Abstract 5882: Prevention of antibiotic-induced dysbiosis in human volunteers by DAV132 and preservation of responsiveness to anti-PD-1 demonstrated by transplantation of human feces into tumor-bearing mice
Meriem MessaoudeneNathalie Saint-LuFrédérique Sablier-GallisStéphanie FerreiraMayra PonceClément Le BescopThomas LoppinetTanguy CorbelCéline FégerFabien VitryAntoine AndremontJean de GunzburgBertrand Routy
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Abstract Background: Over the last decade, studies unraveled the cancer-immune dialogue in the setting of immune checkpoint inhibitors (ICI) and influenced by the gut microbiota. The first evidence of the key role of the microbiota in ICI modulation was observed during antibiotics (ATB) treatment, where altering the microbiota composition by ATB inhibited ICI responses. DAV132 (DAV) is an orally administered colon-targeted ATB adsorbent capsules designed to prevent ATB-induced dysbiosis. We investigated whether DAV co-administered with ATB could prevent ATB-related dysbiosis and ICI response. Methods: 72 human healthy volunteers (HV) were randomized to receive either IV ceftazidime-avibactam (CZA) or Piperacillin tazobactam (PTZ) alone or in combination with oral DAV. CZA and PTZ plasmatic and fecal pharmacodynamic levels were measured using HPLC-MS/MS. Microbiome was profiled with metagenomics at different timepoints. FMT experiments in germ-free mice were performed using fecal samples from HV from the trial, before (D1) or after 6 days (D6) of CZA or PTZ+/-DAV; subsequently mice were inoculated with MCA205 or B16 tumors and treated with anti-PD-1. Tumor infiltrating lymphocytes (TILs) were analyzed by flow cytometry. Results: DAV did not impact plasmatic CZA or PTZ concentrations, but significantly reduced ceftazidime and piperacillin concentrations in feces compared to ATB groups alone. DAV significantly prevented the reduction in microbiota alpha-diversity at D6 and was associated with a rapid return to baseline microbiota. 50 and 43 metagenomics species were preserved in the CZA+DAV vs CZA, or PTZ-DAV vs PTZ such as Faecalibacterium praunistzii, Alistipes Spp and Blautia obeum. FMT in germ-free mice using feces collected at D1 exhibited a significant anti-PD-1 activity. This anti-tumor response was inhibited in two tumors models in mice transplanted with D6 feces from patients in the CZA or PTZ alone groups. Conversely, the anti-tumor response was maintained in mice transplanted with D6 feces from HV treated with CZA+DAV or PTZ+DAV groups. Flow cytometry on TILs demonstrated that CZA decreased CD8+T cell and CD8+/Treg ratio compared to CZA+DAV. Conclusions: DAV prevented ATB-induced dysbiosis in HV treated with CZA or PTZ without influencing plasmatic concentrations. In avatar mice FMT from HV treated with CZA+DAV was able to preserve anti-PD-1 efficacy. These results provide rationale to launch clinical trials combining DAV in patients on ATB amenable to ICI. Citation Format: Meriem Messaoudene, Nathalie Saint-Lu, Frédérique Sablier-Gallis, Stéphanie Ferreira, Mayra Ponce, Clément Le Bescop, Thomas Loppinet, Tanguy Corbel, Céline Féger, Fabien Vitry, Antoine Andremont, Jean de Gunzburg, Bertrand Routy. Prevention of antibiotic-induced dysbiosis in human volunteers by DAV132 and preservation of responsiveness to anti-PD-1 demonstrated by transplantation of human feces into tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5882.Keywords:
Dysbiosis
Piperacillin/tazobactam
Avibactam
Piperacillin/tazobactam
Tazobactam
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Objective:To evaluate clinical efficacy and safety of piperacillin tazobactam treatment in acute bacterial infections.Methods:In this study 131 patients were randomized to receive either piperacillin tazobactam 8～12g/d or ticarcillin clavulanate 9.6～12.8g/d for 7～14 days.Sixty seven patients received piperacillin tazobactam and 64 patients received ticarcillin clavnlanate.Results:The cure rates in piperacillin tazobactom and ticarcillin clavulanate groups were 62.7% and 60.9% respectively and the efficary rates 89.6% and 84.4% respectively.Bacterial eradication rates were 91.5% and 89.1% respectively.The side effect rates were 11.9% and 6.25% respectively.There were no significant differences between two groups.Conclusion:Piperacillin tazobactam is a kind of safe and effective anti infection medicine.
