Vibrio cholerae (Cholera)
Authors: Carlos Seas, M.D., Eduardo Gotuzzo, M.D.
MICROBIOLOGY
Cholera is caused by Vibrio cholerae serogroup O1 and since 1992 by Vibrio cholerae serogroup O139. Both are curved Gram negative bacilli that belong to the family Enterobacteriaceae. Vibrio cholerae serogroup O1 is classified in serotypes and biotypes. The three serotypes (Inaba, Ogawa, and Hokojima) are identical in both clinical and epidemiological parameters. Two biotypes are recognized for V. cholerae O1: the classical and El Tor biotypes. The biotype El Tor is responsible for the current seventh pandemic, it survives in specific aquatic environments, it has more widespread distribution, and it is associated with more asymptomatic infections than the classical biotype (111). The classical biotype is restricted to Bangladesh. These two biotypes have coexisted for decades in their natural environment, possibly interacting genetically to produce hybrids, as has been reported recently from Asia and Africa (3, 101). The O139 serogroup is composed of an assortment of genetically dissimilar strains with at least nine different ribotypes (37). This new serogroup is genetically similar to El Tor V. cholerae, and might have been originated through recombination of genetic material between O1 and non-O1 strains. Recent investigations suggest that the agents of the last pandemic that affected Asia in the 1960s, Africa in the 1970s, and more recently Latin America in the 1990s belong to a same clonal complex. Strains affecting each continent may represent independent variants of the same clonal complex (86). V. cholerae O1 is in constant genomic change. Altered biotypes carrying genes that encode for the cholera toxin of both the classical and El Tor biotypes have been found responsible for epidemics of severe diarrhea in Bangladesh, where they have almost completely replaced the El Tor biotype, and may have caused the most recent epidemic in Haiti in 2010 (22, 102, 113). More recently, using whole-genome sequence to compare strains of past and current epidemics, it has been possible to demonstrate that alterations in the gene encoding for the B sub-unit of the cholera toxin have been responsible for major changes in the evolution of V. cholerae O1 (60).
EPIDEMIOLOGY
Cholera is one of the most feared epidemic infectious diseases that can affect human beings. Seven pandemics of cholera have been recorded since 1817. Each one of these pandemics caused significant morbidity and mortality, had a negative impact on the economy, trade, and commerce of the affected countries, and caused panic amongst the general public. The last pandemic of cholera originated in Indonesia in 1961, and was caused by Vibrio cholerae O1 biotype El Tor.
A resurgence of cholera worldwide is clearly apparent (5, 125). Epidemics of clinical cholera in endemic areas such as the Indian subcontinent and Africa occur every year. The largest epidemics during the past century occurred in Latin America in 1991 and in Zaire in 1994 (18, 43, 110). In addition, a novel and unexpected pathogen, Vibrio cholerae O139 caused an epidemic of clinical cholera in Asia in 1992, the first non-O1 vibrio to cause such a phenomenon (23). The disease caused by this novel pathogen could not be distinguished from cholera caused by O1 vibrio (34). Additionally, multiply-resistant strains of V. cholerae O1 to common antimicrobials used for its treatment are becoming prevalent in endemic and epidemic areas, complicating the selection of proper antimicrobial therapy (17, 42, 81). In October 2010, Haiti was affected by a rapidly spreading cholera epidemic ensuing few months after a devastating earthquake that had collapsed the health infrastructure of the country (19). In the first two years of the epidemic 604,634 cases were reported, almost half of these cases were admitted in hospitals, the cumulative attack rate was 5.1%, the overall case fatality rate was below 1%, but higher mortality was seen in remote areas (5, 87). The disease spread to neighboring countries in the region affecting the Dominican Republic, Venezuela and the USA (55). Cases from Haiti accounted for 58% of all cases reported worldwide to the World Health Organization in 2010. The current seventh pandemic of cholera is still going on in many countries. Forty-seven countries officially reported 129,064 cases to the World Health Organization in 2013, with 2102 deaths; 47% of these cases were reported from America, mostly from Haiti (121).
The natural reservoirs of V. cholerae are aquatic environments, where Vibrio lives attached to algae or to crustacean shells and copepods or forming biofilms (13, 26, 38). Environmental conditions such as temperature, salinity, availability of nutrients, cyclic climatic changes and presence of lytic phages modulate abundance of V. cholerae (124). V. cholerae may switch from a metabolically active state to a dormant state in the presence of adverse conditions to growth, status that may be reversed when favorable conditions return (26). From its aquatic environment, V. cholerae is introduced to humans through contamination of water sources and contamination of food. It has been recently proposed that Vibrio acquired as a hyperinfectious state after infecting humans, being able to transmit the disease from humans to humans (84). Drinking unboiled water, introducing hands into containers used to store drinking water, drinking beverages from street vendors, drinking beverages when contaminated ice had been added, and drinking water outside the home are recognized risk factors to acquire cholera. On the other hand, drinking boiled water, acidic beverages, and carbonated water, as well as using narrow-necked vessels for storing water, are protective. During the most recent epidemic in Haiti, factors associated with cholera transmission were close contact with a case, eating food from street vendors and washing dishes with contaminated water (50). Seasonality is another typical characteristic of cholera. The El Niño–southern oscillation (ENSO), a periodic phenomenon representative of global climate variability, is strongly associated with cholera transmission in Bangladesh and proposed for Latin America also (67, 95, 105). Some host factors are important in the transmission of cholera. Among those studied are infection by H. pylori, the effect of the O blood group and the protective effect of breast milk (52, 71, 91).
