Review

Cholera: Overview of Epidemiologic, Therapeutic, and Preventive Issues Learned from Recent Epidemics Carlos Seas, MD;” and Eduardo Gotuzzo, MD*

ABSTRACT and treatment than is known concerning any other diarrheal illness. The concept by which was con- Cholera still represents a major public health problem in devel- sidered a predictable disease has been challenged oping countries, and it is associated with significant morbidity recently, as new areas of the globe are becoming affected, and mortality in spite of the fact that more is known about its such as South and Central America.’ Devastating epi- epidemiology, pathophysiology, and treatment than is known demics of VWio cbolerae 01 have occurred in Zaire,’ concerning any other diarrhea1 illness. During the past 5 years multiple-resistant strains of Rcholerae 01 are becoming cholera has gained the attention of the scientific community prevalent in Bangladesh and India,3 and finally, a new because of three events: the extension of the seventh pan- demic of El Tor V&io cholerae 01 to South and Central Amer- agent, K cholerae 0139, with potential ica in 1991; the appearance of a novel non-01 V: cholerae, appeared in 1993 in India and Bangladesh.* referred to as \/: cholerae 0139 or “Bengal” strain in October This report presents data from recent epidemics of 1992 in India and Bangladesh; and the explosive epidemic of Kcholerae 01 El Tor in South America and Africa, as multiple-resistant K cholerae 01 El Tor among Rwandan well as data on the more recent epidemic of Vcbolerae refugees in Zaire in 1994, with the highest mortality ever 0139 in Asia, focusing on epidemiologic, clinical, and reported. This report presents data on recent epidemics of preventive issues. cholera, focusing on epidemiologic, clinical, therapeutic, and preventive issues. Lessons learned from these epidemics should help researchers to prevent or control future epidemics, EPIDEMIOLOGIC ASPECTS More effective vaccines than are currently available, with broad coverage against new agents, clearly are needed. Since 1817, seven of cholera with worldwide extension have been recorded.5 The first six pandemics of cholera originated in the Indian subcontinent and were Key Words: antimicrobial, cholera, cholera vaccines, caused by the classic biotype of R cholerae 0l.j The diarrhea/ diseases. most recent pandemic of R cholerae 01 has a number of differences from the previous six pandemics; it was Int J Infect Dis 1996; 1:37-46. produced by the serotype El Tor instead of the classic Cholera is the most feared of all diarrhea1 diseases in his- serotype. It originated in Indonesia instead of the Indian tory Few infectious diseases can influence so negatively subcontinent; it is the largest pandemic in terms of geo- graphic area and number of people affected; and it is the the economy of developing countries as cholera does. Even nowadays, more than 100 years after the identifi- longest pandemic ever recorded, lasting more than 34 cation of its route of acquisition and the discovery of its years since its beginning in 1961. The latter can be causative agent, cholera is still associated with significant explained by the increased ability of the El Tor biotype morbidity and mortality in developing countries in spite to survive in the environment compared to the classic of the fact that more is known about its pathophysiology biotype, and the high proportion of asymptomatic car- riers of R cholerae observed during epidemics caused by this serotype. These carriers can easily spread the dis- ease to distant places from the initial focus.6 During the past 5 years, cholera has gained the atten- tion of the scientific community, basically due to three * Institute de Medicina Tropical “Alexander von Humboldt,” Universidad Peruana Cayetano Heredia, and Departamento de Enfermedades events: (1) the extension of the seventh pandemic of El Tor Transmisibles, Hospital National Cayetano Heredia, Lima, Peru. Vcholeme 01 to South and Central America in 1991,’ (2) Address correspondence and requests for reprints to Dr. Eduardo the appearance of a novel non-01 Rcholerae, referred to Gotuzzo, Instituto de Medicina Tropical ‘&Alexander von Humboldt,” as Vcholerae 0139 or the “Bengal” strain, with pandemic Universidad Peruana Cayetano Heredia, AP 4314, Lima 100, Peru. potential, in October 1992 in India and Bangladesh,* and

37 38 International Journal of Infectious Diseases / Volume 1, Number 1, July 1996

