Inoculum effect of methicillin-susceptible Staphylococcus aureus against broad-spectrum beta-lactam antibiotics

  • Kyoung-Ho Song
  • Sook-In Jung
  • Shinwon LeeEmail author
  • Sohee Park
  • Eu Suk Kim
  • Kyung-Hwa Park
  • Wan Beom Park
  • Pyoeng Gyun Choe
  • Young Keun Kim
  • Yee Gyung Kwak
  • Yeon-Sook Kim
  • Hee-Chang Jang
  • Sungmin Kiem
  • Hye-In Kim
  • Hong Bin Kim
  • the Korea INfectious Diseases (KIND) study group
Original Article


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.


Staphylococcus 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

Ethical approval

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).

Transparency declarations

Nothing to declare.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Kyoung-Ho Song
    • 1
  • Sook-In Jung
    • 2
  • Shinwon Lee
    • 3
    Email author
  • Sohee Park
    • 3
  • Eu Suk Kim
    • 1
  • Kyung-Hwa Park
    • 2
  • Wan Beom Park
    • 4
  • Pyoeng Gyun Choe
    • 4
  • Young Keun Kim
    • 5
  • Yee Gyung Kwak
    • 6
  • Yeon-Sook Kim
    • 7
  • Hee-Chang Jang
    • 8
  • Sungmin Kiem
    • 9
  • Hye-In Kim
    • 10
  • Hong Bin Kim
    • 1
  • the Korea INfectious Diseases (KIND) study group
  1. 1.Department of Internal MedicineSeoul National University Bundang HospitalSeongnamRepublic of Korea
  2. 2.Department of Infectious DiseasesChonnam National University Medical SchoolGwangjuRepublic of Korea
  3. 3.Department of Internal MedicinePusan National University School of Medicine and Medical Research Institute, Pusan National University HospitalBusanRepublic of Korea
  4. 4.Department of Internal MedicineSeoul National University HospitalSeoulRepublic of Korea
  5. 5.Department of Internal MedicineYonsei University Medical SchoolWonjuRepublic of Korea
  6. 6.Department of Internal MedicineInje University Ilsan Paik HospitalGoyangRepublic of Korea
  7. 7.Division of Infectious DiseasesChungnam National University Hospital, Chungnam National University School of MedicineDaejeonRepublic of Korea
  8. 8.Department of Internal MedicineChonnam National University Hwasun HospitalHwasunRepublic of Korea
  9. 9.Department of Internal MedicineInje University College of MedicineBusanRepublic of Korea
  10. 10.Department of Internal MedicineDaegu Fatima HospitalDaeguRepublic of Korea

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