing extended-spectrumβ-lactamases (ESBLs) and cephalosporins enzyme (AmpC enzyme). But because of thewide and irrational use of carbapenems,in recent years, carbapenems resistance have beenincreased seriously, especially to pseudomonas aeruginosa and other non-fermentingbacterias. Doripenem, which developed by Shionogi&Co LTD (Japan), is the newestaddition to carbapenem antibiotics and launched in2005in Japan. Doripenem’s chemicalstructure is similar to that of meropenem, except that at position2the dimethylcarbamoylside chain of meropenem is replaced by the sulfamoylaminoethyl-pyrrolidinylthio group ofdoripenem. Doripenem was approved for the treatment of complicated intraabdominalinfections and complicated urinary tract by the US Food and Drug Administration in2007.According to the European Medicines Agency (EMEA), doripenem was indicated for thetreatment of the following infections: nosocomial pneumonia(includingventilator-associated pneumonia), complicated intra-abdominal infections, complicatedurinary tract infections, and cases with concurrent bacteremia in2008.OBJECTIVESTo evaluate the safety and efficacy of doripenem developed by JCTT PharmaceuticalCo., Ltd.in the treatment of acute moderate to severe infections of respiratory tract andurinary tract.METHODSThe study was designed as a multicenter, prospective,randomized, single-blinded,positive drug parallel-controlled and non-inferiority trial,comparing doripenem withmeropenem produced by Sumitomo Pharmaceuticals (Suzhou) Company.The patients wererandomized into trial group and control group,treated with doripenem0.25g andmeropenem0.5g3times daily intravenously,respectively. The duration of treatment was7to14days.The primary efficiacy endpoints were the clinical efficiacy of clinical cure and clinical invalid after treatment. The secondary efficacy endpoint was bacterial clearancerate after treatment. The evaluation standard security indicators were adverse events andadverse reactions.RESULTSThe study was completed by9sets,including the Shanghai Changzheng Hospital,Shanghai Sixth People’s Hospital, Central South University Xiangya Hospital.A total of282patients were enrolled（142in the trial group and140in the control group）.FAS showsthat in the respiratory tract infections, the cure rates of the trial group and control groupwere89.55%and85.07%, respectively; in the urinary tract infections, the cure rates of thetrial group and control group were87.50%and85.71%, respectively; the total cure thetotal cure rates of the trial group and control group were88.49%and85.40%，respectively;there was no significant difference between the two groups（P＞0.05）. The bacterialclearance rates of the trial group and control group were96.49%and98.25%，respectively,there was no significant difference between the two groups（P＞0.05）. The severe adverseevents rates of the trial group and control group were0.71%and1.45%respectively;Theadverse events rates of the trial group and control group were14.89%and10.87%respectively; The adverse reaction rates of the trial group and control group were6.38%and5.07%respectively; there was no significant difference between the two groups（P＞0.05）. The adverse reaction mainly included rash, elevated transaminase, leukopenia,neutropenia. The degree of the adverse reaction were mainly mild and disappeared at thefollow up.CONCLUSIONSDoripenem is safety and effective in the treatment of acute moderate to severerespiratory tract and urinary tract infections and is therapeutically non inferior tomeropenem.Part Ⅱ Study on the in vitro activity of doripenem against pseudomonasaeruginosa and resistant mechanisms of the carbapenem-resistantpseudomonas aeruginosaBACKGROUNDSPseudomonas aeruginosa is one of the most common opportunistic pathogens and hasstrong resistance and adaptability to external environment. Pseudomonas aeruginosa canlead to hospital-acquired pneumonia (including ventilator-associated pneumonia), urinary tract infections, wound infections, skin and soft tissue infections, bacteremia, and so on.Pseudomonas aeruginosa adds to difficulties on the treatmen of nosocomial infectionsbecause of its strong and complex mechanisms of resistance.OBJECTIVESTo valuate the antibacterial activity of doripenem against pseudomonas aeruginosain vitro and investigate the relationship between carbapenem-resistant pseudomonasaeruginosa with producing metallo-β-lactamase, loss of outer membrane protein OprD2and overexpression of efflux pump system.METHODSMICs of doripenem,meropenem,imipenem and other9kinds of antibiotics against105pseudomonas aeruginosa isolated from hospitalised patients in Changzheng Hospital and6hospitals in East China participating in clinical trials of antibacterial drugs in January toDecember,2012, were determined by broth dilution method.Metallo-enzymes phenotypicscreening of the carbapenem-resistant strains were examined by combined disk test.Polymerase Chain Reaction confirmed the blaVIM,blaIMP and OprD2gene. Expression ofthe efflux gene MexA, MexC,MexE,MexX were determined by realtime PCR.RESULTSThe rates of imipenem, aztreonam and piperacillin were above25%. The rates ofceftazidime, gentamicin, levofloxacin, meropenem-resistance were21~25%. The rates ofpiperacillin/tazobactam, ciprofloxacin-resistance were15~20%. The rates of doripenem,cefepime,amikacin-resistance were15%or less. MIC50of doripenem was equal to that ofmeropenem and2-fold potent than that of imipenem against pseudomonas aeruginosa.MIC90of doripenem was2-fold potent than that of meropenem and4-fold potent thanthat of imipenem against pseudomonas aeruginosa.The results of combined disk testshowed that no strains is positive.There were no blaIMP and blaVIM-type MBLsdetected in the30carbapenem-resistant pseudomonas aeruginosa by PCR. Twenty-fivecarbapenem-resistant PA were determined as lack of OprD2gene.The gene of5carbapenem-sensitive PA and ATCC27853were normal. All of the25PA loss of OprD2were resistant to imipenem,but7PA loss of OprD2were sensitive to meropenem and13were sensitive to doripenem.Eighteen stains overexpressed MexA,3stains overexpressedMexC,5stains overexpressed MexE and5stains overexpressed MexX. There were nooverexpression of efflux pump gene in the IMPRMEMSDORSandIMPSMEMSDORSgroup.The overexpression level of mexA in the meropenem and doripenem-resistant group was higher than that of the meropenem and doripenem-sensitive group, with significant difference between the two groups. The expressionlevel of mexA between the imipenem-resistant group and the imipenem-sensitive groupwas no significant. There were no significant difference between the doripenem,meropenem and imipenem-resistant group and the doripenem, meropenem andimipenem-sensitive group in the expression level of mexC,mexE,mexXCONCLUSIONSThe study showed that carbapenem resistance of pseudomonas aeruginosa wasserious in East China．MBLs were not the main mechanism of carbapenem resistance forpseudomonas aeruginosa in East China．Loss of OprD2was the main mechanism ofimipenem-resistant pseudomonas aeruginosa.Overexpression of MexAB-OprM was themain mechanism of doripenem, meropenem-resistant pseudomonas aeruginosa in EastChina.