Antimicrobial resistance from a one health perspective in Cameroon: a systematic review and meta-analysis

The necessity to improve human health, animal health and agricultural productivity in low- and middle-income countries has led to the extensive use of antimicrobials without respecting therapy guidelines. However, farmers’ ignorance of the hazards related to antibiotic therapy and the widespread use of antimicrobials in food-producing animals has escalated the emergence of antimicrobial resistance (AMR) [1]. Thus, the worldwide public health concerns with respect to the antibiotics used in food-producing animals is due to the fact that they are closely related to those used in human medicine and select for resistance. Cross-species transmission of resistant bacteria or resistance genetic elements from animals or environment to humans has been reported [2, 3]. The World Health Organization (WHO) global report on AMR indicates that resistance of common bacteria has reached alarming levels in many parts of the world with high level resistance of Escherichia coli and Klebsiella spp to third-generation cephalosporin’s and carbapenems of up to 54% [4, 5]. High resistance rates have been described in bacteria isolated from food-producing animals to major antimicrobials used in human medicine [6‐8]. In addition, high resistance rates in bacteria isolated from vegetables and environment have been reported [9].

Largescale and worldwide surveillance is critical to global AMR response. According to a WHO report, Africa has the largest gaps in data on AMR [5, 10]. A desktop analysis of the implementation of WHO’s Policy Package to combat AMR in the WHO African region revealed that two countries -Ethiopia and South-Africa (4.3%), have national AMR plans in place while 7(14.9%) other countries have only infection prevention and control policies. Four of these countries are from Eastern Africa (Tanzania, Zimbabwe, Ethiopia, and Kenya), two from southern Africa (Lesotho and South Africa) and one West Africa (Ghana). Furthermore, no African country has a national surveillance system that routinely generates representative, robust data on antimicrobial use and resistance [11].

There is dearth of information on AMR in livestock and agricultural sectors in Africa. Moreover, major gaps exist in the surveillance and sharing of data on AMR emergence among food-borne bacteria and the potential impact on animal and human health [12]. Due to resource constraints, the choice of antibiotic in most parts of Africa including Cameroon is usually not based on knowledge of bacterial-susceptibility. Lack of reliable and quantitative data challenges local and regional treatment guidelines and highlights the need for sustainable efforts by stakeholders towards coordination and harmonization of competences to assess and monitor AMR emergence.

AMR is suspected when there is therapeutic failure evidenced by no convalescence. Limited diagnostic capacity coupled with a high burden of life-threatening bacterial infections has encouraged a pattern of largely empirical antibiotic prescription in human and veterinary medicine in Cameroon. Also, a small repertoire of generic antimicrobials which are often poor quality [13], sold in open markets with little or no regulations, quality control and inappropriate prescription practices [13, 14], are regularly used. Poor personal and environmental hygiene practices have favored the spread of drug resistant pathogens within the hospital environment, causing hospital-acquired infections [15, 16]. The use of antimicrobials as growth promoters in agriculture has been associated with resistant food borne pathogens and relatively risky to human, animal and environmental health [17]. It is based on this context that this review was done to analyze the available information on AMR emergence in humans, animal and environment as key to effective interventions in Cameroon.

The initial search strategy of the online databases in this study identified a total of 509 citations. Additional 58 records were identified by contacting experts in the field of antibiotic use and resistance (12), searching reference lists of included studies (44) and local database (2). A total of 89 duplicates were removed and 478 records were screened for eligibility based on review of title and content of the abstracts. Overall, 381 records were excluded for non-relevance to the research objectives while 97 full-text articles were assessed for eligibility with 66 records meeting the inclusion criteria for the study (Fig. 2). Of these 66 studies included in the review, 52 were rated as good quality (low risk of bias) and 14 were of moderate quality (medium risk of bias). A total of 45 studies reported on the outcome of antibiotic resistance in humans [15, 27‐69], 9 reported on the outcome of antibiotic resistance in animals [70‐78] and 12 on the environment [9, 15, 16, 57, 62, 64, 75, 79‐83] (Table 1). Five studies reported outcome of antibiotic resistance in both human and environment while one study reported on the outcome of antibiotic resistance for animals, humans and environment. The largest number of human studies originated from the Centre region (46.7%) followed by the West (17.8%), South-West (15.6%), Littoral (11.1%) and other (North-West, Adamawa, Far-North) (4.4%) regions of the country (Fig. 3). These sources were journal articles (100%), published in English (88.9%) with focus on both sex (95.6%) and 4.4% strictly on women. These studies investigated Urinary Tract infections (UTIs) (29; 64.4%), Bloodstream infections (BSIs) (17; 37.8%), Gastro-intestinal infections (GIIs) (15; 33.3%), and Respiratory tract infections (RIs) (14; 31.1%). Overall, 25 types of samples were reported in the various studies, the most abundant being urine samples (26; 57.8%), followed by vaginal swabs (14; 31.1%), stool samples (14; 31.1%), pus (12; 26.7%), blood (12; 26.7%), wounds swabs (10; 22.2%) and others: skin (6; 13.3%), nasal swabs (4; 8.9%), Urinary catheter (4; 8.9%), pleural fluid (4; 8.9%), seminal fluid (3; 6.7%), bone fragment (3; 6.7%), septum (3; 6.7%), sinusitis (3; 6.7%), fingerprinting (3; 6.7%), throat swabs (2; 4.4%), eye discharge (2; 4.4%), ear discharge (2; 4.4%), urethral smear (2; 4.4%), corpus and antral biopsy (1; 2.2%), surgical site (1; 2.2%), cerebrospinal fluid (1; 2.2%), ostitis (1; 2.2%) and bronchitis (1; 2.2%).

