# Brucella’s Emerging Threat: A Global Systematic Review and Meta‐Analysis Revealing Temporal, Geographic and Species‐Specific Patterns of Antimicrobial Resistance

## TL;DR

This study reviews global patterns of antibiotic resistance in Brucella bacteria, finding significant resistance to two key antibiotics, especially before 2010 and in non-Asian regions.

## Contribution

The paper provides the first global systematic review and meta-analysis on antimicrobial resistance in human Brucella isolates.

## Key findings

- Significant resistance was found in Brucella to trimethoprim-sulfamethoxazole and rifampicin.
- Resistance was more common in isolates before 2010 and in non-Asian regions.
- Meta-analysis showed MIC50 values of 1.00 μg/mL for rifampicin and 0.50 μg/mL for trimethoprim-sulfamethoxazole.

## Abstract

Antimicrobial resistance (AMR) can lead to treatment failure in human bacterial infections, resulting in increased morbidity and mortality. Brucellosis is a globally significant zoonotic infection caused by Brucella spp. bacteria, yet the frequency and extent of AMR in Brucella populations from humans are poorly characterised. This systematic review and meta‐analysis investigated AMR in populations of Brucella species responsible for the vast majority of brucellosis in humans (B. melitensis, B. abortus, B. suis and B. canis). The search and inclusion criteria identified studies which used testing methods of minimum inhibitory concentration (MIC: E‐test, broth and agar dilution), with the main (doxycycline, streptomycin and rifampicin) and alternative (trimethoprim‐sulfamethoxazole, gentamicin and ciprofloxacin) antibiotics utilised in the treatment of human brucellosis. Out of 704 studies identified via SCOPUS, 2 were non‐English, 401 were irrelevant, 230 were lacking key inclusion criteria and 20 had incomplete details and were excluded, leaving 51 for review; however, for Z‐tests and meta‐analysis, the absence of MICmin/max data left 49 studies. The Newcastle–Ottawa Scale and the Grading of Recommendations, Assessment, Development and Evaluation systems were used to assess the risk of bias in the included studies. Two of the antibiotics considered (trimethoprim‐sulfamethoxazole and rifampicin) exhibited significant resistance. This resistance was reflected in 1‐sample Z‐tests, of which 39/228 (17.1%) produced an outcome of ‘non‐susceptible’ or ‘not proven to be susceptible’, and these predominantly belonged to trimethoprim‐sulfamethoxazole (15/34; 44.11%) and rifampicin (21/49; 42.85%). The type of meta‐analysis was generic inverse variance weighted average. For rifampicin and trimethoprim‐sulfamethoxazole, sensitivity analysis produced a MIC50 of 1.00 μg/mL (95% CI: 0.98, 1.01) and 0.50 μg/mL (95% CI: 0.49, 0.51), respectively. For rifampicin and trimethoprim‐sulfamethoxazole, AMR was linked to the years before 2010, non‐Asian continents and Brucella species when tested in mixed isolates. Therefore, more careful stewardship in the use of rifampicin and trimethoprim‐sulfamethoxazole antibiotics is necessary to prevent the development of AMR in Brucella.