CLINICAL MANIFESTATIONS
The clinical manifestations of cholera are the result of the isotonic dehydration induced by a potent enterotoxin. The dehydration ranges in severity from none-to-severe. Onset of the disease is sudden and characterized by profuse watery diarrhea without strain, tenesmus, or prominent abdominal pain, rapidly followed or sometimes preceded by vomiting. As the diarrhea keeps on, other symptoms of severe dehydration arise, such as generalized cramps and oliguria. Physical examination will show an alert patient, fever is observed in less than 5% of cases, the eyes are very sunken, mucous membranes are dry, the skin has lost its elasticity and when pinched retracts very slowly, the voice is almost nonaudible, and the intestinal sounds are prominent. This status of severe dehydration is seldom caused by any other pathogen. Laboratory abnormalities result from the isotonic dehydration and include increase in packed cell volume, serum specific gravity, and total proteins. Biochemical and acid-base laboratory abnormalities typical of severe dehydration are prerenal azotemia, metabolic acidosis with a high anion gap, normal or low serum potassium levels, and normal or slightly low sodium and chloride levels. Hyperglycemia caused by high concentrations of epinephrine, glucagon, and cortisol stimulated by hypovolemia is more commonly seen than hypoglycemia (12). Acute renal failure is the most severe complication of cholera. All age groups are at risk to develop this complication, but the mortality rate is higher particularly among the elderly (45).
Clinical presentation of cholera in children is similar to that in adults. Some unique features of this age group are higher rates of hypoglycemia, seizures, fever, and mental alteration. Cholera in pregnant women and in the elderly carries a bad prognosis and present with more severe clinical illness (24). A study conducted during the epidemic in Haiti among pregnant women showed fetal death of 8%, with severe dehydration as the main driver of bad fetal outcomes, no mortality among pregnants was observed (25). Another study documented that 50% of household contacts of index cases admitted in a hospital developed diarrhea within 48 hours of disease onset in the index case, few of these secondary cases presented with severe dehydration (118).
LABORATORY DIAGNOSIS
The laboratory diagnosis of cholera is made by isolating V. cholerae O1 or O139 in a proper medium. The TCBS medium is one the most commonly used enrichment medium is advised for handling environmental samples. Characteristic tiny yellow colonies are observed on the surface of the TCBS medium after within 48 hours of incubation. Specific tests for detecting the serotype and biotype of O1 V. cholerae are recommended. Detection of V. cholerae in a single tube reaction by using a quadruplex PCR that identifies simultaneously the serotype, biotype, toxigenic potential and virulence genes may allow early diagnosis (65). More sensitive methods than available PCR tests have been designed more recently. One of them, loop-mediated isothermal amplification detects cholera toxin producing V. cholerae in 35 minutes using culture samples or 70 minutes using direct stool samples from patients (123). Rapid diagnostic tests that detect the lipopolysaccharide of both O1 and O139 by the use of monoclonal antibodies have less than optimal sensitivity and specificity, but may be useful in the setting of outbreaks (59).
PATHOGENESIS
V. cholerae O1 and O139 secrete a potent enterotoxin: the cholera toxin. The enterotoxin has two sub-units: A and B. The B sub-unit binds to a specific receptor in the small intestine, allowing the active sub-unit A to work. In a process mediated by cAMP, the A sub-unit induces diarrhea by blocking the absorption of sodium and chloride by the vellous cells, and by promoting the secretion of chloride and water by the crypt cells. These events lead to the production of watery diarrhea with electrolyte concentrations similar to that of plasma. The infectious dose varies with the vehicle; higher doses are needed when water is the vehicle. Conditions that reduce gastric acidity, such as the use of antacids or histamine receptor blockers, gastrectomy, or chronic gastritis induced by Helicobacter pylori, increase the risk of getting the disease and predispose the patient to more severe clinical forms. The incubation period varies with the infectious dose and gastric acidity and lasts 12 to 72 hours. The genomic sequence of V. cholerae O1 El Tor has been fully elucidated. Two circular chromosomes, the larger containing 3 megabases, and the smaller containing 1.07 megabases contain all the genetic information (53). There are three main virulence genes: ctxA and ctxB that encode for cholera toxin subunits A and B; and tcpA, which codes for toxin coregulated pilus.
SUSCEPTIBILITY IN VITRO AND IN VIVO
Vibrio cholerae O1 is susceptible in vitro to a number of antimicrobials, including tetracycline, doxycycline, ampicillin, cephalosporins, erythromycin, chloramphenicol, cotrimoxazole, and furazolidone. O139 V. cholerae is susceptible to all these antimicrobials with the exception of cotrimoxazole and furazolidone. Table 1 presents data on in vitro susceptibility of O1 and O139 V. cholerae strains isolated from patients enrolled in clinical trials. Both O1 and O139 strains were highly susceptible to quinolones and tetracyclines including doxycycline, but 63% of O1 strains from Bangladesh were resistant to tetracycline.
An international survey to evaluate the global sensitivity patterns to common antimicrobials from endemic areas including India, Bangladesh and Peru found several subtypes of O1 and O139 strains (122). Multiple-antimicrobial-agent resistance (MAR) phenotypes designated 1 and 2 were identified. The MAR phenotype 1 was shared by the major susceptibility pattern of O139 and O1 El Tor Indian strains and the major susceptibility pattern A of O1 El Tor strains from Bangladesh. This pattern showed multiple resistance to chloramphenicol, furazolidone, streptomycin and cotrimoxazole. The MAR phenotype 2 was associated with major susceptibility pattern B of O1 El Tor strains form Bangladesh and was characterized by resistance to tetracycline in addition to the pattern exhibited by the MAR phenotype 1. The incidence of resistance to tetracycline, measured by disk diffusion method, among O1 V. cholerae strains isolated from Bangladesh shows a sharp increase in recent years: 1.9% in 1990 to 85.4% in 1993, while Indian and Peruvian strains showed a highly sensitivity pattern to tetracyclines from 1991 on.
