In vitro Combined Inhibitory Activities of β-Lactam Antibiotics and Clavulanic Acid Against blaKPC-2-Positive Klebsiella pneumoniae

Background The spread of KPC-producing Enterobacteriaceae has triggered a global public health concern, with KPC-2-positive strains being the most prevalent in China. We hereby studied the in vitro combined inhibitory activities of three kinds of β-lactam antibiotics and clavulanic acid at different concentrations against blaKPC-2-positive Klebsiella pneumoniae to explore the antimicrobial characteristics of these combinations and alternative therapeutic regimens for infections caused by blaKPC-2-positive K. pneumoniae strains. Materials and Methods In this study, 153 clinically isolated blaKPC-2-positive K. pneumoniae strains from 19 provinces in China were collected from 2016 to 2018. Antimicrobial susceptibility testing of imipenem/clavulanic acid, meropenem/clavulanic acid, ceftazidime/clavulanic acid, and each antimicrobial agent alone was performed by broth microdilution technique according to the CLSI guidelines. The concentration ratios of β-lactam antibiotics to clavulanic acid were as follows: 1:1, 1:2, 1:4, 1:8, 1:16, 1:32. The antimicrobial susceptibility of the combinations was determined according to the breakpoints of Imipenem, meropenem, and ceftazidime established by the CLSI directives for Enterobacteriaceae. Results The MICs of all three combinations gradually declined with increments in the proportion of clavulanic acid in the regimens, and the most significant decline in the MIC50 and MIC90 was seen in combinations at the concentration ratio of 1:1 (also 1:2 for meropenem/clavulanic acid). When the concentration of clavulanic acid was restricted to 4 mg/L, the susceptibility of more than 70% of the isolates to the regimens could be restored with imipenem MIC 2–4 mg/L, meropenem MIC 2–8 mg/L or ceftazidime MIC 8mg/L. However, the percentage decreased to 30 to 40% when the initial MIC level was higher. Conclusion The highest combined inhibitory activity of β-lactam antibiotics/clavulanic acid at low concentration ratios against blaKPC-2-positive K. pneumoniae may offer a new way to optimize the effects of these antimicrobial regimens.

[1]  Wenhong Zhang,et al.  Tracking Carbapenem-Producing Klebsiella pneumoniae Outbreak in an Intensive Care Unit by Whole Genome Sequencing , 2019, Front. Cell. Infect. Microbiol..

[2]  H. Zahid,et al.  Clinical Pharmacokinetics of Clavulanic Acid, a Novel β- Lactamase Isolated from Streptomyces clavuligerus and Its Variability , 2018, Medicinal Chemistry.

[3]  Sarwan Kumar,et al.  Amoxicillin/clavulanic acid-induced pancreatitis: case report , 2018, BMC Gastroenterology.

[4]  P. Sorum,et al.  High-dose versus standard-dose amoxicillin/clavulanate for clinically-diagnosed acute bacterial sinusitis: A randomized clinical trial , 2018, PloS one.

[5]  Liangjing Lu,et al.  Use of Next Generation Sequencing and Synergy Susceptibility Testing in Diagnosis and Treatment of Carbapenem-Resistant Klebsiella pneumoniae Blood Stream Infection , 2018, Case reports in infectious diseases.

[6]  Y. Liu,et al.  Emergence and establishment of KPC-2-producing ST11 Klebsiella pneumoniae in a general hospital in Shanghai, China , 2017, European Journal of Clinical Microbiology & Infectious Diseases.

[7]  Yuying Liang,et al.  Clonal replacement of epidemic KPC-producing Klebsiella pneumoniae in a hospital in China , 2017, BMC Infectious Diseases.

[8]  D. Paterson,et al.  Multihospital Occurrence of Pan-Resistant Klebsiella pneumoniae Sequence Type 147 with an ISEcp1-Directed blaOXA-181 Insertion in the mgrB Gene in the United Arab Emirates , 2017, Antimicrobial Agents and Chemotherapy.

[9]  M. Bassetti,et al.  The management of multidrug-resistant Enterobacteriaceae , 2016, Current opinion in infectious diseases.

[10]  Jiezhun Gu,et al.  Amoxicillin–Clavulanate-Induced Liver Injury , 2016, Digestive Diseases and Sciences.

[11]  Xiaoli Cao,et al.  Clonal dissemination of KPC-2 producing Klebsiella pneumoniae ST11 clone with high prevalence of oqxAB and rmtB in a tertiary hospital in China: results from a 3-year period , 2016, Annals of Clinical Microbiology and Antimicrobials.

[12]  Xinli Mu,et al.  Cefepime combined with amoxicillin/clavulanic acid: a new choice for the KPC-producing K. pneumoniae infection. , 2015, International Journal of Infectious Diseases.

[13]  J. Rossen,et al.  An outbreak of colistin-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in the Netherlands (July to December 2013), with inter-institutional spread , 2015, European Journal of Clinical Microbiology & Infectious Diseases.

[14]  J. Rossen,et al.  An outbreak of colistin-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in the Netherlands (July to December 2013), with inter-institutional spread , 2015, European Journal of Clinical Microbiology & Infectious Diseases.