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Ticarcillin
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To determine effectiveness and safety of generic piperacillin/tazobactam (Astaz-P) that has been available as a substitute for original piperacillin/tazobactam (Tazocin) in Siriraj Hospital since October 2011.Medical records of hospitalized adult patients who received piperacillin/tazobactam for at least 48 hours from January 2011 to June 2012 were reviewed. The data on demographics, clinical features of infections, antibiotic treatments, clinical courses and outcomes of the patients who received original piperacillin/tazobactam and generic piperacillin/ tazobactam were analyzed and compared.The medical records of 300 patients who received original piperacillin/tazobactam and 300 patients who received generic piperacillin/tazobactam were included. The characteristics of the patients and clinical and microbiological features of infections of the patients in both groups were not significantly different. Overall favorable clinical outcome and overall mortality were comparable between generic and original groups (74.0% vs. 74.7%, p = 0.93; 18.3% vs. 18.0%, p = 1.00, respectively). No significant difference of adverse effect was found between two groups. The non-inferiority test indicated that the clinical outcome and overall mortality of the patients who received generic piperacillin/tazobactam were not inferior to those who received original piperacillin/tazobactam (p = 0.004 and p = 0.001, respectively).Generic piperacillin/tazobactam (Astaz-P) was not inferior to original piperacillin/tazobactam (Tazocin) for therapy of infections in the hospitalized patients at Siriraj Hospital.
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The post-antibiotic effects (PAE) of ceftazidime, ciprofloxacin, imipenem, piperacillin and tobramycin were studied for ten strains of Pseudomonas cepacia isolated from patients with cystic fibrosis. Antibiotic concentrations used for exposure were either the MIC of each agent for the sensitive isolates or the recommended sensitivity breakpoint concentrations for the resistant iso1ates After 2 h of exposure, cultures were rapidly diluted 1000-fold to eliminate the antibiotic. Out of the ten isolates, there were eight sensitive to ceftazidime six to ciprofloxacin, six to imipenem, nine to piperacillin and five to tobramycin. All antibiotics tested demonstrated PAE for some isolates of P. cepacia, however, each antibiotic failed to produce a PAE for at least one isolate. The mean PAE was 1·35 h for ceftazidime, 2·38 h for ciprofloxacin, 2·39 h for imipenem, 2·16 h for piperacillin and 1·77 h for tobramycin. Imipenem demonstrated PAE of ≥ 0·5 h for all sensitive isolates tested; ceftazidime, piperacillin, ciprofloxacin and tobramycin demonstrated PAE of ≥ 0·5 h for 6/8, 8/9, 5/6 and 2/5 sensitive isolates, respectively. These data indicate that several antibiotics have significant ( ≥ 0·5 h) PAE for isolates of P. cepacia.
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This study evaluated the in vitro pharmacodynamics of combinations of ceftazidime and the non-β-lactam β-lactamase inhibitor, avibactam, against ceftazidime-, piperacillin/tazobactam- and meropenem-multiresistant Pseudomonas aeruginosa by a quantitative time-kill method.MICs of ceftazidime plus 0-16 mg/L avibactam were determined against eight isolates of P. aeruginosa . Single-compartment, 24 h time-kill kinetics were investigated for three isolates at 0-16 mg/L avibactam with ceftazidime at 0.25-4-fold the MIC as measured at the respective avibactam concentration. Ceftazidime and avibactam concentrations were measured by LC-MS/MS during the time-kill kinetic studies to evaluate drug degradation.Avibactam alone displayed no antimicrobial activity. MICs of ceftazidime decreased by 8-16-fold in the presence of avibactam at 4 mg/L. The changes in log 10 cfu/mL at both the 10 h and 24 h timepoints (versus 0 h) revealed bacterial killing at ≥1-fold MIC. Significantly higher concentrations of ceftazidime alone, as compared with those of ceftazidime in combination, were required to produce any given kill. Without avibactam, ceftazidime degradation was significant (defined as degradation t 1/2 < 24 h), with as little as 19% ± 18% of the original concentration remaining at 8 h for the most resistant strain. In combination with avibactam, ceftazidime degradation at ≥ 1-fold MIC was negligible.The addition of avibactam protected ceftazidime from degradation in a dose-dependent manner and restored its cidal and static activity at concentrations in combination well below the MIC of ceftazidime alone.
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Piperacillin-tazobactam is a commonly used antibiotic that belongs to penicillin and beta-lactam inhibitors, which has a wide range of gram-negative bacteria and limited gram-positive activity. This case report presents one of the rare ADR of piperacillin–tazobactam –thrombocytopenia where a dramatic improvement within 24hrs in platelet count was observed after withdrawing the drug. Few cases of piperacillin tazobactam-induced thrombocytopenia have been reported.
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We evaluated the in vitro activity of piperacillin alone or in combination with the beta-lactamase inhibitor tazobactam against clinical isolates of Legionella species. At an inoculum of approximately 10(4) CFU, tazobactam, piperacillin, and the 8:1 combination had equivalent activities against Legionella spp. At an approximately 10-fold higher inoculum, the following results were obtained, expressed as MICs for 50 and 90% of strains tested (MIC range): piperacillin, 4 and 16 (0.25 to 32) micrograms/ml; tazobactam, 0.5 and 1 (0.125 to 2) micrograms/ml; and piperacillin-tazobactam (expressed in terms of MIC of piperacillin) 0.5 and 1 (0.03 to 2) micrograms/ml. Tazobactam alone and the combination with piperacillin were more active than piperacillin alone at the higher inoculum.
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Piperacillin/tazobactam
Tazobactam
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Agar dilution
Agar Dilution Method
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Gram-Negative Bacteria
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Piperacillin/tazobactam
Sulbactam
Tazobactam
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