(3) the explosive epidemic of multiple-resistant Vcholerue Organization.11~12 From January 1991 to September 1994, 01 El Tor among Rwandan refugees in Zaire in 1994, with Peru had reported 625,259 cases, representing 60% of the highest mortality ever reported.2 Additionally, imported the total number of cholera cases reported in the region.” cases of cholera from these areas into developed coun- The total number of deaths reported during that period tries have been reported.7-9 was 9642. Approximately 46% of these death cases occurred in Peru, but the case fatality rate for Peru was The Latin American Extension the lowest during that period: 0.7%.11 of the Seventh Cholera Pandemic The evolution of the cholera epidemic in Peru from 1991 to 1995 is presented in Figure 2. Incidence rates The Latin American extension of the seventh cholera pan- (per 100,000 habitants) have shown a trend to decline demic is probably the best-documented epidemic of from 1436.55 at the beginning of the epidemic to 69.0 cholera in recent years. The epidemic started during the during the first 4 months of 1995. Epidemiologic studies last week of January 199 1, almost simultaneously, in three conducted in Peru at the beginning of the epidemic coastal cities of Peru.’ El Tor Rcholerae 01 serotype showed consistently high attack rates, low case fatality Inaba was isolated from stool samples of patients with rates, and high proportion of acute diarrhea1 cases being severe dehydration at the Peruvian National Institute of caused by I? cholerae 0 1. 13-i6A study conducted during Health and confirmed at the Centers for Disease Control February and March 1991 in Trujillo, a northern city of and Prevention by February 1991.” The epidemic spread Peru, showed attack and case fatality rates of 2.6% and rapidly not only within Peru but also to other Latin Amer- 0.4%, respectively.13 In that study, Rcholerue 01 was iso- ican countries. By March 1991, cases with cholera had lated from 79% of patients with severe dehydration who been reported from the three natural regions in Peru; the presented at a local hospital.13 In another study, K coast, the Andean valleys, and the Amazon forest, and cholerae 01 was isolated from 79% of adult patients who 83% of the Peruvian departments reported cases by the presented at a local hospital in Piura during March 1991 fifth week of the epidemic. Other Latin American coun- with acute watery diarrhea irrespective of the degree of tries were involved in the epidemic at a rate of almost one dehydration. I4 Additionally, 34% of asymptomatic people country per month, by the end of 1993 the majority of showed serologic evidence of being exposed to V them had reported cases with the exception of Uruguay.” cholerae during the study period. Similar figures were Figure 1 illustrates the spread of the cholera pandemic reported from a study conducted in Trujillo during 199 1: among Latin American countries. 88% of cases with acute diarrhea observed at two local Peru was definitely the most severely affected coun- hospitals were attributable to Rcholerae 01, with a shift try with 322,562 cases during the first year of the epi- in the serotype from Inaba at the beginning of the epi- demic, representing 82% of the total number of cases demic to Ogawa during the study. I6 The Peruvian Gen- reported from Latin America to the Pan American Health eral Office of Epidemiology estimated that the ratio of asymptomatic to symptomatic cases was around 20 dur- ing the beginning of the epidemic.” Lower attack and case fatality rates were observed in coastal than in Andean and Amazon cities in Peru.15 For instance, attack and case fatality rates in villages 5 hours distant from Iquitos, the capital of the Peruvian Amazon forest, were 6% and 13.5% during May and June 1991, in contrast with national fig- ures of 1 to 2% and l%, respectively.” Surveillance of bacterial pathogens associated with acute diarrhea conducted from December 1992 to March 1993 in a suburban area of Lima, the capital of Peru, showed that R cholerae 01 accounted for 31% of the cases, with an estimated attack rate of 2.2 cases per 1000 for the total population. l* Isolation rates for Rcholerae * initial epidemics: January 1991 01 were higher in adults than in children in that study August 1991 (41% vs. I6%, P = O.OOl), a pattern consistent with the February 1992 recent introduction of cholera in that community. Sur- November 1992 veillance conducted among adults who presented at a large university hospital in Lima seeking care for acute diarrhea from February to April 1994 showed that V cbolerae 01 accounted for nearly 50% of the cases, with Figure 1. The spread of the Latin American epidemic of cholera. watery diarrhea and severe dehydration as the best pre- From Center for Disease Control,11 with permission. dictors of a cholera case.19 Cholera: Issues Learned / Seas and Gotuzzo 39

