In vitro Bactericidal Activities of Combination Antibiotic Therapies Against Carbapenem-Resistant Klebsiella pneumoniae With Different Carbapenemases and Sequence Types

Jocelyn Qi-Min Teo; Nazira Fauzi; Jayden Jun-Yuan Ho; Si Hui Tan; Shannon Jing-Yi Lee; Tze Peng Lim; Yiying Cai; Hong Yi Chang; Nurhayati Mohamed Yusoff; James Heng-Chiak Sim; Thuan Tong Tan; Rick Twee-Hee Ong; Andrea Lay-Hoon Kwa

doi:10.3389/fmicb.2021.779988

In vitro Bactericidal Activities of Combination Antibiotic Therapies Against Carbapenem-Resistant Klebsiella pneumoniae With Different Carbapenemases and Sequence Types

Front Microbiol. 2021 Dec 13:12:779988. doi: 10.3389/fmicb.2021.779988. eCollection 2021.

Authors

Jocelyn Qi-Min Teo^{1

2}, Nazira Fauzi¹, Jayden Jun-Yuan Ho¹, Si Hui Tan¹, Shannon Jing-Yi Lee¹, Tze Peng Lim^{1

3

4}, Yiying Cai¹, Hong Yi Chang¹, Nurhayati Mohamed Yusoff¹, James Heng-Chiak Sim⁵, Thuan Tong Tan⁶, Rick Twee-Hee Ong², Andrea Lay-Hoon Kwa^{1

4

7}

Affiliations

¹ Department of Pharmacy, Singapore General Hospital, Singapore, Singapore.
² Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
³ Singhealth Duke-NUS Pathology Academic Clinical Programme, Singapore, Singapore.
⁴ Singhealth Duke-NUS Medicine Academic Clinical Programme, Singapore, Singapore.
⁵ Department of Microbiology, Singapore General Hospital, Singapore, Singapore.
⁶ Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore.
⁷ Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore.

Abstract

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is becoming increasingly problematic due to the limited effectiveness of new antimicrobials or other factors such as treatment cost. Thus, combination therapy remains a suitable treatment option. We aimed to evaluate the in vitro bactericidal activity of various antibiotic combinations against CRKP with different carbapenemase genotypes and sequence types (STs). Thirty-seven CRKP with various STs and carbapenemases were exposed to 11 antibiotic combinations (polymyxin B or tigecycline in combination with β-lactams including aztreonam, cefepime, piperacillin/tazobactam, doripenem, meropenem, and polymyxin B with tigecycline) in static time-kill studies (TKS) using clinically achievable concentrations. Out of the 407 isolate-combination pairs, only 146 (35.8%) were bactericidal (≥3 log₁₀CFU/mL decrease from initial inoculum). Polymyxin B in combination with doripenem, meropenem, or cefepime was the most active, each demonstrating bactericidal activity in 27, 24, and 24 out of 37 isolates, respectively. Tigecycline in combination with β-lactams was rarely bactericidal. Aside from the lower frequency of bactericidal activity in the dual-carbapenemase producers, there was no apparent difference in combination activity among the strains with other carbapenemase types. In addition, bactericidal combinations were varied even in strains with similar STs, carbapenemases, and other genomic characteristics. Our findings demonstrate that the bactericidal activity of antibiotic combinations is highly strain-specific likely owing to the complex interplay of carbapenem-resistance mechanisms, i.e., carbapenemase genotype alone cannot predict in vitro bactericidal activity. The availability of WGS information can help rationalize the activity of certain combinations. Further studies should explore the use of genomic markers with phenotypic information to predict combination activity.

Keywords: bactericidal; carbapenemase; combination; enterobacterales; in vitro; polymyxin; tigecycline.