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The Addition of Avibactam Renders Piperacillin an Effective Treatment Meir et al. Antimicrobial Resistance and Infection Control (2018) 7:151 https://doi.org/10.1186/s13756-018-0448-4 LETTERTOTHEEDITOR Open Access The addition of avibactam renders piperacillin an effective treatment for Mycobacterium abscessus infection in an in vivo model Michal Meir1, Pablo Bifani3,4 and Daniel Barkan2,5* Abstract Treating M. abscessus infection is challenging due to the potent β-lactamase BlaMab (Beta-lactamase of M. abscessus). Avibactam is a non-β-lactam, β-lactamase inhibitor shown to inhibit BlaMab. We tested whether avibactem can render piperacillin effective against M. Abscessus. In-vitro, avibactam enhanced the activity of piperacillin by 16–32 fold, with no significant effect on meropenem. In an in-vivo Galleria mellonella model, meropenem and piperacillin/ avibactam significantly decreased infection burden compared to untreated controls. Neither piperacillin nor avibactam alone had a significant effect. Keywords: Mycobacterium abscessus, Combination treatment, Avibactam, Piperacillin, MIC Introduction, results and discussion diseases, plastic surgery, foreign bodies and other clinical Non tuberculous mycobacteria (NTMs) are emerging situations. pathogens in patients with cystic fibrosis (CF), recently es- Most β-lactam antibiotics, bar carbapenems and timated to affect approximately 12% of patients in Western cefoxitin, are ineffective against M. abscessus,asit countries [1]. Of NTM pulmonary infections, Mycobacter- harbors BlaMab [5], a potent β-lactamase able to ium abscessus infection is considered especially concerning degrade both β-lactams and β-lactamase inhibitors. as it is associated with increased morbidity and mortality, Avibactam is a new, non-β-lactam, β-lactamase inhibi- and is a poor prognostic factor even following lung trans- tor, active against BlaMab [5]. Data from zebrafish sug- plantation [2–4]. Treatment of M. abscessus infections is gests avibactam can enhance the activity of ampicillin challenging due to antibiotic resistance and tolerance against M. abscessus, but ampicillin is inactive against mechanisms. Despite prolonged courses of multiple P. aeruginosa. No data exists on whether it can antibiotic treatments, long-term clearance of M. absces- augment the efficacy of the antipseudomonal drug pi- sus from respiratory airway in patients with CF is rarely peracillin, enabling a single agent use against both Pseudo- successful [1]. Multi-bacterial infections, specifically of monas aeruginosa and M. abscessus, a co-infection often M. abscessus, Pseudomonas aeruginosa and sometimes found in patients with CF [2]. Staphylococcus aureus are especially challenging and In this study, we aimed to evaluate the effect of pipera- difficult to treat. Non-CF patients also suffer from M. cillin/avibactam against Mycobacterium abscessus, in vitro abscessus infections, many times related to chronic lung and in vivo, using our recently established infection model in Galleria mellonella larvae [6], Coupled with a lumines- cent M. abscessus mutant (mDB158) [6]. * Correspondence: [email protected] To test the susceptibility of M. abscessus to piperacil- 2 Koret School of Veterinary Medicine, The Robert H. Smith Faculty of lin/avibactam in vivo, we used mDB158 [6], treated by Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel meropenem, piperacillin, or ampicillin, each one with 5Faculty of Agriculture, School of Veterinary Medicine, POB12,, 76100 and without the addition of avibactam. Bacterial growth Rehovot, Israel was assessed by luminescence measurement. Using 96 Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Meir et al. Antimicrobial Resistance and Infection Control (2018) 7:151 Page 2 of 3 well plates, 5*103 CFU of mDB158 were cultured with serial 1:2 dilutions of meropenem (50 to 0 mg/L), pipera- cillin (800 to 0 mg/L) and ampicillin (200 to 0 mg/L), alone or with the addition of 4 mg/L of avibactam. Fol- lowing 72 h of incubation at 37 °C, luminescence was measured using the SpectraMaxi3® microplate detection system. At 72 h, luminescence consistently increased by 103 fold in wells without antibiotics. The luminescence minimal inhibitory concentration (lu-MIC) was thus defined as the concentration in which luminescence remained similar to baseline value or increased no more than 3 fold compared to baseline. As expected, avibactam did not enhance the antibacterial