Nineteen types of pathogens were isolated from samples with the most frequently encountered isolates being Escherichia coli (51.1%) followed by Klebsiella spp (42.2%), Staphylococcus spp (40%), Pseudomonas aeruginosa (24.4%), Enterobacter spp (17.8%) and Enterococcus spp (15.6%). These isolates were tested against 48 antimicrobial agents belonging to 14 families. The studies were conducted in urban settings (34/45; 75.5%), semi-urban (8/45; 17.8%) and rural areas (3/45; 6.7%). The majority of patients were hospitalized (30/45; 66.7%) while 19 (42.2%) were outpatient, 10 (22.2%) members of the community, 6 (13.3%) medical staff and 2 (4.4%) non-medical staff. These were cross sectional prospective studies (93.30%) and longitudinal studies (6.7%). With regards to the type of microbiology laboratory used, the studies were carried out in teaching hospitals partnering with an associated laboratory (22/45; 48.9%), routine clinical laboratories (19/45; 42.2%) as well as research laboratories (4/45; 8.9%). The disk diffusion test (37/45; 82.2%) was predominantly used for antibiotic susceptibility testing followed by dilution test (4/45; 8.9%) and Etest (2/45; 4.4%). Some studies used both diffusion and dilution test (2/45; 4.4%) and diffusion and Etest (1/45; 2.2%). The following microbiological standards were used as references: the Clinical Laboratory Standard Institute (20/45, 44.4%), the French Society of Microbiology (16/45; 35.6%), European Committee on Antimicrobial Susceptibility Testing (1/45; 2.2%), American Type Culture Collection (1/45; 2.2%), and both French Society of Microbiology and European Committee on Antimicrobial Susceptibility Testing (3/45; 6.7%). Four (8.9%) studies did not clearly define the susceptibility laboratory references used.

Animal studies originated from four regions: South-West (33.3%), Adamawa (22.2%), Centre (22.2%), and West (22.2%) while environmental studies were from South-West (41.7%), Littoral (33.3%) and West (25%) regions (Fig. 3). Seven animal’s studies were journal articles published in English and two Doctor of Veterinary Medicine dissertations written in French. A total of 12 environmental studies were journal articles published in English. Animal and environmental studies were cross-sectional designs. Poultry (5/9; 55.6%) was the most studied animal population, followed by beef cattle (2/9; 22.2%). Faecal/cloacal swabs/caecum (7/9; 77.8%) were the most harvested samples in animal studies while in environmental studies, swabs of hospital surfaces and medical devices (50%) and water samples (25%) were the most investigated. Results reported Salmonella spp (66.6%) and Escherichia coli (33.3%) as the most isolated organisms in animal studies and Staphylococcus spp (66.7%), Bacillus spp (50%) and Pseudomonas aeruginosa (33.3%) in environmental studies. For the animal studies, 7 articles made use of disk diffusion tests while 2 used both diffusion and dilution tests. The Clinical Laboratory Standard Institute standards were used as reference in 5(55.6%) studies while the rest used the French Society of Microbiology standards (4/9; 44.4%). All environmental studies made use of disk diffusion tests, but microbiological reference standards of the Clinical Laboratory Standard Institute were used by 63.6%) (7/11) and the French Society of Microbiology by 36.4% (4/11).

