In vitro Optimization of Ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae

Abstract

Ceftazidime/avibactam is an important treatment option for infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp), however, resistance can emerge during treatment. The objective of the study was to define the ceftazidime/avibactam concentrations required to suppress bacterial regrowth in ceftazidime/avibactam susceptible isolates and identify active therapies against ceftazidime/avibactam-resistant KPC-Kp. Time-kill assays were performed against twelve ST258 KPC-Kp isolates that harbored blaKPC–2 or blaKPC–3. Nine KPC-Kp isolates (KPC-Kp 5A, 6A, 7A, 8A, 9A, 24A, 25A, 26A, and 27A) were susceptible to ceftazidime/avibactam, two (KPC-Kp 6B and 7B) were ceftazidime/avibactam resistant and meropenem susceptible, and one (KPC-Kp 1244) was resistant to both ceftazidime/avibactam and meropenem. Sequencing of the blaKPC genes revealed mutations in KPC-Kp 6B (D179Y substitution) and 7B (novel 21 base pair deletion) that both affected the Ω-loop encoding portion of the gene. Time-kill assays showed that against ceftazidime/avibactam-susceptible KPC-Kp, ceftazidime/avibactam concentrations ≥40/7.5 mg/L caused mean 5.42 log10CFU/mL killing and suppressed regrowth. However, regrowth occurred for some KPC-Kp isolates with a ceftazidime/avibactam concentration of 20/3.75 mg/L. Against ceftazidime/avibactam-resistant and meropenem-susceptible KPC-Kp 6B and 7B, bactericidal activity and synergy was observed for ceftazidime/avibactam in combination with meropenem ≤3.125 mg/L, while meropenem concentrations ≥50 mg/L were bactericidal as monotherapy. In contrast, clinically achievable concentrations of ceftazidime/avibactam were bactericidal against KPC-Kp 1244, which was ceftazidime/avibactam-resistant and meropenem-resistant due to outer membrane porin mutations and elevated blaKPC expression. Achieving high ceftazidime/avibactam concentrations may help to suppress bacterial regrowth in the presence of ceftazidime/avibactam. The optimal treatment approach for ceftazidime/avibactam-resistant KPC-Kp likely depends on the mechanism of resistance. Additional studies are warranted to confirm these findings.

Four Types of ST11 Novel Mutations From Increasing Carbapenem-Resistant Klebsiella pneumoniae in Guangdong, 2016–2020

“…ST258 is dominant in Europe and the United States, while ST11 is dominant in East Asia (Berglund et al, 2019). ST11 is also a predominant area in China (Li et al, 2019;Huang et al, 2021). In the present study, ST11 was the most prevalent type, followed by ST54 (7.53%), and ST11 mutation (4.79%).…”

“…At present, Asia is dominated by sequence type 11 (ST11), while Europe and America are dominated by ST258; these strains are closely related (Li et al, 2019). In addition, different types of CR-KP have different antibacterial profiles, virulence, pathogenicity, transmission, and evolutionary trends (Li et al, 2019;Gomes et al, 2021;Hassoun-Kheir et al, 2021;Huang et al, 2021). The distribution of ST11 and ST258 is accompanied by broad-spectrum drug resistance and high virulence, and CR-KP is increasingly regarded as a potential superbug.…”

Nutritional analysis and characterization of carbapenemase producing-Klebsiella pneumoniae resistant genes associated with bovine mastitis infected cow’s milk

“…Tigecycline is a glycylcycline antibacterial drug that has been used to treat CRKP-related infections and has been seen there the most frequently effective against K. pneumoniae that produces carbapenemase [47,48]. For infections brought on by carbapenemase-producing K. pneumoniae (KPC-Kp), Ceftazidime/avibactam is a crucial therapy choice [49]. The urgency to strengthen preventative efforts and treatment approaches is increased by the rising antimicrobial drug resistance to K. pneumoniae in our study, a parallel lack of innovative antimicrobial agent development [45], and the dearth of effective therapeutic choices for treating CRKP-related illnesses [48].…”

Ceftazidime-avibactam based combinations against carbapenemase producing Klebsiella pneumoniae harboring hypervirulence plasmids

“…Static time-kill assays were performed against a starting inoculum of each isolate at ∼10 7 cfu/mL, as previously described. [25] , [26] Aztreonam (ATM), ceftazidime (CAZ), avibactam (AVI), meropenem (MEM), minocycline (MIN), and polymyxin B (PMB) were obtained from Sigma-Aldrich, Inc. On the first day of each experiment, antibiotics were prepared at 50% and 100% of the estimated maximal serum achievable free-drug concentrations ( f C max ), except ATM, which was prepared only at 100% f C max , as it will not be active as monotherapy against these isolates. [27] , [28] , [29] , [30] , [31] Combinations with CAZ/AVI (at 50% and 100% f C max ) and another agent (at the highest concentration that was not bactericidal) were then tested to evaluate for synergy.…”