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Symposium : Gastroenterology & Hepatology

Current Status of Anti-Diarrheal and Anti-Secretory Drugs in the Management of Acute Childhood Diarrhea
Seema Alam and Shrish Bhatnagar
Pediatric Gastroenterology Section, Department of Pediatrics, JNMC, AMU, Aligarh, India.

ABSTRACT
Each year 1.8 million children die due to diarrheal diseases. Indiscriminate use of antibiotics has resulted in increasing resistance to commonly used antibiotics. Moreover the recent outbreaks of shigella and cholera have revealed multi-drug resistance strains. There is a need for review of recommended antibiotics for shigellosis. From recent data it emerges that fluoroquinolones should be the first line of therapy and cephalosporins to be used as the second line. Among the anti-cholera antibiotics, tetracyclines which were the drug of choice for adults, has the advantage of high sensitivity and low cost. Single dose doxycycline would have minimal side effects, hence can be the drug of choice even in children. We should not allow the business pressures to force usage of probiotics and racecadotril as their role in the management of acute diarrhea is yet to be established. Nitazoxanide has high efficacy against Cryptosporodial diarrhea only. Strict adherence to the recommendations for the management of acute childhood diarrhea is needed or else we dilute the effect of standard management. [Indian J Pediatr 2006; 73 (8) : 693-696] E-mail : seema_alam@hotmail.com

Key words : Diarrheal disease; Shigellosis; Anti-cholera antibiotics

Diarrheal diseases, including cholera, shigellosis and rotavirus, kill about 1.8 million children each year, accounting for 17 percent of childhood deaths (http:// www.globalhealth.org). Shigellosis is endemic throughout the world with approximately 164.7 million cases, of which 163.2 million are in developing countries. Each year 1.1 million people are estimated to die from shigella infection. A total of 69% of all episodes and 61% of all deaths attributable to shigellosis involve children less than 5 years of age (http://www.who.int/shigella). ANTIBIOTICS FOR SHIGELLOSIS Dysentery may be simply defined as diarrhea containing blood. Although several organisms can cause dysentery, shigella is the most important. The four serogroups of shigella are S. flexneri, S. dysenteriae, S. sonnei and S. boydii. In the developing world there are outbreaks of S. dysenteriae while in between the outbreaks it is S. flexneri, which is more common. S. sonnei is common in the industrialized countries and S. boydii has been reported from India only. Shigella dysenteriae type 1 (Sd1) is the most virulent of the four serogroups of shigella and the only

Correspondence and Reprint requests : Dr Seema Alam, Reader,

Department of Pediatrics, JN Medical College, AMU, Aligarh, UP.

cause of epidemic dysentery. The IAP task force 1 recommends that, depending upon the sensitivity pattern of the area, cotrimoxazole and flouroquinolones should be the antibiotics used to treat acute dysentery. Indiscriminate use of antibiotics has caused increasing resistance to commonly used antibiotics. Scarcity of data, on the resistance pattern from most parts of the country, is the major challenge in deciding the recommendations. Since the turn of the century there have been reports of outbreaks (2002-03) of multi drug resistant S. dysenteriae type 1 in India (Siliguri2, Diamond Harbour3, Kolkata4-7 & Aizwal 8 ) and Bangladesh. 9,10 A pubmed search for recently published reports (2000-2005) of antibiotic sensitivity in shigella isolates yielded 14 articles from the Indian subcontinent. There were no randomized clinical trials (RCTs) in children reported from the subcontinent in this period. Multi-drug resistance was defined as resistance to more than three antimicrobials. Results of the articles have been presented in a tabulated form (Table 1). The median percentage resistance in isolates to cotrimoxazole (99%), nalidixic acid (97.5%), fluoroquinolones (38.5%) and multi-drug resistance (97%) present a grim picture. The resistance for ciprofloxacin or/and norfloxacin is reported high in Shigella dysenteriae isolates. While the sensitivity for ofloxacin was not tested in one study,4 two reports each found ofloxacin sensitive3,5 and resistant 6,8 isolates respectively. The sensitivity to cephalosporins (cefixime & ceftriaxone) is high although reports are few (Table 1). The majority of reports are from
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TABLE 1. Percentage Resistance to Antimicrobials in the Shigella Isolates (2001-2005) from the Indian Subcontinent Ref 2 3 4 5 6 7 8 9 10 11 12 13 14 Place Siliguri Diamond Harbour Kolkatta Kolkatta Kolkatta Kolkatta Aizawl Dhaka Dhaka Karachi Lahore Chandigarh Vellore Co (%) 100 100 97 100 100 95 100 98 55 88 NT 58 NT 99* NA (%) 100 100 97 100 100 59 100 98 9 39 6 63 94 97* Cx&/Nx (%) NT 100 97 100 75 6 100 0 0 0 0 12 NT 38.5* Cef (%) NT NT NT NT NT NT 0 NT NT 0 0 14 NT 0* serogp Sh dys Sh dys Sh dys Sh dys Sh dys Sh flex Sh dys Sh dys Sh flex Sh flex Sh dys Sh flex Sh son Isolates (n) 30 4 36 152 17 68 169 122 144 193 77 55 MDR (%) 100 97 100 100 90 100 98 40 40 70 43 97**