Changing trends in antibiotic susceptibility of V. cholerae in India over several time periods have been reported (7, 30, 39). One study analyzed the susceptibility pattern of 840 strains isolated from patients attended at the Infectious Disease Hospital in Calcutta from 1992-1997 (39). O1 strains showed increasing resistance to ampicillin, furazolidone, co-trimoxazole, and surprisingly to quinolones over the study period. In contrast, O139 strains recovered the susceptibility to chloramphenicol and co-trimoxazole over the same time period. Both O1 and O139 strains remained susceptible to gentamycin and tetracycline. V. cholerae O1 El Tor resistant to quinolones has also emerged in other regions of India (7, 68). More contemporary data from a study that evaluated the susceptibility pattern of strains isolated from 1184 patients in Delhi from 2001-2006 revealed interesting findings (30). V. cholerae O1 El Tor accounted for 55% of the diarrheal episodes, with the Ogawa serotype predominating over the Inaba serotype. Interestingly, resistance to nalidixic acid, furazolidone and co-trimoxazole was universal; resistance to ciprofloxacin increased significantly, but most of the strains remained susceptible to tetracycline, gentamycin and chloramphenicol. Antibiotic resistant strains of V. cholerae O1 from Vietnam, Thailand and Mozambique have also been reported (28, 29, 78). Increasing resistance to common antimicrobials has been observed from 1997 to 2012 in the Democratic Republic of the Congo (82).
The susceptibility pattern to common antimicrobials varies by geographic region with highly resistant strains from some areas and fully susceptible strains from other areas, particularly from Peru and other Latin American countries. Misuse of antimicrobials to treat diarrheal and respiratory infections by physicians and practitioners is partly responsible for the emergence of resistance. Lack of control on prescription of antimicrobials by non-physicians plays an important role in the genesis of resistance by common bacteria as well.
ANTIMICROBIAL THERAPY
Drug of Choice
Use of antimicrobials in cholera is recommended as adjunctive therapy to fluid and electrolyte repletion (11, 111). Several clinical trials have confirmed the utility of antimicrobials in the treatment of severe cholera. Elegant studies conducted in the sixties in India defined the role of tetracycline in the treatment of cholera (15, 51, 73, 117). Tetracycline reduces the duration of diarrhea by approximately 50% compared to placebo (~ 2 days vs. 4 to 5 days), reduces the volume of diarrhea by 50%, and shortens the duration of vibrio excretion to approximately 48 hours (vs. 7 to 9 days in some studies). These achievements are important when treatment centers are overloaded with severely dehydrated patients, as occurs during epidemics. The rational prescription of antimicrobials not only reduces the hospital stay of patients to approximately 24 hours as it did during the Peruvian cholera epidemic in 1991 (45), but also reduces the expense for fluids to rehydrate patients and other hospital-related expenses.
The World Health Organization recommends tetracycline 500 mg four times a day per 3 days as the treatment of choice for cholera in areas where Vibrio remain susceptible (119). Alternative antimicrobial therapy is listed in Table 2. Tetracycline has been evaluated under epidemic situations in Peru (10, >47, 49) and (>10, 61) Battilana reported both clinical and bacteriological cure rates of 100% in 100 cholera patients who received the standard tetracycline regimen for 3 days in an open randomized study (>10). Gotuzzo et al., in Lima Peru, found that tetracycline and ciprofloxacin had similar clinical and bacteriological results in patients with moderate-to-severe dehydration in a randomized and double-blind clinical trial (47). In another Peruvian study, Grados found that tetracycline was equivalent to trimethoprim/sulfamethoxazole in both clinical and bacteriological parameters in patients with moderate-to-severe dehydration (>49). Resistance to trimethoprim and sulfamethoxazole was observed during the study. Results from these two studies conducted under an epidemic situation were similar than those mentioned above from endemic countries, and confirmed the previous experience with tetracycline. Studies with tetracycline in children have confirmed its utility in this age group (72); however, staining of permanent teeth is a major concern; limiting therapy to three days may minimize this problem in children (73).
Alternative Therapy
Khan et al. evaluated alternatives for tetracycline-resistant vibrio endemic in Bangladesh (61). Ciprofloxacin (1g, single dose) and erythromycin (500 mg four times daily) were the best alternatives; nalidixic acid and pivmecillinam were clearly ineffective. Results with tetracycline were comparable to those for placebo in earlier studies.
Several other multiple-dose regimens have been evaluated in the treatment of severe cholera, including furazolidone (20, 21, 66, 89, 91), chloramphenicol (40) trimethoprim and sulfamethoxazole (16, 40, >49, 88), doxycycline (32, 93), erythromycin (14, 61, 62), nalidixic acid (61), and pivmecillinam (61). All these drugs showed clinical and microbiological outcomes comparable to that of tetracycline with the exception of nalidixic acid and pivmecillinam; these latter two antibiotics have a more important role in the treatment of shigellosis. Erythromycin at an oral dose of 800 mg twice daily in adults and 40 mg/kg in two oral doses in children yielded better results than trimethoprin-sulfamethoxazole and placebo against V. cholerae O1 resistant to tetracyline in Somalia (14). However, two studies conducted in Dhaka, Bangladesh, in children have shown comparable clinical and bacteriological results with erythromycin and trimethoprim-sulphamethoxazole in one trial, and with erythromycin, ampicillin and tetracycline in the second trial (57, 96).
