Background: Contagious bovine pleuropneumonia (CBPP) caused by Mycoplasma mycoides subspecies mycoides (Mmm) is an important disease of cattle that causes serious economic losses. With the known effectiveness of new generation macrolides, tulathromycin and gamithromycin were assessed in comparison with oxytetracycline as a positive control and saline as a negative control for effectiveness in inhibiting lung lesion development, promoting resolution, preventing spread and bacteriological clearance in susceptible local cattle breeds in two separate studies in Kenya and Zambia. Animals were monitored for clinical signs, sero-conversion as well as detailed post-mortem examination for CBPP lesions. Results: Using the Hudson and Turner score for lesion type and size, tulathromycin protected 90%, gamithromycin 80%, and oxytetracycline 88% of treated animals in Kenya. In Zambia, all animals (100%) treated with macrolides were free of lung lesions, while oxytetracycline protected 77.5%. Using the mean adapted Hudson and Turner score, which includes clinical signs, post-mortem findings and serology, tulathromycin protected 82%, gamithromycin 56% and oxytetracycline 80% of the animals in Kenya whereas in Zambia, tulathromycin protected 98%, gamithromycin 94% and oxytetracycline 80%. The saline-treated groups had 93 and 92% lesions in Kenya and Zambia respectively, with Mmm recovered from 5/14 in Kenya and 10/13 animals in Zambia. Whereas the groups treated with macrolides were free from lesions in Zambia, in Kenya 5/15 tulathromycin-treated animals and 6/15 gamithromycin-treated animals showed lesions. Oxytetracycline-treated animals showed similarities with 3/14 and 4/15 showing lesions in Zambia and Kenya respectively and Mmm recovery from one animal in Kenya and six in Zambia. In both studies, lesion scores of saline-treated groups were significantly higher than those of the antibiotic treated groups (p < 0.001). In sentinel animals, CBPP lesions were detected and Mmm recovered from one and two animals mixed with the saline-treated groups in Kenya and Zambia respectively. Conclusions: This study demonstrated that tulathromycin, a mycoplasmacidal, can achieve metaphylactic protection of up to 80%, while non-recovery of Mmm from sentinels suggests macrolides effectiveness in preventing spread of Mmm. It is recommended that further studies are conducted to evaluate strategies comparing vaccination alone or combining vaccination and antibiotics to control or eradicate CBPP.

Background/Objectives: Antimicrobial resistance (AMR) is a major global health threat that undermines treatment in humans and animals. In Zambia, where livestock production underpins food security and livelihoods, AMR challenges are aggravated by limited surveillance, weak diagnostics, and poor regulatory enforcement, facilitating the spread of resistant pathogens across the human–animal–environment interface. This study aims to analyse AMR patterns of bacterial isolates collected from Zambia’s animal health sector between 2020 and 2024, to generate evidence that informs national AMR surveillance, supports antimicrobial stewardship (AMS) interventions, and strengthens One Health strategies to mitigate the spread of resistant pathogens. Methods: We conducted a retrospective descriptive analysis of previously collected routine laboratory data from five well-established animal health AMR surveillance sentinel sites between January 2020 and December 2024. Data were analysed by year, sample type, and antimicrobial susceptibility testing (AST) profiles using WHONET. Results: A total of 1688 samples were processed, with faecal samples accounting for 87.6%. Animal environmental samples (feed, manure, litter, abattoir/meat processing floor, wall, and equipment surface swabs) (collected from abattoirs, water, and farms) increased significantly over time (p = 0.027). Overall, Escherichia coli (E. coli) (50.4%) and Enterococcus spp. (30%) were the most frequently isolated bacteria. E. coli exhibited high resistance to tetracycline (74%) and ampicillin (72%) but remained susceptible to aztreonam (98%), nitrofurantoin (95%), and imipenem (93%). Enterococcus spp. were susceptible to penicillin (84%) and ampicillin (89%) but showed borderline resistance to vancomycin (53%) and linezolid (50%). Klebsiella spp. demonstrated resistance to ciprofloxacin (52%) and gentamicin (40%), whereas Salmonella spp. remained highly susceptible. Notably, resistance to amoxicillin/clavulanic acid rose sharply from 22.2% to 81.8% (p = 0.027). Across 1416 isolates, high levels of multidrug resistance (MDR) were observed, particularly in E. coli (48.4%) and K. pneumoniae (18.6%), with notable proportions progressing toward possible Extensively Drug-Resistant (XDR) and Pan-Drug-Resistant (PDR) states. Conclusions: The findings of this study reveal rising resistance to commonly used antibiotics in the animal health sector. Despite the lack of molecular analysis, our findings underscore the urgent need for AMS programs and integrated AMR surveillance under Zambia’s One Health strategy.