[15]  R. Bonomo,et al.  Carbapenemase-producing Klebsiella pneumoniae: molecular and genetic decoding. , 2014, Trends in microbiology.

[16]  V. Vullo,et al.  Synergistic activity and effectiveness of a double-carbapenem regimen in pandrug-resistant Klebsiella pneumoniae bloodstream infections. , 2014, The Journal of antimicrobial chemotherapy.

[17]  V. Miriagou,et al.  Carbapenemase-Producing Klebsiella pneumoniae Bloodstream Infections: Lowering Mortality by Antibiotic Combination Schemes and the Role of Carbapenems , 2014, Antimicrobial Agents and Chemotherapy.

[18]  A. Verstraete,et al.  Population pharmacokinetics and dosing simulations of amoxicillin/clavulanic acid in critically ill patients. , 2013, The Journal of antimicrobial chemotherapy.

[19]  Hui Wang,et al.  Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. , 2013, The Lancet. Infectious diseases.

[20]  Z. Zong,et al.  Enterobacteriaceae producing the KPC-2 carbapenemase from hospital sewage. , 2012, Diagnostic microbiology and infectious disease.

[21]  D. Paterson,et al.  Treatment Outcome of Bacteremia Due to KPC-Producing Klebsiella pneumoniae: Superiority of Combination Antimicrobial Regimens , 2012, Antimicrobial Agents and Chemotherapy.

[22]  G. Daikos,et al.  Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? , 2011, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[23]  P. Nordmann,et al.  Multiplex PCR for detection of acquired carbapenemase genes. , 2011, Diagnostic microbiology and infectious disease.

[24]  R. Bonomo,et al.  Inhibitor Resistance in the KPC-2 β-Lactamase, a Preeminent Property of This Class A β-Lactamase , 2009, Antimicrobial Agents and Chemotherapy.

[25]  J. Rahimian,et al.  Infection with panresistant Klebsiella pneumoniae: a report of 2 cases and a brief review of the literature. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[26]  J. Jorgensen,et al.  KPC-2-Producing Enterobacter cloacae and Pseudomonas putida Coinfection in a Liver Transplant Recipient , 2008, Antimicrobial Agents and Chemotherapy.

[27]  Jiachang Cai,et al.  Emergence of Serratia marcescens, Klebsiella pneumoniae, and Escherichia coli Isolates Possessing the Plasmid-Mediated Carbapenem-Hydrolyzing β-Lactamase KPC-2 in Intensive Care Units of a Chinese Hospital , 2008, Antimicrobial Agents and Chemotherapy.

[28]  K. Bush,et al.  Novel Carbapenem-Hydrolyzing β-Lactamase, KPC-1, from a Carbapenem-Resistant Strain of Klebsiella pneumoniae , 2008, Antimicrobial Agents and Chemotherapy.

[29]  N. Høiby,et al.  Class A carbapenemases. , 2007, The Journal of antimicrobial chemotherapy.

[30]  K. Bush,et al.  Carbapenemases: the Versatile β-Lactamases , 2007, Clinical Microbiology Reviews.

[31]  Yunsong Yu,et al.  Plasmid-Mediated KPC-2 in a Klebsiella pneumoniae Isolate from China , 2006, Antimicrobial Agents and Chemotherapy.

[32]  N. Hanson,et al.  Detection of Plasmid-Mediated AmpC β-Lactamase Genes in Clinical Isolates by Using Multiplex PCR , 2002, Journal of Clinical Microbiology.

[33]  K. Bush,et al.  Novel Carbapenem-Hydrolyzing β-Lactamase, KPC-1, from a Carbapenem-Resistant Strain of Klebsiella pneumoniae , 2001, Antimicrobial Agents and Chemotherapy.

[34]  S. Mitsuhashi,et al.  In-vitro evaluation of the four beta-lactamase inhibitors: BRL42715, clavulanic acid, sulbactam, and tazobactam. , 1993, The Journal of antimicrobial chemotherapy.

[35]  A. Jones,et al.  Pharmacokinetics of intravenous amoxycillin and potassium clavulanate in seriously ill children. , 1990, The Journal of antimicrobial chemotherapy.

[36]  P. Koeppe,et al.  Pharmacokinetics of amoxicillin and clavulanic acid administered alone and in combination , 1982, Antimicrobial Agents and Chemotherapy.

[37]  P. Nordmann,et al.  In vitro evaluation of dual carbapenem combinations against carbapenemase-producing Enterobacteriaceae. , 2016, The Journal of antimicrobial chemotherapy.

[38]  Thi Thanh Nga Tran,et al.  Characteristics of Extended-Spectrum β-Lactamase-Producing Escherichia coli in Retail Meats and Shrimp at a Local Market in Vietnam. , 2015, Foodborne pathogens and disease.

[39]  H. Lode,et al.  Comparative Pharmacokinetics of Sulbactam/ Ampicillin and Clavulanic Acid/Amoxycillin in Human Volunteers , 2012, Drugs.

[40]  V. Foulongne,et al.  Experimental application of the median-effect principle for in vitro quantification of the combined inhibitory activities of clavulanic acid and imipenem against IRT-4 beta-lactamase. , 2002, International journal of antimicrobial agents.