Single-Dose Regimens
Single dose regimens are preferred over multiple-dose regimens when compliance is the main concern. Furazolidone (91, 92), tetracycline (32, 54, 91, 92) and doxycycline (4, 32, 63, 99) have been extensively studied in endemic areas. In general, clinical outcomes with these regimens were similar to those with multiple-dose regimens, with the exception of furazolidone, which did not differ from placebo in reducing the volume of stools and shortening the duration of diarrhea. Although it was not statistically significant, more relapses and clinical failures were reported with single dose regimens than with multiple-dose regimens. Prolonged excretion of the organism was also documented with these single dose regimens. These drawbacks should be weighed against the potential of ensuring good compliance in patients from developing countries where the acceptance of multiple-dose regimens is low.
The preferred and recommended single-dose regimen is doxycycline 300 mg., orally. Nausea and vomiting have been reported as common side effects during the therapy with single-dose doxycycline regimens. To avoid these complaints, concomitant administration of food is recommended. A more recent evaluation of this regimen against both V. cholerae O1 and V. cholerae O139 in Dhaka and Matlab, Bangladesh, confirmed its utility as an alternative to tetracycline (63). Two oral single-dose regimens: ciprofloxacin 1g and doxycycline 300 mg were evaluated in a double-blind randomized trial in adult patients with severe cholera infected by both O1 and O139 V. cholerae. Single-dose doxycycline was clinically equivalent to ciprofloxacin in patients infected by V. cholerae O139 but inferior in patients infected by O1 V. cholerae. The discrepancy in results in patients infected by different serotypes was attributed to different susceptibility patterns to tetracycline among these serotypes rather than to clinical differences. The O1 vibrio strains were more resistant to tetracycline than O139 strains. Neither significant vomiting nor nausea was observed when doxycycline was administrated with food in this trial, which included the largest number of patients so far in a single trial with doxycycline.
More recently, significant clinical experience has been accumulated with azithromycin, an azalide antimicrobial agent, in patients with cholera in Bangladesh and India. Two large clinical trials have been conducted in Bangladesh using single-dose regimens. The first study was conducted in 128 children (1-15 year old) with severe dehydration (64). Patients were randomized to receive orally either single-dose azithromycin (20 mg/kg) or erythromycin (12.5 mg/kg/d, four times a-day per 3 days), outcomes were evaluated in a double-bind fashion. Azithromycin was comparable to erythromycin in clinical cure (76% vs. 65%, respectively), bacteriological cure (71% vs. 82%, respectively), and duration of diarrhea (24 vs. 42 hours, respectively), but superior in the frequency of vomiting (1 vs. 4, respectively, p=0.019). The second study was conducted in adults infected with O1 V. cholerae (168 patients) or O139 (14 patients) (103). The study followed a randomized-double-blind design and compared oral azithromycin with ciprofloxacin, both given at single-dosing regimens of 1gr in patients with severe cholera. Azithromycin was superior to ciprofloxacin in overall clinical response (73% vs. 27%); bacteriological response (78% vs. 10%); duration of diarrhea (30 vs. 78 hours) and total volume of stools (114 vs. 322 ml/kg). However, V. cholerae O1 but not O139 was resistant to ciprofloxacin, compared to previous susceptibility data from the same center. Therefore, azithromycin was compared to essentially an inactive drug in that trial. Independent predictors of clinical failure in that study identified through multivariate analysis were to have received ciprofloxacin for treatment and severity of illness, as measured by the number of stools before randomization and the volume of stools during the four-hour observation period before staring antimicrobials. A shorter trial that included 56 children (2-10 year old) with confirmed V. cholerae O1 infection and moderate to severe dehydration was conducted in Calcutta, India (8). The study followed a randomized and double-blind design and compared a lower single-dose of azithromycin (10 mg/kg) than the above mentioned trial (64), with the standard three-day erythromycin, both given orally. Azithromycin was superior to erythromycin in shortening the duration of diarrhea (25.8 vs. 33.5 hours) and reducing the volume of diarrhea (2.1 vs. 3.1 liters).
Quinolones
The appearance of strains resistant to common antimicrobials used for the treatment of cholera such as tetracyclines and cotrimoxazole in endemic areas has prompted the search for new alternatives (17, 42, 79, 81). The fluoroquinolones have emerged as the most promising group of antimicrobials for treating enteric infections. Excellent clinical experience with quinolones in typhoid fever, shigellosis and traveler's diarrhea has been reported around the world. The advantages of quinolones include a broad spectrum of activity against most pathogens associated with diarrheal diseases including Escherichia coli, Shigella spp., Salmonella spp., V. cholerae O1 and O139, and Campylobacter spp.; very high intestinal concentrations of the active drug, in excess of the minimal inhibitory concentrations (MIC) for the pathogens mentioned above; easy administration including once-a-day oral regimens; and a good safety profile. A summary of relevant data from studies conducted with quinolones in patients with cholera is presented in Table 3.
The first fluoroquinolone evaluated against cholera was norfloxacin. The pioneer study was conducted in Calcutta, India, and included adult patients with severe dehydration and confirmed infection by V. cholerae O1 (6). Patients were randomly assigned to three oral treatment groups; norfloxacin 400 mg twice daily, trimethoprim (160 mg)/sulfamethoxazole (800 mg) twice daily, and placebo for 5 days. Norfloxacin reduced the volume of stools, duration of diarrhea, and fluid requirements for rehydration, compared with the other two groups. Additionally, excretion of V. cholerae was shortened by half with norfloxacin (1-2 days) compared to the other study groups (4-5 days). The study was limited by the small number of patients included and the appearance of resistance to trimethoprim-sulfamethoxazole during the study period, which precluded adequate comparison with the standard antimicrobial regimen.
