Inoculum effect of methicillin-susceptible Staphylococcus aureus against broad-spectrum beta-lactam antibiotics
Scarce information concerning the inoculum effect (InE) of methicillin-susceptible Staphylococcus aureus (MSSA) against broad-spectrum β-lactam antibiotics is available. We investigated the InE of MSSA against ceftriaxone, cefepime, meropenem, ampicillin/sulbactam and piperacillin/tazobactam. The bacteraemic MSSA isolates were collected at ten Korean general hospitals from Sep 2013 to Mar 2015. The InE was defined if MICs of antibiotics at high inoculum (HI, ~5 × 107 CFU/ml) increased beyond the susceptible range compared to those at standard inoculum (SI, ~5 × 105 CFU/ml). All isolates were sequenced for blaZ gene typing. Among 302 MSSA isolates, 254 (84.1%) were positive for blaZ; types A, B, C and D were 13.6%, 26.8%, 43.4% and 0.3%, respectively. Mean HI MICs of all tested antibiotics were significantly increased and increases in HI MIC of piperacillin/tazobactam (HI, 48.14 ± 4.08 vs. SI, 2.04 ± 0.08 mg/L, p < 0.001) and ampicillin/sulbactam (HI, 24.15 ± 1.27 vs. SI, 2.79 ± 0.11 mg/L, p < 0.001) were most prominent. No MSSA isolates exhibited meropenem InE, and few isolates exhibited cefepime (0.3%) and ceftriaxone (2.3%) InE, whereas 43.0% and 65.9% of MSSA isolates exhibited piperacillin/tazobactam and ampicillin/sulbactam InE, respectively. About 93% of type C blaZ versus 45% of non-type C exhibited ampicillin/sulbactam InE (p < 0.001) and 88% of type C blaZ versus 9% of non-type C exhibited piperacillin/tazobactam InE (p < 0.001). A large proportion of MSSA clinical isolates, especially those positive for type C blaZ, showed marked ampicillin/sulbactam InE and piperacillin/tazobactam.
KeywordsStaphylococcus aureus Beta-lactamase Inhibitor Inoculum effect blaZ Ampicillin-sulbactam
This work was summarised in an abstract (Abstract No. 5020) for the 27th European Congress of Clinical Microbiology and Infectious Diseases, Vienna, Austria, 2017.
We give special thanks to B. E. Murray and her colleagues at the University of Texas Medical School for providing strain TX 0117, a high-level producer of type A β-lactamase.
We thank the members of the Korea INfectious Diseases (KIND) study group and the associated staff for their cooperation in this study. In addition to the authors, the following individuals participated in the study: Kyoung Un Park, Jeong Eun Cho, Yun Jung Choi, Jung In Park (Seoul National University Bundang Hospital); Su-Mi Choi (Chonnam National University Hospital); Sun Hee Lee, Jongyoun Yi (Pusan National University Hospital); Taek Soo Kim, Su Jin Choi (Seoul National University Hospital); Hee Kyoung Choi, Myung Sook Han (Yonsei University Wonju Severance Christian Hospital); Chong Rae Cho, Hyun Suk Song, Young Soon Lee (Inje University Ilsan Paik Hospital); Shinhye Cheon, Jin Hee Hwang, Seon Jin Yun (Chungnam National University Hospital); Seung-Ji Kang, Hyeon-jeong Hwang, (Chonnam National University Hwasun Hospital); Jae Hyun Jeon, Dong-Kie Kim, Sae-Am Song, Min Ji Kang, Jae Gyun Shin (Inje University Haeundae Paik Hospital); Ki Tae Kwon, Seung Min Shin (Daegu Fatima Hospital).
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (grant number NRF-2015R1C1A1A01054293).
Clinical MSSA isolates were collected from the prospective cohort study “Establishment of Network for Clinical Research of Staphylococcus aureus Infection,” which was supported by Grant No. HI10C2020 from the National Strategic Coordinating Center for Clinical Research.
Compliance with ethical standards
The study entitled “Establishment of Network for Clinical Research of Staphylococcus aureus Infection” had been approved by the IRB at each participating hospital, and the protocol used in this study using previously collected clinical information and corresponding isolates was approved by the IRB at Pusan National University Hospital (IRB No. E-2016032).
Nothing to declare.