Antimicrobial resistance is a complex issue of global health concern. AMR is on the increase and threatens the effective management of most bacterial diseases worldwide [5, 84]. However, decreased death and morbidity rates associated with the use of antibiotics based on empirical guidelines are threatened by the development of AMR. Routine susceptibility checks of pathogens as essential keys geared towards strategies against the global AMR crisis have been previously described [10]. The One Health approach based on linking human health and nutrition with animal and environmental health is an improved multi-disciplinary action across these sectors against AMR. The current report reviewed 66 published data of resistance to commonly used antimicrobials in Cameroon. Overall, the review revealed that the level of resistance of bacteria isolated in hospital settings, animal and environment is high for typical empirical antibiotic treatment strategies. Common Enterobacteriaceae pathogens isolated in hospital settings such as E. coli, Klebsiella spp., Enterobacter spp and Proteus spp showed high rates of AMR to ampicillin, amoxicillin, trimethoprim/Sulfamethoxazole, amoxicillin/ clavulanic acid, tetracycline, co-trimoxazole and nalidixic acid. The finding agrees with data obtained in Tanzania (resistance to co-trimoxazole (77.7%) and ampicillin (81.6%) [85] and East Africa (50–100% resistance to ampicillin and cotrimoxazole) [4].

This review highlights serious concerns relating to the use of ampicillin, amoxicillin and tetracycline as the antibiotics of choice for optimal therapy of common pathogens in Cameroon. Vital information on the burden of antibiotic resistance and concerns on diagnostic capacity and second-line treatment options in the country are also presented. The misuse of antibiotics such as inappropriate prescription of antibiotics, excessive use and auto-medication and insufficient hygienic practices in health care settings have been reported to contribute to rising levels of AMR [86, 87]. The moderate resistance level (42%) observed for Staphylococcus spp isolated from hospital settings to third generation cephalosporins, gentamicin and fluoroquinolones was due to the fact that these drugs were usually the last choice of medicine used. This suggests that the choice of antibiotic should be guided by a profile of antimicrobial susceptibility testing results of patients in Cameroon. Multidrug resistance (more than 10 antibiotics) of common bacteria such as E. coli (47.1%), Klebsiella spp (51.0%) and Staphylococcus spp (45.2%) were further evidence of high and widespread AMR in Cameroon. The review revealed that AMR is a growing health problem and major concerns among hospitalized persons and risk communities. Generally, antibiotic resistance is under-investigated and under-reported in the WHO African region including Cameroon [1, 5, 11] due to limited or unavailability of diagnostic tests and lack of microbiology technical resources. These have led to the inability to test clinical isolates for antimicrobial susceptibility as well as contributed to excessive use and misuse of antibiotics and the phenomenon of AMR. Antibiotic resistant strains may be easily transferred within the human-animal-environment interfaces due to high level of interactions. For example, resistant pathogens in food producing animals and environments can be passed easily to human during various interactions.

Pathogens isolated from food producing animals in the current review such as Salmonella spp and E. coli showed high resistance against ampicillin, amoxicillin, STX, tetracycline and doxycycline. This agrees with reported high antibiotic simple (up to 86%) and multidrug (73%) resistance rates in Africa [88]. Considering that these are typically empiric antibiotics used for strategic health management in human and animals, the preservation of these important antibiotics for human health cannot be overemphasized [89, 90]. The multidrug resistance observed in this study for Salmonella spp and E. coli, could be a consequence of overuse or misuse of antibiotics, failure to consult veterinarians before the antibiotherapy, absence of a clear regulation code on the use of antibiotics in animals [91, 92] in Cameroon. The widespread use of substandard drugs [93] and poor hygiene handling of food [94, 95] have been reported earlier in the country. The main route of transmission of drug-resistant strains from food producing animals to humans occur through contamination of edible animal products. Therefore, the misuse of veterinary drugs and misguided therapy in veterinary medicine could select resistant strains in food animals and cause considerable impact on human health [96].

The findings of this review revealed gaps in the surveillance and interdisciplinary sharing of data on the emergence of AMR in foodborne bacteria and their potential impact on both animal and human health in Cameroon. In this context, the One Health Approach for control AMR should include improved integrated surveillance of resistance in bacteria in food-producing animals in the food chain, food products, humans and the environment and prompt sharing of data [96].