Incidence rates (per 100,000 habitants) r TOTAL NUMBER OF CASES/CUMULATIVE INCIDENCE BATES (x 100,000)

1991:322,562cases/1,436.55

1992:239,139cases/l,o65.62

1993: 62,326casesl 277.57 j* ,. 1994: 23,667cases/ 105.47 69.60 1995: 15,626~/ i

Figure 2. Evolution of the cholera epidemic in Peru. Weekly incidence rates from 1991 to the first 18 weeks of 1995 are presented. A trend toward a decline in these rates as the epidemic pro- gresses is clearly observed. Total number of cases per year and cumulative incidence rates are presented. Source: National Office for Epidemiology. Peruvian Health Ministry.

Both waterborne and foodborne transmission were Household transmission of cholera was documented documented in Peru (Table 1). Case-control studies con- at the beginning of the epidemic in Peru21 Using a clini- ducted at the beginning of the epidemic in Piura identi- cal definition of cholera, Gotuzzo et aJzl showed that fied the following independent risk factors to acquire 16.8% of household contacts of index cases with micro- cholera in multivariate analysis: drinking unboiled water, biologically confirmed cholera infection were infected in drinking beverages from street vendors, and introducing 1991. Additionally, 50% of these cases presented at a local hands into drinking water storage vessels.‘* In contrast, hospital for care and received intravenous fluid therapy. drinking boiled water was protective against acquiring Another study conducted between November 1992 and cholera.‘* Eating raw seafood (cebiche) was identified as a risk factor to contract cholera only during the first few Table 1. Risk Factors to Acquire Cholera Identified through Case- months of the epidemic. After the massive campaign Control Studies Conducted during the Peruvian Cholera Epidemic against its consumption, promoted by the Peruvian Min- Percentage of Risk Factor istry of Health, this association could no longer be found. Eating unwashed fruits and cool rice, and drinking Risk Factor Cases Controls Odds Ratio 95% CI unboiled water were associated with cholera in a case- Drinking unboiled water 62 29.8 3.8 1.5-9.8 control study in the Amazon f0rest.l’ Drinking local acidic 59.2 27.7 3.1 1.3-7.3 75 50 2.9 1.3-6.4 beverage was protective in that study. In another study, Drinking stored water 44.0 21.3 2.9 1 .I-7.8 adding ice made from contaminated water to local bev- 31.8 8.6 4.2 1 s14.9 erages was associated with cholera.‘* Waterborne trans- Adding ice to beverages 87.5 62.8 4.0 1.04-l 6.6 Drinking beverages 56.0 19.1 17.0 2.2-I 33.8 mission as the main route of acquisition of cholera in from street vendors Trujillo was hypothesized, based on several facts: V Eating from street 26.0 4.3 16.0 2.0-l 28.0 cholerae 01 was isolated from municipal water samples, vendors Eating unwashed fruits 26.0 5.0 8.0 2.2-28.9 progressive contamination of municipal water during its Eating cool leftover rice 38.0 22.0 2.1 1 .l-4.5 distribution was observed, and high coliform counts were 32.0 17.8 3.3 0.7-6.2 observed in samples taken from city wells to household Drinking boiled water 62.0 91.5 0.1 0.02-0.5 71.4 91.8 0.2 0.1-0.9 storage containers. l3 Other studies conducted in Latin Drinking acidic 52.0 77.0 0.4 0.2-0.7 American countries identified both waterborne and food- beverages borne transmission as welL20 Cl = confidence interval. Modified from Mujica et al,” with permission. 40 Irzternational Journal of Infectious Diseases / Volume 1, Number 1, July 1996

