In vitro and in vivo Synergistic Effects of Florfenicol and Thiamphenicol in Combination Against Swine Actinobacillus pleuropneumoniae and Pasteurella multocida.

Porjai Rattanapanadda,Tsai-Lu Lin,Chi-Hsuan Sung,Hung-Chih Kuo,Chi-Chung Chou,Tirawat Rairat,Sze-Yu Yeh,Thomas W Vickroy

doi:10.3389/fmicb.2019.02430

Porjai Rattanapanadda, Tsai-Lu Lin + Show 6 more

Open Access

https://doi.org/10.3389/fmicb.2019.02430

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Abstract

Potential synergism between florfenicol (FF) and thiamphenicol (TAP) was investigated for in vitro efficacy against Actinobacillus pleuropneumoniae and/or Pasteurella multocida as well as in vivo efficacy in swine. Among isolates of A. pleuropneumoniae (n = 58) and P. multocida (n = 79) from pigs in Taiwan that were tested, high percentages showed resistance to FF (52 and 53%, respectively) and TAP (57 and 53%, respectively). Checkerboard microdilution assay indicated that synergism [fractional inhibitory concentration index (FICI) ≤ 0.5] was detected in 17% of A. pleuropneumoniae (all serovar 1) and 24% of P. multocida isolates. After reconfirming the strains showing FICI ≤ 0.625 with time kill assay, the synergism increased to around 32% against both bacteria and the number could further increase to 40% against resistant A. pleuropneumoniae and 65% against susceptible P. multocida isolates. A challenge-treatment trial in pigs with P. multocida showed that the FF + TAP dosage at ratios correspondent to their MIC deduction was equally effective to the recommended dosages. Further on the combination, the resistant mutation frequency is very low when A. pleuropneumoniae is grown with FF + TAP and similar to the exposure to sub-inhibitory concentration of FF or TAP alone. The degree of minimum inhibitory concentration (MIC) reduction in FF could reach 75% (1/4 MIC) or more (up to 1/8 MIC for P. multocida, 1/16 for A. pleuropneumoniae) when combined with 1/4 MIC of TAP (or 1/8 for A. pleuropneumoniae). The synergism or FICI ≤ 0.625 of FF with oxytetracycline (47%), doxycycline (69%), and erythromycin (56%) was also evident, and worth further investigation for FF as a central modulator facilitating synergistic effects with these antimicrobials. Taken together, synergistic FF + TAP combination was effective against swine pulmonary isolates of A. pleuropneumoniae and P. multocida both in vitro and in vivo. Thus, this study may offer a potential alternative for the treatment of A. pleuropneumoniae and P. multocida infections and has the potential to greatly reduce drug residues and withdrawal time.

Highlights

The continuing emergence of antimicrobial resistance coupled with the slow development of new antimicrobial drugs represents a growing worldwide challenge for both human and animal healthcare (Cheng et al, 2016)
Florfenicol has been authorized for veterinary antimicrobial use in swine in many countries including European Union, United Kingdom, Japan, United States, Canada, and Taiwan (European Medicines Agency [EMA], 1999; Veterinary Medicines Directorate [VMD], 2013; The Japan Food Chemical Research Foundation [JFCRF], 2015; Bureau of Animal and Plant Health Inspection and Quarantine [BAPHIQ], 2019; The United States Food and Drug Administration [US FDA], 2019; Veterinary Drugs Directorate [VDD], 2019), while thiamphenicol is approved in these regions except for the North America
Results of the in vitro susceptibilities of A. pleuropneumoniae and P. multocida isolates to FF and TAP are summarized in Table 1 with values presented as the minimum inhibitory concentration (MIC) distributions, MIC50, MIC90 and % resistance values

Summary

Introduction

The continuing emergence of antimicrobial resistance coupled with the slow development of new antimicrobial drugs represents a growing worldwide challenge for both human and animal healthcare (Cheng et al, 2016). Benefits associated with the use of combined antimicrobial therapy with synergistic activities include the potential for delayed development of bacterial resistance, a broadening of antibacterial spectrum to treat polymicrobial infections, a reduction in drug toxicity and reduced cost or risk of harmful residues in food products (Eliopoulos and Eliopoulos, 1988; Ahmed et al, 2014). The wide range of applications and the use as essential treatments against specific infections, in addition to the lack of sufficient therapeutic alternatives, make amphenicols [including florphenicol (FF) and thiamphenicol (TAP)] critically important antimicrobial agents for veterinary use (VCIA) according to the World Organization for Animal Health (OIE) (OIE, 2015)

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