This study was a comprehensive systematic review and meta-analysis, investigating antibiotic resistance in V. cholerae strains. Unfortunately, V. cholerae strains antibiotic resistance patterns are not well elucidated. Antibiotic therapy could not be used alone to treat the disease, to control and reduce the disease duration by approximately 50%, and to reduce bacterial excretion in the feces (11). Oral or intravenous administration of fluids comprising of sodium chloride, glucose, trisodium citrate, and potassium chloride is the primary option that could be used to treat cholera and protect a patient from dehydration (WHO, 2002). However, only patients with severe dehydration need an appropriate antibiotic therapy (WHO, 2017). The incidence of antibiotic resistance is considered as a serious challenge threatening the efficiency of almost all antimicrobial agents commonly administered to remedy or prevent this infectious disease (12).
The choice of an appropriate antibiotic should be made by taking into account drug resistance patterns of local strains of V. cholerae O1 or O139. Repeated antibiotic therapy also imposes destructive and harmful ecological effects on the community and further increases the global burden of antibiotic resistance, especially in low and lower-middle income countries. This negatively affects control programs and threatens active treatment of cholera (6).
Treatment of a whole community with an antibiotic is not recommended by WHO. To further complicate the epidemiology of antibiotic resistant cholera, it is sufficient to mention that there is a wide range of antibiotics to which V. cholerae could be resistant. If V. cholerae strain is thought to be sensitive, some antimicrobial agents may be effective in its treatment, including doxycycline, ciprofloxacin, and azithromycin (13). Currently, some V. cholerae strains have emerged in Haiti, which are sensitive to tetracycline (a proxy for doxycycline) and azithromycin, while resistant to nalidixic acid, sulfisoxazole, and trimethoprim–sulfamethoxazole (14).
In this study, the antibiotic resistance pattern of V. cholerae strains was comprehensively evaluated globally, and its high resistance to various antibiotics in several regions of the world was shown. This study results demonstrated that resistance to furazolidone, trimethoprim-sulfamethoxazole, nitrofurantoin, streptomycin, nalidixic acid, and ampicillin was the most common antibiotic resistance pattern worldwide (Table 2,3).
The use of doxycycline in combination with oral rehydration solutions is suggested in some cholera cases; also, tetracyclines are extensively used against V. cholerae infection. Erythromycin is another effective option used to reduce cholera symptoms in children and pregnant women (15). In the present study, V. cholerae resistance rate to erythromycin antibiotic was 26% in Africa and developing countries, such as Mozambique and Sierra Leone. Furthermore, due to low resistance rate of V. cholerae strains to macrolide antibiotics, especially azithromycin, they are considered as the drugs of choice for cholera treatment in children and adults.
Chloramphenicol is another effective option which acts through inhibiting protein synthesis and is commonly prescribed for cholera therapy. The use of chloramphenicol has been restricted in some country such as India in the past due to the availability of more effective antibiotics with less side effects (16). Significant increase in furazolidone resistance might be attributed to the increased consumption of this antibiotic in countries with lower level of socioeconomic development. Generally, the choice of an appropriate antibiotic depends on drug resistance pattern of local strains. Inappropriate antibiotic prescription, over-the-counter availability of antibiotics without valid prescription, and consumption of inappropriate or partial antibiotic regimens could be the reasons for the emergence of antibiotic resistance crisis. In this regards, antimicrobials resistance is on the rise, and a recent concern is the development of antimicrobial resistance in V. cholerae strains in endemic areas (17).
This study showed that the pooled prevalence rates of V. cholerae strains which were resistant to trimethoprim–sulfamethoxazole, erythromycin, nalidixic acid, ampicillin, streptomycin, and ceftriaxone varied from 0% in countries such as Brazil, Austria, Slovakia, and Maryland (trimethoprim–sulfamethoxazole); Austria, Togo, Ivory Coast, Vietnam, and Maryland (erythromycin); Brazil, Bangladesh, Nepal, Guinea, German, Maryland, Senegal, and Namibia (nalidixic acid); Bangladesh, Zambia, Congo, Togo, Ivory Coast, Vietnam, and Namibia (ampicillin); Maryland (streptomycin); and India, China, Bangladesh, Guinea, Congo, Togo, Ivory Coast, Kenya, and Namibia (Ceftriaxone) to 100% in countries such as Zambia, Nepal, Togo, Kenya, Ethiopia, and Senegal (trimethoprim–sulfamethoxazole); Mozambique and Sierra Leone (erythromycin); Ivory Coast and Zambia (nalidixic acid); Uganda (ampicillin); Namibia, Senegal, and Nepal (streptomycin); and Mozambique (ceftriaxone). These differences in antibiotic resistance rates could be observed even within countries. It could be justified by taking into account that antibiotic resistance depends on multi factors in each geographical area (2).
Significant differences in antibiotic resistance rates from 0 to 100% in most WHO regions might be attributed to the lack of a uniform consumption pattern and access to the same antibiotics in different countries. The use of low-price antibiotics for treating this infection in developing countries, over-the-counter availability of these antibiotics, and their widespread consumption in these areas and countries might explain these outcomes. Furthermore, uncertainty about the effectiveness of simple rehydration solutions for mild and moderate dehydration could be considered as another cause of antibiotic resistance (18). Antibiotic resistance rate tended to be higher in African and Asian regions, especially in low and lower-middle income developing countries. More cholera outbreaks in these areas are the reasons for the increase in antibiotic resistance. Research results have displayed that susceptibility pattern of V. cholerae O1 strains to antimicrobials has altered over time, and that the spread of resistance to antibiotics commonly used for cholera treatment is on the rise in Africa and Asia (19). Resistance to azithromycin was higher in European countries, such as Slovakia, than in other countries. These findings collectively suggest that pattern of antibiotic consumption in these countries should be according to antibiotic resistance pattern.
V. cholerae is an environmental pathogen that could obtain resistance genes through direct contact with inherently resistant organisms carrying resistant genes on mobile genetic elements. This meta-analysis showed that 20% of samples studied were environmental. Antibiotic resistance mechanisms including efflux pumps, spontaneous chromosomal mutation or the development of genetic resistance via the exchange of conjugative plasmids, transposons, integrons, or self-transmissible chromosomally integrating SXT element could be accounted for the mechanisms of antibiotic resistance action in V. cholerae strains.
Antibiotic resistance genes could be exchanged between V. cholerae strains and other bacteria as well as commensals or enteric microorganisms in the human intestine, raising doubt about the reliability of several of these outcomes. The results showed that resistance patterns fluctuate may be induced via stable plasmids and plasmid-mediated mechanisms. Few studies investigated (21.4%) antibiotic resistance genes, but other studies did not investigate or discuss about the mechanisms of V. cholerae resistance or these alarming results (15). However, it is recommended that more investigations be carried out in order to determine the exact mechanisms of resistance action.
There are several limitations in this study. First, publications in some countries were very unusual. Between-study variation among the included studies was significant. Second, studies conducted on bacterial infections in few countries employed heterogeneous methodologies. A certain challenge was the lack of a standardized panel of antimicrobials against V. cholerae strains tested, thereby making it difficult to combine the results of these studies. The majority of studies performed only disc susceptibility testing without further MIC and ESBL testing or determination of MDR and XDR V. cholerae strains due to differences in patterns of economic development, antimicrobial consumption, and transmission of V. cholerae genotypes. High-quality antibiotic susceptibility testing is considered as a significant public health method; identifying AMR contributes to the update of local treatment guidelines and prevents the use of ineffective antibiotics. These issues are vital as our antimicrobial facilities are limited, especially in low-income epidemic areas.