April 1993 in Lima showed rates of household transmis- reinforce the use of ORT, but especially to establish sion significantly lower than those mentioned above.22 In regional treatment centers during epidemic situations.15 that study, only 2% of household contacts of confirmed In that study, the majority of deaths occurred at home index cases acquired cholera. within 36 hours after disease onset, and the use of ORT Why did cholera have such an explosive behavior in had been suboptimal. l5 The protective factor against mor- Peru? Several factors may explain the rapid spread of tality was to have received treatment by a health care cholera throughout Peru and Latin America. worker with either ORT or intravenous fluids. Wbrio cholerae 01 El Tor serotype Inaba was respon- The poor sanitary conditions and increased poverty sible for this epidemic. The agent was similar to the R prevalent in Peru and other neighboring countries cholerae 01 that caused the seventh pandemic but dif- during 1991. ferent from the agent responsible for small epidemics in The high prevalence of 0 blood group among the North America and Australia.29 A shift in the serotype South American population. A study conducted in was observed after the first year of the epidemic from Lima showed that patients with 0 blood group had Inaba to the Ogawa serotype.16 Current evidence sup- a significant risk to present severe dehydration ports the hypothesis that this epidemic was the result of ([relative risk] RR 4.8, 95% CI: 2.2-10.6).23 Similar the extension of the seventh pandemic more than due to observations have been made during the seventh mutation of non-01 or non-toxigenic 01 vibrios previ- cholera pandemic.** ously isolated in Latin American countries.29 The association between infection by Helicobacter pylori and chronic gastritis. It has been recognized The Eighth Pandemic of Cholera? that infection by H. pylori is prevalent in developing In October 1992, cases of acute watery diarrhea clini- countries, and that patients with chronic gastritis cally indistinguishable from the diarrhea caused by induced by this agent experience hypochlorhydria.2j Rcholerae 01 were observed in Madras, India.4a30 The As a consequence, hypochlorhydria puts them at epidemic spread rapidly along the Bay of Bengal. To date increased risk to acquire bacterial enteropathogens. 11 countries have been affected in the region, and The association between infection by H. pylori and approximately 100,000 cases have been reported.11,31 the risk to acquire cholera has been evaluated Imported cases in developed countries have also been recently.26 The risk to acquire cholera was signifi- reported. 9,32,33Spread of 0139 cholera epidemic is illus- cantly higher among people infected by H. pylori trated in Figure 3. This epidemic has a number of inter- (RR 1.61, 95% CI:1.07-2.42) and the risk of severe esting features. cholera was higher among people infected with H. pylori with no previous contact with Vcholerae (RFC 1. It was caused by a non-01 Rcholerae, referred to as 2.88, 95% CI:1.28-6.48) as determined by negative 0139 or Bengal strain.34 Non-01 vibrios had been serum vibriocidal test.26 The fact that infection by H. associated with small epidemics of watery diarrhea pylori with previous exposure to Rcholerae was pro- but never had shown pandemic potential. The rapid tective against severe cholera suggest that the increased risk to acquired severe cholera in patients with chronic gastritis due to H.pyZori may be over- come by using cholera vaccines.26

Case fatality rates during the Latin American epidemic were the lowest reported during the seventh pandemic of cholera. The case fatality rate for Latin America was 0.9% for the period 1991 to 1994.11,27 Peru had the low- est case fatality rate among all Latin American countries. A well-organized national response to the epidemic, extensive promotion of the use of oral rehydration ther- apy (ORT) throughout the country, adequate adminis- tration of fluids for replacement therapy even in remote places, and dedication of physicians and nurses through- out the country, with a special commitment to reduce * Initial Epidemic October 1992 the mortality to figures near zero, were responsible for such an excellent achievement.10~28 However, the expe- rience in the jungle of Peru, where high mortality rates - October 1944 were observed, underscores the necessity to train health Figure 3. The spread of % cholerae 0139 epidemic in Asia, care workers to adequately treat patients with cholera, to 1992-1994. From Center for Disease Control,” with permission. Cholera: Issues Learned / Seas and Gotuzzo 41