activity of meropenem, as carbapenems are not considerably de- graded by the β-lactamase of M. abscessus.Thelu-MIC of ampicillin was reduced approximately 16 fold when Fig. 2 Piperacillin/avibactam is effective in treating Mycobacterium augmented with avibactam, showing activity at 3.125 abscessus Galleria mellonella – in a infection model. We inoculated 60 mg/L of ampicillin. Most importantly the activity of G. mellonella larvae with luminescent M. abscessus on day 0, and piperacillin was enhanced 16–32 fold when combined treated larvae with meropenem, piperacillin, avibactam alone, or with avibactam, also showing substantial antibacterial piperacillin/avibactam on days 1 and 2. Using IVIS® imaging, we activity at 3.125 mg/L. Avibactam alone did not inhibit measured infection progression in live infected larvae on day 3. “ ” M. abscessus growth. Healthy are un-infected larvae All the experiments/concentrations were done in trip- licates, and repeated 3 times with similar results. For vis- To test if this combination is also effective in-vivo, we ual representation of these findings we analyzed a single used our previously described G. mellonella larvae as a 96-well plate with a single well for each concentration model of M. abscessus infection [6]. We inoculated 60 using the IVIS® imaging system (Fig. 1) with the above larvae with luminescent M. abscessus mDB158 on day 0 antibiotic combinations. and kept them at 37 °C. On days 1 and 2 we treated larvae Fig. 1 Avibactam lowers MIC of piperacillin for M. abscessus. A broth dilution assay was performed using 5*103 CFU of a luminescent M. abscessus mutant with serial 1:2 dilutions of meropenem (50 to 0 mg/L), piperacillin (800 to 0 mg/L) and ampicillin (200 to 0 mg/L) alone or with the addition of 4 mg/L of avibactam. Image showing luminescence demonstrated by IVIS® following 72 h of incubation. Mero – meropenem, pip – piperacillin, amp – ampicillin, avi – avibactam. Dotted white line borders the test area. White numbers show mero/pip/amp concentrations Meir et al. Antimicrobial Resistance and Infection Control (2018) 7:151 Page 3 of 3 with 40 μg (200 mg/kg) meropenem, 100 μg(500mg/kg) Funding piperacillin, 0.2 μg (1 mg/kg) avibactam alone, or piperacil- MM is supported by an internal institutional grant, “Ofakim” (Horizons). μ μ lin combined with avibactam (100 g/0.2 g), approximat- Availability of data and materials ing two daily doses of antibiotics. Using IVIS® Lumina Data sharing not applicable to this article as no datasets were generated or Series III (Caliper LifeSciences), we measured infection analyzed during the current study. progression in live infected larvae on day 3 (We previously Authors’ contributions showed RLU correlates well with CFU – [6]). Larvae Both MM and DB conceived and performed the study, and wrote the treated with either meropenem or piperacillin/avibactam manuscript. All authors read and approved the final manuscript. had a significantly lower infection burden compared to Ethics approval and consent to participate untreated controls (p <0.0001and p = 0.004 respectively). Not applicable. Piperacillin and avibactam alone had no significant inhibi- Consent for publication tory effect (Fig. 2). A second experiment with only one Not applicable. injection of antibiotics on day 1 showed similar results. It is well established that pulmonary infection with M. Competing interests The authors declare that they have no competing interests. abscessus is a poor prognostic factor for patients with CF, independently associated with a progressive decline ’ – Publisher sNote in lung function [2 4, 7]. Treatment necessitates pro- Springer Nature remains neutral with regard to jurisdictional claims in longed multi-drug regimens including a carbapenem back- published maps and institutional affiliations. bone [1]. Use of a narrower spectrum β-lactam backbone Author details has so far been hindered due to the M. abscessus potent 1The Ruth Rappaport Children’s Hospital, Rambam Health Care Campus, 2 β-lactamase BlaMab [5]. Avibactam was recently shown to Haifa, Israel. Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of inhibit BlaMab, yet its role in treating this infection is Jerusalem, Rehovot, Israel. 3Department of Microbiology and Immunology, unclear. Some in vitro data and in vivo zebrafish data dem- Yong Loo Lin School of Medicine, National University of Singapore, onstrated an ampicillin/avibactam combination to have
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