Another study with norfloxacin, conducted during the cholera epidemic in Lima, Peru, in 1991 confirmed the utility of this quinolone in the treatment of severe cholera when given in a multiple dosing regimen (45). This study included adult patients in a University Hospital in Lima who had proven infection by V. cholerae O1 with acute watery diarrhea and moderate-to-severe dehydration. Three study groups were tested in an open, controlled and randomized trial: norfloxacin 800 mg single-dose, norfloxacin 400 mg twice daily for three days, and tetracycline 500 mg four times a day for 3 days. The oral single-dose norfloxacin arm of the study had to be stopped after an interim analysis showed more clinical and bacteriological failures in this study group. The two multiple-dose regimens of norfloxacin and tetracycline were similar in all clinical parameters including duration of diarrhea, volume of stools, and fluid requirements for rehydration, but norfloxacin attained faster clearance of vibrio from the stools than tetracycline (18% of patients in the norfloxacin group were positive after 24 hours of therapy vs. 47% in the tetracycline group). The MIC for norfloxacin was 0.007 ug/ml. The reason for such a negative result using a single-dose regimen of an antimicrobial that reaches high luminal concentrations was not apparent from the trial. All strains were sensitive to norfloxacin, ruling-out the possibility of resistance to explain these results. Intestinal concentrations were not measured in the patients included in the study. It may be speculated that in high stool purgers, norfloxacin does not reach sufficient stool concentrations when given in single-dose regimens. This hypothesis remains to be proven. Another study conducted in Thailand, compared a 3-day regimen of oral tetracycline and norfloxacin in patients with severe cholera caused by both O1 and O139 V. cholera (83). Similar clinical efficacy between the two study groups was found in the study, that included children and adults, but no microbiological superiority of norfloxacin over tetracycline was observed. An open study using oral norfloxacin, 800 mg, single-dose in 32 patients with cholera in Salta, Argentina, showed good clinical and bacteriological results (112). The absence of a control group limits the interpretation of the data, however. Three other quinolones, lomefloxacin, fleroxacin and ofloxacin, showed excellent clinical and microbiological results in open trials (10, 35, 46).
Ciprofloxacin is the most extensively studied quinolone to date. Studies conducted in open and double-blind and controlled designs have confirmed the excellent results with this fluoroquinolone even when used in oral single-dose regimens. Two open studies conducted in Peru at the beginning of the cholera epidemic in 1991 with ciprofloxacin at 250 mg and 500 mg twice-a-day for 3 days showed clinical efficacy of 90% and microbiological efficacy of 100% (48). Another two open studies evaluated the efficacy of ciprofloxacin in cholera caused by multiply resistant V. cholerae O1 in endemic areas. Khan evaluated the efficacy of ciprofloxacin 500 mg twice daily against four other regimens including erythromycin, nalidixic acid, pivmecillinam and tetracycline in patients infected by O1 V. cholerae resistant to tetracycline in Bangladesh (61). Ciprofloxacin was the most effective antimicrobial in that study. All the strains had in vitro susceptibility to ciprofloxacin as determined by disk-diffusion methods. Doganci et al. evaluated a regimen of 1g/d per 2 days of ciprofloxacin in 7 patients with nonsevere cholera in Ankara, Turkey with good clinical and bacteriological results (35).
Ciprofloxacin was also tested against O139 V. cholerae in Bangladesh during the large epidemic caused by this novel pathogen in 1992 (62). An open study evaluated a single-dose regimen of ciprofloxacin (1g) and doxycycline (300 mg) against two multiple-dose regimens of tetracycline and erythromycin (500 mg four times a day for 3 days). The single-dose ciprofloxacin group had the best overall outcome, with similar clinical efficacy to the other regimens but significantly better bacteriologic results.
Two large randomized, double-blinded, and controlled studies conducted in Peru and Bangladesh have confirmed the excellent efficacy observed in the open studies with ciprofloxacin presented above. The study conducted in Peru under epidemic conditions evaluated a single daily dose of ciprofloxacin (250 mg) compared to tetracycline (500 mg four times daily) both for three days in patients with moderate-to-severe dehydration due to V. cholerae O1 infection (47). Almost 90% in both groups had severe dehydration on arrival. Ciprofloxacin yielded clinical and bacteriological outcomes similar to those with tetracycline. Although not statistically different, failure rates were higher than previously reported for tetracycline and ciprofloxacin (11% and 16%, respectively). Bacteriologic cure rates were, however, very high in both study groups.
The largest clinical trial conducted to date evaluating the efficacy of ciprofloxacin in the treatment of cholera caused by either O1 or O139 V. cholerae was conducted in Bangladesh (63). In this study, 260 adult male patients (130 infected by O1 and 130 infected by O139 V. cholerae) were randomized to receive a single-dose regimen of either ciprofloxacin (1g) or doxycycline (300 mg). Ciprofloxacin was more effective in bacteriological outcomes than doxycycline, irrespective of the infecting serotype of V. cholerae, but was only superior to doxycycline in clinical outcomes against O1 V. cholerae-infected patients. Differences in the susceptibility to tetracycline and doxycycline of O1 vibrio explained these results; 99% of O1 isolates were susceptible to doxycycline in vitro, but only 63% were susceptible to tetracycline. The latter group had higher rates of clinical failure; 52% (14 of 27) in patients infected with tetracycline-resistant strains vs. 8% (3 of 37) of patients infected with tetracycline-sensitive strains (P < 0.001). The study also revealed new information about the efficacy of antimicrobials in patients with diarrhea. Serum and especially stool concentrations of the study drugs were determined during the study and correlated with the MICs of the infecting pathogen. Interestingly, the ratio between the peak stool concentration and the MIC of V. cholerae was almost 10 times higher with ciprofloxacin than with doxycycline (8690 with ciprofloxacin vs. 882 with doxycycline). The higher stool concentrations several times in excess of the MIC may explain the excellent bacteriologic results obtained in this study irrespective of the infecting serotype of V. cholerae. Another study conducted in Turkey confirmed the clinical and bacteriologic efficacy of single-dose ciprofloxacin in cholera (115).