extension of this epidemic gained the attention of cholera ensued.* The first case of cholera was identified the scientific community, alerting for the possibility on July 20, 1994. El Tor Rcholerae 01, resistant to tetra- of a new pandemic of cholera.35 cyclines, was isolated from patients with acute watery 2. Age groups affected by this new strain were differ- diarrhea in Zaire. During the next 4 weeks, the world ent than those previously identified in India and observed what has probably been the worst epidemic of Bangladesh, showing that no protection was con- cholera during this century, and definitely the epidemic ferred by previous exposure to Rcholerue 01, and with the highest attack and case fatality rates ever that vaccines against 01 vibrios may not be effec- reported.2 The estimated number of cholera cases ranged tive in controlling this epidemic30 between 50,000 and 80,000, with attack rates between 3. The clinical picture was similar to that produced by 7.3% and 16%, according to population estimates. Crude 01 vibrios.36s37 The only direct comparison of the mortality rates from July 14 to August 14 ranged between clinical picture and toxin production by 0139 and 19.5 and 31.2 per 10,000 habitants. Approximately 88% 01 vibrios conducted in Dhaka, Bangladesh, showed of deaths were caused by diarrhea1 diseases, and 57% of that the disease produced by these two agents was them were due to cholera. The city of Coma was the clinically similar, but patients who acquired 0139 most severely affected. Factors associated with mortality cholera were less hypothermic, purged lower vol- were similar to those identified during the epidemic of umes of stools, and required lesser volumes of fluids cholera in the jungle of Peru.** Lessons learned from this to be rehydrated during the first 24 hours of ther- epidemic were: apy than 01-infected patients.38 However, these dif- ferences are clinically unimportant and do not help 1. Diarrhea1 diseases, including cholera and shigellosis, to differentiate between these two infections. Both can produce dramatic epidemics with high case fatal- serum and stool electrolyte concentrations, as well ity rates. as acid-base abnormalities were similar in Ol- and 2. Observation of warning systems should not be 013Pinfected patients in that study. These obser- ignored by decision-making authorities. vations confirm the initial impression of similar clin- 3. Significant improvement of emergency preparedness ical pictures produced by these two vibrios. should be made to deal with future disasters.2 4. Molecular epidemiologic tools have shown that this novel agent is closer to El Tor Rcholerae 01 than to other non-01 vibrios, and it is totally different from CLINICAL AND THERAPEUTIC ASPECTS 01 strains isolated from North America and Aus- tralia.39,40 Although different ribotypes have been The hallmark of cholera is a profuse secretory diarrhea observed among Asiatic strains, the meaning of that induced by an enterotoxin secreted by either Rcholerae finding is not clear.*l 01 or, more recently, by K cholerae 0139. That entero- 5. The new agent was resistant to cotrimoxazole, but toxin, commonly referred to as cholera toxin, does not sensitive to . In contrast, 01 Kcholerae, produce intestinal inflammation, but instead produces endemic in India and Bangladesh before the appear- secretion to the intestinal lumen of huge amounts of elec- ance of this novel vibrio was resistant to tetracyclines trolytes, mainly sodium and chloride as well as bicar- and trimethoprim-sulfamethoxazole, but sensitive to bonate, resulting in dehydration ranging from mild to . Because it was not possible to distin- severe, and metabolic acidosis especially in severely dehy- guish clinically the infection produced by these two drated patients. At least three other toxins secreted by V vibrios, erythromycin was the antimicrobial of choice cholerae 01 have been identified, but their role in the to treat cholera in Bangladesh during the epidemic. pathogenesis of the disease is not fully understood.6 6. The epidemic had subsided in Bangladesh by the end The dehydration that this enterotoxin produces is of 1994; few cases are being reported. Once again, isotonic; the stool electrolyte concentrations are similar 01 vibrios are prevalent in India and Bangladesh. to those of serum. Hence, treatment is aimed at replac- ing these electrolytes plus water, using fluids with simi- This new epidemic has stressed the need of main- lar concentrations to those lost as a result of diarrhea taining continuous surveillance across the world to detect and vomitus. If adequate replacement of electrolytes and changes in the etiologic and epidemiologic features of water can be ensured rapidly, mortality associated with cholera.33 It also has demonstrated the limited utility of cholera should be near zero. Recent experience with current cholera vaccines to control this epidemic. cholera epidemics in Latin America and Africa summa- rized above, have shown low case fatality rates in the Recent Cholera Epidemics in Zaire former, but incredibly high figures in the later. Factors responsible for such a difference have been delineated Following a massive migration of Rwandan Hutus to Zaire above, with difference in the quality of care and scarcity after a political crisis in July 1994, a huge epidemic of of resources as the main reasons. 42 International Journal of Infectious Diseases / Volume 1, Number 1, July 1996