Co=Cotrimoxazole, NA=Nalidixic acid, Cx&/Nx=Ciprofloxacin&/Norfloxacin, Cef=Cefixime/Ceftriaxone; NT=Not tested; MDR= Multidrug resistance; *Median percentage resistance to the antimicrobials; ** Median percentage Multidrug resistance.

the eastern or northeastern part of the subcontinent. With the present state of information one of the fluoroquinolones (ciprofloxacin/norfloxacin/ofloxacin) should be the first line of treatment for shigellosis. If there is no improvement (disappearance of blood), on the fluoroquinolone, within 48 hours then depending upon the general condition the patient should be shifted to a oral (cefixime) or intravenous (ceftriaxone) cephalosporin. Drug dosage and schedule should be as mentioned in table 2. Based on its efficacy, safety and reduced cost, ciprofloxacin has been recommended by WHO 15 as the first line antibiotic for shigellosis.
TABLE 2. Drugs Dosage and Schedules for the Antibiotics Against Shigellosis Drug Ciprofloxacin (PO) Norfloxacin (PO) Ofloxacin (PO) Ceftriaxone (IV) Cefixime (PO) Dosage (mg/ kg/day) 20 20 15 100 8 Divided dose 2 2 2 2 2 Duration (days) 5 5 5 5 5

associated with tetracyclines occur on prolonged use. Keeping in view, the good sensitivity, 19 low cost and minimal adverse effects possible with single dose, we use single dose doxycycline (5 mg/kg) at our center.20 Forty of the 45 vibrio cholarae isolates from children in our center (between July 2003 & Sept 2004) were 01 El tor Ogawa and the rest 5 were non 01 & non 0139. Ninety percent of our cases responded to single dose doxycycline (unpublished data). High degree of sensitivity 19, 21 of Vibrio cholerae to fluoroquinolones and cephalosporins has been reported. Successful treatment in 60% cases, but with high relapse rate, with single dose ciprofloxacin [20 mg/kg] was seen in a recent study. 22 The high cost and multiple dose schedules of these drugs are the limitations to their usage. Single dose of azithromycin [20 mg/kg max: 1 gm] as an alternative treatment has also been reported.23 The high cost of the drug is the major disadvantage. PROBIOTICS IN ACUTE DIARRHEA Commercial preparations of probiotics are flooding the market and being promoted as anti-diarrheals. Physicians are not aware that only the live strain of a specific probiotic (lactobacillus GG) was found to have a consistent role in shortening the duration of diarrhea particularly in rotaviral gastroenteritis.24-26 Till recently only tyndalized strains of the probiotics (not lactobacillus GG ) were available in the Indian market. Moreover, majority of the studies included in the meta-analyses24-26 have been done in the developed world where the etiological profile of diarrhea is quite distinct from that of the developing countries. The IAP taskforce therefore recommends withholding the usage of probiotics in diarrhea. 1 Subsequently there have been at least three RCTs in the developing countries negating the beneficial effect of
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PO = Per oral, IV= intravenous