What is the role of the quinolones in the treatment of cholera? We believe they should be recommended in the treatment of severe cholera in areas of the globe where strains resistant to other alternatives are prevalent (107). Oral single-dose ciprofloxacin (1g) or single-daily dose (250 mg) per 3 days are the recommended regimens. The use of the quinolones has a number of restrictions that should be taken into account before routine use is recommended even in areas where strains resistant to other antimicrobials are commonly found. The two most important issues are the cost of therapy, and the restriction for use in children due to articular involvement reported from young animals. Although there is no conclusive evidence of toxicity in humans (106), the fluoroquinolones should be used in this age group only when no other alternative is available. Alternative antimicrobials such as erythromycin might be preferred for children. Quinolones are expensive and people from developing countries who are most affected by cholera cannot afford them. A challenge for these countries is to make quinolones available for those of low socioeconomic status.
Antibiotic treatment of other vibrio species associated with diarrheal diseases is less beneficial compared to the treatment of O1 and O139 V. cholerae. The reduction in the duration of diarrhea, requirement for fluids, and excretion of vibrio O1 and O139 following antibiotic therapy have not been consistently observed with other vibrio species. The diarrheal disease associated with these pathogens is usually self-limited and replenishment of fluids is sufficient.
A recent Cochrane meta-analysis of 39 clinical trials conducted in 4623 patients concluded that antibiotic therapy reduced duration of diarrhea and volume of stools by half, and reduced the duration of Vibrio shedding by 3 days compared to no antibiotics or placebo. No difference in efficacy was observed when comparing tetracyclines and quinolones. Azithromycin offered advantages over quinolones and erythromycin in shortening the duration of diarrhea (70).
VACCINES
Controlling the spread of cholera by use of vaccines was originated soon after the etiologic agent of cholera was discovered. For a vaccine to be effective, an immune response similar than that elicited by the natural infection should be produced. Protection against vibrio is mediated by secretory immunoglobulins generated in the intestine, with antibacterial immunity being more important than the antitoxic component (58). Parenteral vaccines are no longer recommended as they induce only transient protection and are associated with side effects. Although the parenteral vaccines induce a secretory response in the intestine, a more prolonged and effective immune response is stimulated by vaccines given orally.
The ideal vaccine against cholera should be given orally (preferably in a single-dose regimen), should induce a rapid and long-lasting immune response irrespective of the age and the previous exposure to vibrio, and should be affordable by developing countries or preferably should be manufactured in endemic areas of cholera. Such a vaccine is not yet available. However, significant advances have been made in recent years with two particular kinds of oral cholera vaccines.
The most extensively studied oral cholera vaccine contains whole inactivated vibrio plus the B sub-unit. A field study conducted in Matlab, Bangladesh showed that the overall protection after three years of follow-up was only 50%, with higher protection after 6 months (85%). Additionally, the protection in children below 5 years was only 25% after three years of follow-up. Persons carrying the O blood group had lower protection against severe infection, and protection against the classical biotype was significantly better than that attained against the El Tor biotype (27). At least two doses are required which is also a disadvantage, especially for developing countries. This vaccine confers moderate direct protection, but interestingly it confers also indirect protection (herd immunity) in young infants and other residents in endemic areas (1, 2, 75), and protective efficacy rates of 78% after mass vaccination in refugee settings in Africa (76, 116). The use of this vaccine is not advocated in outbreak settings, because of the significant delay in reaching maximal efficacy (20-24 days from the first dose).
Live attenuated cholera vaccines have shown promising results in clinical trials (58). The third generation of these vaccines, CVD 103 HgR, is the most promising. This vaccine elicits a significant immune response, with minimal excretion of the strain to the environment and with rates of diarrhea not different from that observed in placebo groups (31, 44). A study of the single-dose live attenuated CVD 103 HgR cholera vaccine enrolled more than 67,000 persons, aged 2-41 years in Jakarta, Indonesia (94). The vaccine was moderately immunogenic, but the efficacy was only 14%. The incidence of cholera during the study period, 1993-1997, was lower than expected, however. People carrying the O blood group living in endemic areas may positively react to the vaccine. Other potential live oral cholera vaccines are being evaluated in phase II and III trials (100, 114).