- 1.Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Bolger AF, Levison ME, Ferrieri P, Gerber MA, Tani LY, Gewitz MH, Tong DC, Steckelberg JM, Baltimore RS, Shulman ST, Burns JC, Falace DA, Newburger JW, Pallasch TJ, Takahashi M, Taubert KA (2005) Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the committee on rheumatic fever, endocarditis, and Kawasaki disease, council on cardiovascular disease in the young, and the councils on clinical cardiology, stroke, and cardiovascular surgery and anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 111(23):e394–e434Google Scholar
- 3.Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O'Grady NP, Bartlett JG, Carratala J, El Solh AA, Ewig S, Fey PD, File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL (2016) Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 63(5):e61–e111CrossRefGoogle Scholar
- 4.Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG, Deery HG, Embil JM, Joseph WS, Karchmer AW, Pinzur MS, Senneville E (2012) 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 54(12):e132–e173CrossRefGoogle Scholar
- 5.Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG (2007) Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl 2):S27–S72CrossRefGoogle Scholar
- 9.Lee S, Kwon KT, Kim HI, Chang HH, Lee JM, Choe PG, Park WB, Kim NJ, Oh MD, Song do Y, Kim SW (2014) Clinical implications of cefazolin inoculum effect and beta-lactamase type on methicillin-susceptible Staphylococcus aureus bacteremia. Microbial drug resistance (Larchmont, NY) 20(6):568–574CrossRefGoogle Scholar
- 10.Nannini EC, Stryjewski ME, Singh KV, Bourgogne A, Rude TH, Corey GR, Fowler VG Jr, Murray BE (2009) Inoculum effect with cefazolin among clinical isolates of methicillin-susceptible Staphylococcus aureus: frequency and possible cause of cefazolin treatment failure. Antimicrob Agents Chemother 53(8):3437–3441CrossRefGoogle Scholar
- 11.Song KH, Jung SI, Lee S, Park S, Kiem SM, Lee SH, Kwak YG, Kim YK, Jang HC, Kim YS, Kim HI, Kim CJ, Park KH, Kim NJ, Oh MD, Kim HB (2017) Characteristics of cefazolin inoculum effect-positive methicillin-susceptible staphylococcus aureus infection in a multicentre bacteraemia cohort. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 36(2):285–294CrossRefGoogle Scholar
- 12.Lee S, Song KH, Jung SI, Park WB, Lee SH, Kim YS, Kwak YG, Kim YK, Kiem SM, Kim HI, Kim ES, Park KH, Kim NJ, Jang HC, Kim HB (2017) Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective multicentre cohort study in Korea. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect DisGoogle Scholar
- 14.Docobo-Perez F, Lopez-Cerero L, Lopez-Rojas R, Egea P, Dominguez-Herrera J, Rodriguez-Bano J, Pascual A, Pachon J (2013) Inoculum effect on the efficacies of amoxicillin-clavulanate, piperacillin-tazobactam, and imipenem against extended-spectrum beta-lactamase (ESBL)-producing and non-ESBL-producing Escherichia coli in an experimental murine sepsis model. Antimicrob Agents Chemother 57(5):2109–2113CrossRefGoogle Scholar
- 15.Kang CI, Cha MK, Kim SH, Wi YM, Chung DR, Peck KR, Lee NY, Song JH (2014) Extended-spectrum cephalosporins and the inoculum effect in tests with CTX-M-type extended-spectrum beta-lactamase-producing Escherichia coli: potential clinical implications of the revised CLSI interpretive criteria. Int J Antimicrob Agents 43(5):456–459CrossRefGoogle Scholar
- 18.Saeki M, Shinagawa M, Yakuwa Y, Nirasawa S, Sato Y, Yanagihara N, Takahashi S (2017) Inoculum effect of high concentrations of methicillin-susceptible Staphylococcus aureus on the efficacy of cefazolin and other beta-lactams. J Infect Chemother Off J Jpn Soc ChemotherGoogle Scholar
- 20.National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Seventh Edition: Approved Standard M07-A7. NCCLS, Wayne, PA, USA, 2008Google Scholar
- 23.Chong YP, Park SJ, Kim ES, Bang KM, Kim MN, Kim SH, Lee SO, Choi SH, Jeong JY, Woo JH, Kim YS (2015) Prevalence of blaZ gene types and the cefazolin inoculum effect among methicillin-susceptible Staphylococcus aureus blood isolates and their association with multilocus sequence types and clinical outcome. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 34(2):349–355CrossRefGoogle Scholar
- 25.Rincon S, Reyes J, Carvajal LP, Rojas N, Cortes F, Panesso D, Guzman M, Zurita J, Adachi JA, Murray BE, Nannini EC, Arias CA (2013) Cefazolin high-inoculum effect in methicillin-susceptible Staphylococcus aureus from south American hospitals. J Antimicrob Chemother 68(12):2773–2778CrossRefGoogle Scholar
- 27.Shuford JA, Piper KE, Hein M, Trampuz A, Steckelberg JM, Patel R (2006) Lack of association of Staphylococcus aureus type a beta-lactamase with cefazolin combined with antimicrobial spacer placement prosthetic joint infection treatment failure. Diagn Microbiol Infect Dis 54(3):189–192CrossRefGoogle Scholar
- 28.Wi YM, Park YK, Moon C, Ryu SY, Lee H, Ki HK, Cheong HS, Son JS, Lee JS, Kwon KT, Kim JM, Ha YE, Kang CI, Ko KS, Chung DR, Peck KR, Song JH (2015) The cefazolin inoculum effect in methicillin-susceptible Staphylococcus aureus blood isolates: their association with dysfunctional accessory gene regulator (agr). Diagn Microbiol Infect Dis 83(3):286–291CrossRefGoogle Scholar