Uncontrolled use and/or misuse of antimicrobials (use without prior laboratory susceptibility testing) in agriculture has been linked to increase in the rates of drug resistance [5, 84] since contaminating bacteria usually tend to be treated with dosage rates lower than required for the treatment or exposed to an ineffective drug. In this review, Staphylococcus spp, Bacillus spp and Vibrio cholerae isolated from the environment (hospital surfaces and devices, water and abattoirs drain) were highly resistant to the first line antibiotics used in human and animals and showed high multidrug resistance rates. Poor hygiene of hospital surfaces and inadequate management of expired drugs could be responsible for the high AMR rates. Easy transmission of resistant bacteria from the environment to humans and animals also play a role in the highly resistant Staphylococcus spp reported in human studies and most of these inappropriately used antimicrobials often end up in wastewater in low and middle-income countries including Cameroon as previously reported [97]. Drug-resistant pathogens have higher chances of surviving and emerging when they are found in sewage. Also, antibiotic-resistant bacteria in the environment may be due to the dynamism and acquisition of antibiotic resistance genes that can be transferred horizontally from one bacteria to another [3]. This could explain high relationship between resistance in the environmental studies and overuse and uncontrolled use of antimicrobials in human and animal medicine since part of the drugs are excreted or secreted in the environment [3].

The current review also highlights lack of published AMR data on human, animal and environmental health in three, six and seven regions in Cameroon, respectively. Bridging the knowledge gaps and enhancing AMR surveillance in Cameroon to reduce the threat of AMR on public health cannot be overemphasised. As part of the global One Health Strategic plan against public threats and enhance the Global Antimicrobial Resistance Surveillance System [20], Cameroon has instituted a National Action Plan to fight against Antimicrobial Resistance (NAP-RAM 2018–2020) [98] to reduce the burden of AMR in the country. The plan is multisectoral involving seven key ministerial departments and technical partners and has six major objectives: (1) to improve awareness and understanding of antimicrobial resistance through effective communication, education and training; (2) to strengthen knowledge and evidence through monitoring and research; (3) to reduce the incidence of infections by applying effective sanitation, hygiene and infection control measures; (4) to optimize the use of antimicrobials in human, animal and plant health; (5) to develop economic arguments for sustainable investments and the production of new medicines, diagnostic tools, vaccines and other interventions for the fight against AMR; (6) to improve governance in the sector through strengthening of standardization, regulation and accountability. Effective implementation of the actual national action plan according to the “One Health” concept could be a reliable effort to reduce the burden of AMR at the national level. However, certain barriers for implementation exist including as poverty, remote nature of many rural zones and risk of emerging diseases. In addition, the lack of experts trained in ‘One Health Approach’ and the inadequacy of curriculum of educational programs regarding antimicrobial prescription, use and AMR could constitute other limitations to the application of this current plan.

This review does not only give an estimate of the level of AMR in Cameroon but revealed large knowledge gaps. Short comings were related to the representativeness of data which focused on AMR reports which did not support evaluation since absence of resistance cases were not routinely declared. Existing data were concentrated on four regions of the country. Also, very few reports from animal and environment were available. A further limitation is combining AMR results from different patient groups across different regions of the country to compare. The high-level resistance rates observed could be due to the approach used. Nonetheless, the review revealed the general trend and developments of AMR. Finally, for the purpose of this review, resistance data gotten using laboratory methodologies were combined. Variation in AMR methodology has minimal effect on the quality of final results and many studies used the disk diffusion method and CLSI guidelines [1]. Intense therapeutic studies will highlight further knowledge on the clinical impact of AMR and disadvantages of strategies that rely on empirical use of broader-spectrum drugs. The emergence of AMR in Cameroon is a real threat that cannot be ignored.

The present review highlights the high prevalence of resistance to commonly used antibiotics in humans, animals and the environment in Cameroon. Multi-drug resistance was observed to be a real and rising threat. All bacteria isolated showed resistance to more than one drug of choice in different or similar drug lines. In the Cameroon context where infectious diseases are highly endemic, there is insufficient data from interventional studies in the struggle to contain AMR. Given that there is dearth of data on hospital, community-acquired infections, animal infections and prevalence of AMR in Cameroon, systemic investigations and surveillance cannot be overemphasized. Long-lasting measures encouraging the implementation of antimicrobial stewardship in Cameroon such as pharmacy, laboratory quality control, full microbiology investigations and the development and distribution of standard antibiograms nationwide should be reinforced. Public health education on prescription, sensitization of users and elaboration of stringent drug regulations and fight against counterfeit drugs are essential to reduce AMR in Cameroon. The national action plan to reduce the burden of AMR can succeed only through continued data sharing as well as global collaboration, harmonization, and coordination between all partners involved in the implementation of AMR surveillance.