ANTIBIOTICS FOR CHOLERA The eighth pandemic of cholera in 1992 was due to 0139 Bengal serogroup. In between there are outbreaks of 01 El tor Ogawa and Inaba . Resistance to cotrimoxazole 16,17, ampicillin18 and furazolidone16,17, in vibrio cholarae isolates, has uniformly been described. Tetracycline [500mg qid for 3 days] and doxycycline [300mg single dose] are the drugs of choice in treatment of cholera in adults (http:// www.who.int/cholera). In children the effective single dose therapy has not been identified. It is well known that the adverse effects like enamel and skeletal defects
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Current Status of Anti-Diarrheal and Anti-Secretory Drugs in the Management of Acute Childhood Diarrhea lactobacillus GG27, 28 and lactobacillus acidophilus29 in acute childhood diarrhea. Hence probiotics may look promising but the effect needs to be substantiated in our population before they are included in the management of acute diarrhea. ANTISECRETORY DRUGS: RACECADOTRIL Amongst the antisecretory drugs loperamide, an opiate receptor agonist, increases intestinal transit time. Associated adverse effects, like constipation and toxic megacolon, have discouraged its use. Recently another anti-secretory drug, an d opiate receptor agonist, called racecadotril has generated some interest. The enkephalins, endogenous opiate substances, act as neurotransmitters of digestive tract where they cause antisecretory activity without affecting intestinal transit time or motility. Enkephalins after release are rapidly inactivated by enzyme enkephalinase. Racecadotril, an enkephalinase inhibitor, reinforces the physiological activity of endogenous enkephalins. The antisecretory mechanism involves activation of d opiate receptor leading to reduced secretion of intracellular cAMP. Two RCTs have studied the efficacy of racecadotril in acute childhood diarrhea. But these studies have been funded by the manufacturers of the drug. In 135 Peruvian boys (3-35 months), 46% reduction in 48 hours stool output was seen in the racecadotril group as compared to the placebo group.30 Similar results have been reported by Cezard31et al in 172 boys and girls less than 4 years of age. Addition of the girls in the study group makes the primary outcome questionable because urine separation from stool output would be difficult in girls. Moreover 9 cases from the racecadotril and 4 from placebo group were withdrawn during the study. Five cases from the racecadotril and 1 from the placebo group were withdrawn because of adverse events like vomiting or dehydration. Moreover, a RCT32 done in 110 adults with severe cholera reports comparable total stool output, total ORS intake or duration of diarrhea between the racecadotril and loperamide groups. The results of this trial further strengthen the role of standard management of cholera with ORS and doxycycline. A recent RCT33 comparing racecadotril and loperamide for stopping acute diarrhea in adults found comparable clinical success rates and mean duration of diarrhea. More patients on loperamide had reactive constipation and itching was notably higher in the racecadotril group. Despite the subsequent claim,34 that the patients were monitored for 5 days (of which the last 2 days were after the cessation of treatment with racecadotril), none of the clinical trials have mentioned studying the effect of withdrawal of the drug. The question35 raised about the suppression of the scientific data under business pressures is a serious issue. Well designed RCTs with
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adequate sample size and independent of any competitive interest, studying the efficacy and safety of racecadotril in acute childhood diarrhea, are needed before we reach any conclusion regarding the role of the drug in the management of acute diarrhea. NITAZOXANIDE: ANTIPROTOZOAL AGENT Nitazoxanide (2-acetyloxy-N-benzamide), is a synthetic oral antiprotozoal agent. Drug Controller General of India has approved Nitazoxanide (100 mg in 1-3 years and 200 mg in 4-11 years: bd. for 3 days respectively) for treatment of diarrhea caused by Cryptosporidium parvum and Giardia lamblia (http://cdsco.nic.in/DRUGSAPRVD.htm). Single treatment with nitazoxanide had 100% efficacy against cryptosporidial 36-38 diarrhea. Whereas, even third treatment with nitazoxanide could achieve only 80% eradication rate of giardia lamblia. 37 In a double blind randomized controlled trial nitazoxanide had equivalent efficacy to metronidazole in children with giardiasis. 39 Moreover nitazoxanide did not show improvement in the resolution of diarrhea, eradication rate and mortality among HIV- seropositive children with cryptosporodial diarrhea.38 Hence nitazoxanide has an established role against cryptosporidial diarrhea in immuno-competent children but no added benefits are seen over metronidazole in Giardia lamblia infection in children. It is important to follow the recommendations in the management of acute diarrhea strictly, since indiscriminate usage of drugs results in development of resisitance. Addition of so called harmless but unnecessary drugs under business pressures shifts the emphasis from the standard management (oral rehydration solution, feeding and zinc supplementation) of acute childhood diarrhea. Not to forget that such additions also bring unnecessary financial burden on the community. REFERENCES
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Yoshida S. Shigella dysenteriae Serotype 1, Kolkata, India. Emerging Infectious Diseases 2003; 9: 11: 1471-1474. Pazhani GP, Sarkar B, Ramamurthy T, Bhattacharya SK, Takeda Y, Niyogi SK. Clonal Multidrug-Resistant Shigella dysenteriae type 1 Strains Associated with Epidemic and Sporadic Dysenteries in Eastern India. Antmicrob Agents Chemother 2004; 48: 2: 681684. Niyogi SK, Pazhani GP. Multiresistant Shigella species isolated from childhood cases from Kolkatta, India. Jpn J Inf Dis 2003; 56: 33-34. Niyogi SK, Sarkar K, Lalmalsawma P, Pallai N, Bhattacharya SK. An Outbreak of Bacillary Dysentery Caused by Quinolone-resistant Shigella dysenteriae type 1 in a Northeastern State of India. J Health Popul Nutr 2004 Mar; 22(1): 97. Talukder KA, Islam AM, Khajanchi BK, Dutta DK, Islam Z, Safa A, Alam K, Hossain A, Nair GB, Sack DA. Temporal Shifts in the Dominance of Serotypes of Shigella dysenteriae from 1999 to 2002 in Dhaka, Bangladesh. J Clin Microbiol 2003; 41: 11: 5053-5058. 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