Table 2. Clinical Findings in Patients with Cholera according to Degree of Dehydration Finding Mild Dehydration Moderate Dehydration Severe Dehydration Loss of fluid < 5% 5-10% > 10% Mentation Alert Restless Drowsy or comatose Radial pulse Rate Normal Rapid Very rapid Intensity Normal Weak Feeble or impalpable Respiration Normal Deep Deep and rapid Systolic blood pressure Normal Low Very low or unrecordable Skin elasticity Retracts rapidly Retracts slowly Retracts very slowly Eyes Normal Sunken Very sunken Voice Normal Hoarse Not audible Urine production Normal Scant Absent

From Bennish,@ with permission from the publisher.

Clinical symptoms and signs according to the degree half, and to reduce the excretion of vibrios to the envi- of dehydration are presented in Table 2. The first step in ronment.44~47~48In recent years, however, the selection of the evaluation of a cholera case is to estimate properly effective drugs has been complicated due to the appear- the degree of dehydration. This evaluation can be per- ance worldwide of resistant strains.3,49,j0Improper use of formed by any health care worker with supervised train- antimicrobials to treat infectious diseases in developing ing by experienced physicians. Current recommended countries, the lack of control programs to avoid non-physi- solutions to rehydrate patients with cholera are presented cian prescription of antimicrobials, and the massive use in Table 3. Specific recommendations to rehydrate of prophylaxis in some countries in an attempt to control patients with cholera have been extensively reviewed cholera spread have been responsible for this phenome- elsewhere,43,44 and practical guidelines relevant to devel- non. This situation has prompted the search for adequate oping countries recently have been discussed.45 A sum- alternatives to treat these resistant strains. Currently, ery- mary of these recommendations is presented in Table 4. thromycin is the first choice to treat cholera caused by R The use of ORT cannot be overemphasized. The cholerae 01 in Bangladesh, and pivamdinocillin is the recent experience in Peru in both children and adults antimicrobial of choice to treat shigellosis in that country.** shows clearly how a scientific discovery can be so suc- However, the appearance of resistant strains to these cessfully applied at bedside to reduce mortality under antimicrobials is anticipated. epidemic conditions. 1o,46 Among the new antimicrobial agents to treat cholera, the fluoroquinolones are probably the group most exten- Antimicrobial Therapy sively studied. A summary of relevant results from these Whereas treatment of dehydration is easy to accomplish studies is presented in Table 5. Several quinolones have and represents the mainstay of cholera treatment, the use been tested against cholera, including ,51,52 of antimicrobials is only adjunctive to rehydration ther- lomefloxacin,53 and ciprofloxacin.54-59 Ciprofloxacin has apy. Antimicrobial agents have been shown to reduce the been the quinolone most extensively tested in cholera. duration of disease, to shorten the volume of stools by Three open studies have been conducted in Peru and

Table 4. Practical Guidelines for the Treatment of Cholera Table 3. Electrolyte Concentration of Cholera Stools and 1. Evaluate the degree of dehydration on arrival. Common Solutions Used for Treatment 2. Rehydrate the patients in two phases: a. Rehydration phase: lasts 2-4 hours. Electrolyte and Glucose b. Maintenance phase: lasts till diarrhea abates. Concentration (mmol/L) 3. Register output and intake volumes in pre-designed charts and Na+ C/P K’ HCO, review the data collected periodically. 4. Use the intravenous route only to rehydrate: Cholera stool a. Severely dehydrated patients during the rehydration phase, in Adults 130 100 20 44 whom an infusion rate of 50-l 00 ml/kg/h is advised. Children 100 90 33 30 b. Moderate patients who do not tolerate the oral route. Intravenous solutions c. High stool purges (>I 0 ml/kg/h) during the maintenance Ringer’s lactate 130 109 4 28* phase. Dhaka 133 98 13 48 5. Use ORT for patients during the maintenance phase at a rate of Normal saline 154 154 0 0 800-l 000 cc/h, matching ongoing losses with ORT. Peru polyelectrolyte 90 80 20 30 6. Discharge patients to the treatment center if the following WHO ORT 90 80 20 30+ conditions are fulfilled: a. Oral tolerance >lOOO cc/h, *Ringer’s lactate does not contain HCO, but, instead, lactate; +Bicar- b. Urine volume 240 mVh, and bonate is replaced with trisodium citrate, which persists longer than c. Stool volume 5400 mUh. bicarbonate in sachets. ORT = . ORT = oral rehydration therapy. Modified from Seas et al,45 with permission. Cholera: Issues Learned / Seas and Gotuzzo 43

