| The increasing emergence of multidrug-resistant bacteria and even pan-resistant bacteria which is caused by extensively using of broad-spectrum antibiotics,immunosuppressive agents and invasive manipulation,is an important threat to the clinical anti-infective therapy.Tigecycline,one of a new class of glycylcyclines which been approved for clinical use in mainland China since 2012,remains active against many bacterial strains.Tigecycline resistant strain has not been discovered in China before 2013.However,in recent years,Shanghai Huashan Hospital detected the clinical tigecycline-resistant Acinetobacter baumannii and took knowledge of the resistant mechniasm of it.The potential development of resistance to tigecycline during treatment is of concern.The main purpose of this study was to investigate the potential resistance and efflux-mediated tigecycline-resistant mechanisms in Klebsiella(K.)pneumoniae.1.The mutant prevention concentrations(MPCs)of tigecycline for K.pneumoniaeDetermine the minimum inhibitory concentration(MIC)and the mutant prevention concentrations(MPCs)of tigecycline for K.pneumoniae clinical isolates with four different resistant statuses.Correlations between MICs and MPCs were analysed.We combined with tigecycline pharmacokinetics parameter to estimate the propensity of developing resistance to tigecycline monotherapy in K.pneumoniae.The MPCs of tigecycline for the cabapenem-and fluoroquinolone-resistant isolates were found to be 8-fold higher than those for cabapenemand quinolones-susceptible isolates.Our data showed that the MPC range and the MPC90 value of tigecycline were 4 μg/ml-512 μg/ml and 64μg/ml,respectively,which were much higher than the tigecycline concentrations in serum and tissues.Tigecycline monotherapy may be prone to the emergence of resistance with K.pneumoniae,and the monotherapy regimen was not recommended.2.The efflux-mediated tigecycline-resistant mechanisms of K.pneumoniaeInvestigate the efflux-mediated resistant mechanisms of K.pneumoniae and the role of pump regulators in promoting tigecycline resistance.Nine tigecycline-resistant K.pneumoniae isolates were obtained in the study,and six of them isolated before 2010.In order to check the clonality of the selected isolates,the isolates were typed by Multilocus sequence typing(MLST)and pulsed-field gel electrophoresis(PFGE).We identified two novel STs,namely ST 1414 and ST 1415.The expression levels of the efflux components acrA,acrB,tolC,oqxA,oqxB and the acrR,marA,soxS,rarA,rob,ramA regulator genes were assessed using RT-FQ-PCR.For the strains with an MIC value of 16 μg/ml,not only the AcrAB-TolC but also the OqxAB efflux pumps overexpression contributed to the tigecycline-resistance.3.Efflux pump transfer:a novel mechanism of tigecycline resistanceTo investigate a new mechanism behind tigecycline-resistance in K.pneumoniae using resistant clinical isolate A363R and susceptible isolate A363S derived from A363R.Contrasting the differences between the two strains by whole-genome sequencing,the plasmid genome sequencing and resistance gene annotation.Strain A363S and its parental strain A363R both belong to ST 11.The PFGE map showed only one band in isolate A363R that was absent from A363S.Compared to isolates A361 and A368 that have the same tigecycline MIC(16 μg/ml),the expression levels of efflux pump genes and pump regulators(acrB,oqxB,marA,rarA)were relatively low in strain A363R and very low in A363S.Of particular note,tigecycline resistant isolate A363R did not show high expression of oqxB.Synteny analysis and genome annotation showed that strain A363R had some DNA fragments that were missing from A363S;one contained the resistance gene mexd that leads to intrinsic tigecycline resistance in Pseudomonas(P.)aeruginosa.The MexCD efflux pump may be could transfer from P.aeruginosa to K.pneumoniae and plays a major role in tigecycline-resistance,and this transfer may be caused by plasmid-mediated.4.The effectiveness of tigecycline-based combination treatment versus monotherapy:a systematic reviewWe systematically reviewed the clinical efficacy of TGC alone or in combination with other antibiotics.PubMed,Embase,and the Cochrane Library,and relevant references and conference proceedings were searched for randomised controlled trials,cohort studies,case series,and case reports,according to a set of inclusion criterias.Nine comparative studies(1510 episodes)and 22 non-comparative studies(26 episodes)were finally included for review.Comparative studies showed no significant differences between TGC-based combination and TGC monotherapy.However,23 out of 26 cases demonstrated better clinical efficacy of TGC combination therapy.Additionally,utilization of TGC plus colistin,or a carbapenem,or an aminoglycoside,or a fluoroquinolone seemed more frequently among the combination regimens.In conclusion,there is no sufficient data to allow any statement as to the "best" combination therapy,even if one assumes that monotherapy is not adequate.In the future,it requires more prospective,randomized,comparative clinical trials to provide solid evidence with respect to the effectiveness of TGC-based combination and TGC monotherapy. |
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