The appearance of a new non-O1 V. cholerae, the O139 strain, capable of producing epidemic cholera complicates the problem further. The absence of cross protection between O1 and O139 infections means that the vaccinated population remains at risk of acquiring cholera caused by O139 V. cholerae. Clearly, new vaccines including this novel serogroup should be evaluated for efficacy in endemic and epidemic areas. A study evaluating 5-year efficacy of a bivalent vaccine pre-qualified by the World Health Organization showed substantial protection (65%) but lower efficacy in children below 5 years of age in an endemic area, similar findings were observed more recently using local resources and health care personnel, demonstrating the feasibility of implementing large-scale vaccination programs in endemic settings (9, 120). Potential indications for cholera vaccines include travelers and situations where high attack rates of cholera are expected, such as after environmental disasters, in refugee camps, and in urban slums in endemic areas. A study conducted in 1997 among refugees in Uganda who received two doses of the killed whole-cell recombinant B-subunit cholera vaccine, showed excellent coverage at reasonable expense, not including the cost of vaccines (69). Short-term protection (6-months) of 87% among recipients of a currently qualified oral vaccine by the World Health Organization has been recently shown in a study in Guinea under epidemic conditions (77). Rapid access to stockpile vaccines and low cost of the vaccines are necessary for a successful vaccination campaign. Manufacturing the vaccines locally, as has been shown in Vietnam, the total cost per immunized person using a bivalent vaccine, directed against O1 and O139 Vibrio cholera, was $0.91 only (85). A study showed that using the killed whole-cell vaccine, WC-BS, and covering 50-70% of the population it is possible to achieve 89% reduction in cholera incidence in an endemic area (74). The World Health Organization has pre-qualified two oral cholera vaccines; Dukoral (that protects only against O1 V. cholerae) and Shanchol (that protects against both O1 and O139 V. cholerae). Current recommendations for using these vaccines are limited by the lack of enough production and stockpile. Therefore, the recommendations are to use oral vaccines in addition to other measures in endemic settings and in a reactive way during epidemics (121).
ENDPOINTS FOR MONITORING THERAPY
Duration of diarrhea is the primary endpoint for monitoring therapy. In patients requiring hospitalization because of severe dehydration, volume of stools, volume of urine per hour, volume of intravenous fluids for rehydration, and volume of oral rehydration solutions are also endpoints. The objectives of these follow up studies are to identify a subset of severely affected patients for whom closer monitoring is needed and to formulate criteria for safe patient discharge (45).
ADJUNCTIVE THERAPY
Antiemetics, analgesics and antimotility agents have no role in the treatment of cholera. A number of antisecretory drugs have been evaluated in clinical trials. Only racecadrotel, an inhibitor of the enzyme encephalinase, showed reduction of duration of diarrhea and the volume of stools in Peruvian children with acute watery diarrhea (104). Few patients had cholera in this trial (3 in the racecadrotil group, and 4 in the placebo group); however, it is expected that racecadrotil will be efficacious for cholera given the mechanism of action of this drug. Further evaluation of this drug in severe cholera is warranted. A recent study has shown significant beneficial effects of supplementing zinc (30 mg of elemental zinc) to children with severe cholera (97). Oral zinc was superior to placebo in shortening the duration of diarrhea (12% reduction) and reducing the volume of stools (11% reduction) in a randomized and double-blind clinical trial. The authors recommend routine use of zinc in patients with cholera.
PREVENTION AND INFECTION CONTROL MEASURES
Antibiotic Prophylaxis
While the role of antimicrobials for the treatment of severe cholera has been clearly defined, its use as a prophylactic measure to curtail cholera transmission is uncertain (108, 109). The rationale behind antimicrobial prophylaxis is to reduce the acquisition of V. cholerae by household contacts of an index case by reaching high intestinal concentrations of antimicrobials during the period of maximum risk (88). A review of antibiotic prophylaxis suggested that it was not cost-effective (41). The main concern about antibiotic prophylaxis is the fact that the target population, household contacts of index cases with clinical cholera, represent only a minority of the people exposed to V. cholerae. El Tor V. cholerae, the agent of the most recent epidemics in the world, tends to produce more asymptomatic infections than the classical biotype. The ratio of asymptomatic: symptomatic people was about 20:1 during the Peruvian cholera epidemic in 1991. These asymptomatic people are extremely important in dissemination of the disease. However, under special situations of high transmission, the use of prophylaxis may be considered as an adjunctive measure. Tetracyclines have been the preferred agents in these situations (56, 80), with sulfadoxine (33) and chloramphenicol (80) as alternatives.
The pharmacological properties of the fluoroquinolones mentioned above make them an attractive group of antimicrobials for evaluation as prophylactic agents against cholera. Ciprofloxacin reaches high concentrations in the intestinal lumen for prolonged time, making it attractive as a prophylactic measure. In a randomized, double-blinded trial of adult household contacts of cholerae infection, oral ciprofloxacin (250 mg, single-dose) or placebo was administered as soon as the infection was confirmed in the index cases. Ciprofloxacin did not prevent development of diarrhea nor acquisition of vibrio infection among household contacts (36). The trial lacked the statistical power to detect a difference in protective efficacy of ciprofloxacin and placebo because of a dramatic reduction in the rate of secondary transmission during the study period. However, a secondary analysis showed a trend toward faster eradication of vibrio from the stools and lower incidence of watery diarrhea in 30 patients already infected by V. cholerae who had received ciprofloxacin. Studies of larger sample size are needed to define the role, if any, of fluoroquinolones in the prophylaxis of cholera. Finally, the problems associated with the use of prophylactic antimicrobials should be emphasized. They include the false sense of security of recipients, the potential of inducing resistant strains and the possibility of drug-related adverse reactions. We do not recommend routine use of antibiotic prophylaxis for prevention of cholera in either epidemic or endemic areas (107). The prophylactic use of antimicrobials may be considered under special situations when high transmission of the disease takes place, e.g., the epidemic of O1 cholera in Zaire.
General Preventive Measures
Prevention of cholera transmission in endemic countries has been difficult. Specific measures have been reviewed elsewhere (111). Nosocomial transmission of cholera has been reported, and it is usually associated with poor adherence to hygienic practices.