Table 5. Summary of Results from Clinical Trials Using Fluoroquinolones in Cholera Duration Clinical Bacteriologic Number of Diarrhea Cure Cure Quinolone Study Design Dosing Regimens of Patients Mean Hours (SD) n (%) n (%) Norfloxacin I. Randomized, double- a. Norfloxacin, 400 mg bid, 3 d 13 19.2 (4.4) NS NS blind, and controlled5’ b. TMPSMX, 1601800 mg 12 27.5 (4.0) NS NS bid, 3 d c. Placebo 12 29.3 (4.5) NS 2. Open, randomized, a. Norfloxacin, 400 mg bid, 3 d 25 60.8 (18.4) 25 (74) 3N4qloo) and controlledsz b. Norfloxacin, 800 mg single-dose 34 91.04 (50.1) 13 (52) 19 (76) c. , 500 mg qid, 3 d 35 61.66 (23.2) 27 (77) 31 (91)

Lomefloxacin Open, non-controlled53 400 mg once per day, 3 d 68 49.6 (16.9) 61 (90) 48 (100)

Ciprofloxacin 1. Open, non-controlled54 500 mg bid, 3 d 20 53.6 (14) 18 (90) 20 (100) 2. Open, non-controlled54 250 mg bid, 3 d 21 48.3 (14.4) 19 (90) 21 (100) 3. Open, randomized, a. Ciprofloxacin, 500 mg bid, 3 d 15 NS 14 (93) 15 (100) and controlled55 b. Tetracycline, 500 mg qid, 3 d 12 NS 5 (42) 6 (50) 4. Randomized, double- a. Ciprofloxacin, 250 mg 100 51.2 (17.4) 84 (84) 99 (99) blind, and controlled56 once-a-day, 3 d b.Tetracycline, 500 mg qid, 3 d 102 48.0 (20.6) 91 (89) 97 (95) 5. Randomized, double- a. Ciprofloxacin, 1 g single-dose 66 NS+ 62 (94) 63 (95) blind, and controlled57 b. , 300 mg single-dose 64 NS 47 (73) 44 (69) 6. Open, non-randomized E* Ciprofloxacin, 1 g single-dose 16 41 (19) NS NS* 7. Randomized, double- a. Ciprofloxacin, 1 g single-dose 59 NS+ 54 (91.5) 58 (98) blind, and controlled§5g b. Doxycycline, 300 mg single-dose 70 NS 64 (91.4) 55 (79) *Patients in the ciprofloxacin group had shorter duration of diarrhea than patients in the tetracycline group (Kaplan-Meier survival curve, P = 0.004 by log-rank test); Ciprofloxacin group had shorter duration of diarrhea than single-dose doxycycline group in V cholerae 01 -infected patients, but not in !/ choierae 0139-infected patients (Kaplan-Meier survival curve, P = 0.0451 and P = 0.435 by log-rank test, respectively): *Diarrhea stopped in all patients within 72 hours of therapy. Stool cultures were neaative for 1! cholerae 0139 durina the third dav of theraov: Ftudies conducted in !L cbolerae 0139.infected oatients. TMP/SMX = trirn~thoprim-sulfarnethoxazole; NS = not specified. .

