Melioidosis is an important public health disease in Southeast Asia and Australia, but it is still considered a potential emerging infectious disease in tropical developing countries[2,13-18]. A 2016 modelling study estimated that there are ~165,000 cases of melioidosis in humans per year worldwide, of which 89,000 (54%) are estimated to be fatal[19]. Although quinolones have slight antibacterial activity in vitro, their treatment failure rate is relatively high[8,20]. The mortality of melioidosis ranges from 14 to 40% and may be as high as 80% if effective antibiotics are not given[21]. With the early use of antibiotics, the mortality rate can also be reduced to under 10%[22]. However, B. pseudomallei is intrinsically resistant to many antibiotics (such as penicillin, ampicillin, first- and second-generation cephalosporins, macrolides, aminoglycosides, streptomycin, polymyxin, etc.)[23-24]. At present, only TMP/SMX, ceftazidime, tetracycline, doxycycline, amoxicillin/clavulanic acid and imipenem have MIC breakpoints for B. pseudomallei in the CLSI guidelines[11]. Therefore, the selection of antimicrobial agents is limited for the treatment of melioidosis.
Piperacillin, as with all other β-lactam antibiotics, interferes with the final stage of peptidoglycan synthesis by inhibiting penicillin-binding proteins (PBPs), which crosslink peptidoglycan polymers[25]. Tazobactam extends piperacillin’s spectrum of activity to include bacteria producing many Ambler class A β-lactamases,
narrow- and extended-spectrum (TEM-, SHV-, and CTX-M-type) β-lactamases and some class C (AmpC-type) β-lactamases[26-27]. Piperacillin-tazobactam has the broadest spectrum of activity among the penicillin class of β-lactam antibiotics and is generally active against most of the typical human pathogens, including aerobic and anaerobic gram-positive and gram-negative bacteria[25]. Piperacillin/tazobactam is widely distributed in various tissues and body fluids after injection, and its clinical indications are also relatively broad, such as respiratory tract infection, bacterial septicaemia, and subcutaneous abscess[25]. The clinical infection of the target bacteria we studied is also complex and diverse and is considered "like a hundred diseases". Piperacillin/tazobactam has a sensitive CLSI breakpoint for Enterobacteriaceae bacteria but no MIC breakpoints for non-fermentative bacteria except Pseudomonas aeruginosa, Acinetobacter baumannii and Haemophilus influenzae.
Therefore, we compared the MICs of piperacillin/tazobactam with those of six antibiotics(with a CLSI MIC breakpoints) and meropenem (with an EUCAST MIC breakpoint) to provide additional choices for the treatment of melioidosis in this study. The results showed that the MIC50 and MIC90 of piperacillin/tazobactam were 0.25 μg/ml and 0.5 μg/ml, respectively. The MIC50 of piperacillin/tazobactam was lower than that of the other seven antibiotics. In addition, the MIC90 was also lower than that of the other six antibiotics, except for imipenem (the MIC90 of piperacillin/tazobactam was equal to that of imipenem). This result indicates that the antibacterial activity of piperacillin/tazobactam is stronger than that of the other tested antibiotics in vitro. Regarding the pharmacokinetic characteristics in vivo (see Table 3), it was found that both the peak value of the plasma concentration of China and Italy formulations is far higher than the MIC50 and MIC90 values of piperacillin/tazobactam. It is generally believed that antibiotics have bacteriostatic or bactericidal effects in vivo when the blood concentration of antibiotics is 4-6 times higher than the MIC value of target bacteria. In the published literature, the criteria used in these studies to analyse the susceptibility to piperacillin/tazobactam and meropenem to B. pseudomallei were mostly based on the MIC breakpoint of P. aeruginosa in the CLSI guidelines[28]. In studies published in Bangladesh, Dutta et al. found that 20 isolates of B. pseudomallei were uniformly sensitive (100%) to piperacillin–tazobactam (refer to the MIC breakpoint of P. aeruginosa in the CLSI guidelines), and both the MIC50 and MIC90 values were 2 μg/ml[28]. These values are obviously higher than the results of our study. However, the number of samples in Dutta’s study may be too few, and both the MIC50 and MIC90 values of all isolates to three common antibiotics (imipenem, ceftazidime, and amoxicillin/clavulanic acid) were relatively higher (great than or equal to 2 μg/ml, agar dilution method). This result indicated that the MIC values of the 20 isolates of B. pseudomallei in Dutta's study were relatively high. In view of the above information, this study still has certain reference significance. It can be used as the theoretical basis for the clinical treatment of B. pseudomallei infection with piperacillin–tazobactam.
In this study, we conducted a preliminary study on the MIC of piperacillin–
tazobactam for B. pseudomallei in vitro. We hope that this study can play a valuable role, arousing more attention to antibiotic selection for B. pseudomallei infection to improve the cure rate and reduce mortality. Therefore, the laboratory should work closely with the clinic to obtain a more clinical pharmacodynamic summary of piperacillin/tazobactam in the treatment of B. pseudomallei infection and provide more powerful evidence for its treatment.
Limitations
In this paper, we have not summarized the MIC breakpoint of piperacillin-tazobactam to B. pseudomallei, but still need a lot of data analysis and summary.