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Tables
Table 1. In-vitro Susceptibility of O1 and O139 V. cholerae Strains Isolated from Patients Enrolled in Clinical Trials
| Antimicrobial agent | No. of strains | MIC50(ug/ml) | MIC90 (ug/ml) | Range | Ref |
|---|---|---|---|---|---|
| Tetracycline | 12 102 |
1.56 ND |
ND 0.250 |
1.25-2.5 0.06-0.5 |
|
| Doxycycline | 260* |
ND |
0.125 |
ND |
|
| Cotrimoxazole | 32 |
1.47 |
ND |
0.2-3.2 |
|
| Lomefloxacin | 68 |
ND |
0.06 |
ND |
|
| Ciprofloxacin | 100 260* 168† 14‡ |
ND ND 0.250 0.0230 |
0.007 0.003 ND ND |
0.0007-0.25 ND ND ND |
|
| Norfloxacin | 32 |
ND |
ND |
0.008-0.016 |
|
| Azithromycin | 123§ |
ND |
ND |
0.125 |
|
| Erythromycin | 123§ |
ND |
ND |
1.0 |
Table 2. Antimicrobial Regimens for the Treatment of Cholera
| Drug | Dose Adults | Children |
|---|---|---|
| Tetracycline | 500 mg four times-a-day for 3 days | 50 mg/kg of body weight four times-a-day for 3 days |
| Doxycycline | 300 mg as a single-dose | Not evaluated |
| Furazolidone | 100 mg. four times-a-day for 3 days | 5 mg/Kg of body weight per day four times-a-day for 3 days, or 7 mg/Kg as a single dose |
| Cotrimoxazole | 160 mg of trimethoprim/800 mg of sulfamethoxazole twice-a-day for divided in 3 days | 8 mg of trimethoprim-40 mg of sulfamethoxazole/kg divided in two doses for 3 days |
| Norfloxacin | 400 mg. twice-a-day for 3 days | Not recommended |
| Ciprofloxacin | 250 mg. once-a-day for 3 days or 1g single-dose | Not recommended |
| Azithromycin | 1g, single-dose | 20 mg/kg, single-dose |
Table 3. Results from Studies with Fluoroquinolones in Cholera
| Quinolone | Study Design | Dosing Regimens | No. of patients | Duration of Diarrhea (h)* | Clinical Cure, n (%) | Bacteriological Cure, n (%) | Ref |
|---|---|---|---|---|---|---|---|
| Norfloxacin | 1.Randomized double-blind, and controlled | a. Norfloxacin, 400mg bid, 3 days b. TMP/SMX, 160/800mg, bid, 3 days c. Placebo |
13 12 12 |
19.2 (4.4) 27.5 (4.0) 29.3 (4.5) |
NS† NS NS |
NS NS NS |
|
| 2. Open, randomized, and controlled | a. Norfloxacin, 400 mg bid, 3 days b. Norfloxacin, 800 mg single-dose c. Tetracycline,500mg qid, 3 days |
25 34 35 |
60.8 (18.4) 91.04 (50.1) 61.66 (23.2) |
25 (74) 13 (52) 27 (77) |
34 (100) 19 (76) 31 (91) |
||
| 3. Open, non-controlled | Norfloxacin, 800mg, single-dose | 32 |
------ |
NS |
32 (100) |
||
| 4.Randomized controlled | a. Norfloxacin 400mg, bid, 3 days in adults, or 7.5mg/Kg bid in children b. Tetracycline,500mg qid, 3 days in adults, or 12.5mg/Kg qid in children |
12 13 |
1.25 (NS) days 1.31 (NS) days |
NS NS |
NS NS |
||
| Lomefloxacin | Open, non controlled | 400 mg, once per day, 3 days | 68 |
49.6 (16.9) |
61 (90) |
48 (100) |
|
| Ofloxacin | Open, non controlled | 400 mg per day, 2 days | 42 |
NS |
NS‡ |
NS |
|
| Fleroxacin | Open, randomized and controlled | 400 mg per day, single dose | 100 |
NS |
100 (100) |
100 (100) |
|
| Ciprofloxacin | 1. Open, non controlled | 500 mg, bid. 3 days | 20 |
53.6 (14) |
18 (90) |
20 (100) |
|
| 2. Open, non controlled | 250 mg, bid, 3 days | 21 |
48.3 (14.4) |
19 (90) |
21 (100) |
||
| 3. Open, non controlled | 1g per day, 2 days | 7 |
NS |
NS |
NS |
||
| 4. Open, randomized, and controlled | a.Ciprofloxacin,500mg bid, 3 days b.Tetracycline,500mg qid, 3 days |
15 12 |
NS § NS |
14 (93) 5 (42) |
15 (100) 6 (50) |
||
| 5.Randomized double-blind, and controlled | a.Ciprofloxacin,250mg once-a-day, 3 days b.Tetracycline,500mg qid, 3 days |
100 102 |
51.2 (17.4) 48.0 (20.6) |
84 (84) 91 (89) |
99 (99) 97 (95) |
||
| 6.Randomized double-blind, and controlled | a. Ciprofloxacin,1g single-dose b. Doxycycline,300mg single-dose |
66 64 |
NS ¶ NS |
62 (94) 47 (73) |
63 (95) 44 (69) |
||
| 7. Open, non randomized | Ciprofloxacin, 1g single-dose** | 16 |
41 (19) |
NS †† |
NS†† |
||
| 8.Randomized double-blind, and controlled | a. Ciprofloxacin, 1g single- dose b. Doxycycline,300mg single-dose |
59 71 |
NS ¶ NS |
54 (92) 65 (92) |
58 (98) 56 (79) |
||
9. Open, randomized, controlled |
a. Ciprofloxacin, 1g single-dose b. Ciprofloxacin,500mg bid, 1day c. Doxycycline,100mg bid, 3 days d. Placebo |
21 19 21 13 |
1.9 (0.6) 2.5 (0.7) 2.8 (0.9) 4 (0.6) |
NS NS NS NS |
20 (95) 17 (90) 19 (91) 2 (15) |
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