Bangladesh using ciprofloxacin at different dosing regi- reported for Kcholerae. Biliary excretion, transepithelial mens: two studies were conducted in patients with secretion, and reduced absorption of ciprofloxacin may severe cholera due to Rcholerae 01 El Tor,54,5j and one explain these high stool concentrations.60 study in severe cholera caused by 0139 K choZerae.58 Current available data favor the use of quinolones as Additionally, three randomized and double-blinded stud- an alternative choice to tetracycline and erythromycin ies using single daily dose or single dose (1 g) have been to treat severe cholera. The use of quinolones should be conducted.5G~57~59 restricted to the management of severe cholera and Data from these well-conducted studies show clearly shigellosis in areas where resistant strains to common that the quinolones are equally as effective as the stan- antimicrobials are prevalent, because its extensive use to dard therapy (multiple dose tetracycline regimen or single- treat any infectious diarrhea may cause the appearance dose doxycycline regimen) in all clinical parameters (i.e., of resistant strains, as has occurred with many antimi- duration of diarrhea, fluid requirements for rehydration, crobials in developing countries. Disadvantages of the and total volume of stools) but attained earlier eradica- fluoroquinolones are their high cost and the potential tion of the bacterium from the stools. The early eradica- toxicity to the growing cartilage in humans that precludes tion of R cholerae from the stools of a patient with its use in pregnant women and in children. Although cholera may reduce the household transmission of the there is no compelling evidence that this toxicity could disease and may help in controlling its spread. This be present in humans, the use of fluoroquinolones in hypothesis merits further evaluation especially under epi- children is still not recommended. Among the quinolones demic conditions. evaluated, the authors recommend ciprofloxacin either Recent pharmacokinetic studies conducted in patients in a single dose (1 g) or 250 mg once-a-day for 3 days, as with diarrhea due to Kcholerae 0139 and Shigella spp the best choices. treated with single-dose ciprofloxacm (1 g) in Bangladesh, provide adequate explanation for the excellent results observed in the trials discussed above.60 Stool concentra- PREVENTIVE ISSUES tions of ciprofloxacin were more than 200 times higher than the minimal inhibitory concentration (MIC) of R The recent epidemics of cholera in South America, Africa, cholerae 0139 after 48 hours of therapy, values for and Asia have stressed the necessity of implementing and Shigella spp-infected patients were even higher than those reinforcing global programs to control cholera and other 44 International Journal of Infectious Diseases / Volume 1, Number 1, July 1996

diarrheal diseases. The ability of Rcholerae to survive in The use of antimicrobials as a prophylactic measure the environment even at nondetectable levels for standard against cholera has proven historically not to control the microbiologic techniques, 61 the appearance of new vib- spread of the disease. 67 Prophylactic agents may be rec- rios with pandemic potential,* and the extremely poor san- ommended under conditions of high transmission rates, itary and hygienic conditions existing in many developing for instance, during the devastating epidemic of cholera countries around the globe, predict that cholera control in Zaire during July and August 1994, where attack rates will be very difficult if not impossible by the year 2000. of nearly 22% were reported at the peak of the epidemic. It is clear from these epidemics that by providing The use of this measure when the rate of transmission of safe drinking water, ensuring adequate disposal of exc- the disease is low is not advised, even using fluoro- reta, and changing hygienic practices of the population quinolones.22 Problems associated with massive use of at risk, it is possible to control the transmission of cholera antimicrobial prophylaxis are the potential induction of and other diarrhea1 diseases. On the other hand, it is also resistant strains, the induction of potential serious side evident that to implement these measures a political deci- effects, and the feeling of complete protection by users. sion and investment of significant financial resources are Another important problem is how to control its admin- necessary.‘O Two alternative ways to control the spread istration to only high-risk populations in developing coun- of cholera should be mentioned: the use of vaccines and tries, where self-prescription of antimicrobials is highly mass chemoprophylaxis with antimicrobials. common. The ideal vaccine against cholera still is not available. This vaccine should be administered in a single oral dose, REFERENCES should induce a prompt and lasting immunologic response, should be well tolerated, and most importantly, 1. Centers for Disease Control. Cholera-Peru, 1991. MMWR its cost should be reasonable and affordable for devel- 1991; 40:108-109. oping countries. 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