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Review
2003 © Ashley Publications Ltd ISSN 1465-6566 1315
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1. Introduction
2. Goal of therapy
3. Available therapy
4. Current best practices
5. Factors influencing choice of
therapy
6. Expert opinion
7. Conclusion
Monthly Focus: Anti-infectives
An evaluation of current shigellosis treatmentSujit Kumar Bhattacharya† & Dipika Sur†National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata,
Kolkata – 700 010, India
Shigellosis or bacillary dysentery, characterised by the passage of frequentloose stools mixed with blood and mucous, is caused by Shigella spp. whichcan be subdivided into four serotypes, namely, S. sonnei, S. boydii, S. flexneriand S. dysenteriae. S. dysenteriae type 1 produces severe dysentery and maybe associated with many complications like leukaemoid reaction and haemo-lytic-ureamic syndrome. It is known to produce protracted epidemics andpandemics and is usually multi-drug resistant. Antibiotics are the mainstay oftherapy of all cases of shigellosis. Antibiotics such as tetracycline, ampicillinand co-trimoxazole, were previously highly effective. Newer fluoroquinolo-nes such as norfloxacin, ciprofloxacin, ofloxacin, azithromycin and ceftriax-one are effective. Although single dose of norfloxacin 800 mg andciprofloxacin 1 g have been shown to be effective, they are currently lesseffective against S. dysenteriae type 1 infection. Oral rehydration salt shouldbe given concurrently to prevent or correct dehydration. Antimotility agentsare contraindicated. Feeding during and after shigellosis is emphasised.Hand-washing practices with plenty of water and soap help to prevent thetransmission of infection from person to person. A search is on for aneffective vaccine against shigella.
Keywords: antibiotics, drug resistance, epidemics, shigella, shigellosis, therapy
Expert Opin. Pharmacother. (2003) 4(8):1315-1320
1. Introduction
Shigellosis or bacillary dysentery is characterised by the passage of frequent loosestools mixed with blood and mucus. At least 140 million cases of shigellosis occurworldwide, resulting in 600,000 deaths annually: > 60% of these deaths are inchildren < 5 years of age. [1]. Even today, the disease remains to be a major cause ofmorbidity and mortality, especially in situations involving poor sanitation, over-crowding and lack of personal hygiene. Shigellosis is caused by Shigella spp.,which are divided into four serotypes, namely, S. sonnei, S. boydii, S. flexneri andS. dysenteriae. S. sonnei produces mild dysentery in the developed countries.S. flexneri and S. dysenteriae type 1, particularly the latter, produce fulminatingdysentery in developing countries and the strains of S. dysenteriae type 1 are usu-ally multi-drug resistant and therefore, difficult to treat. Deaths are mostlybecause of shigellosis caused by S. dysenteriae type 1. Starting in Central Americancountries in 1969 – 1970 [2], S. dysenteriae type 1 infection spread to widely differ-ent geographical areas of Asia and Africa [3]. A severe shigellosis epidemic wasexperienced in Bangladesh during 1972 – 1978 [4-7], Southern India(1972 – 1973) [8], Sri Lanka (1976) [9,10], Maldives (1982) [11], Eastern India(1984) [12,13], and Andaman & Nicobar Islands, India (1985) [14].
The clinical spectrum of shigella infections range from asymptomatic bowelinfection, mild-to-moderate watery diarrhoea accompanied by fever and abdominalcramps to severe dysentery manifested by high fever, watery diarrhoea changing
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1316 Expert Opin. Pharmacother. (2003) 4(8)
rapidly to dysentery, tenesmus and abdominal cramps. Chil-dren with shigellosis may develop convulsions. A largenumber of complications have been observed in associationwith shigella infection particularly S. dysenteriae type 1 [15-17].These include convulsions, rectal prolapse, leukaemoid reac-tion (WBC count > 50,000/cm3 in peripheral blood), haemo-lytic uraemic syndrome (HUS; a triad of microangiopathichaemolytic anaemia, thromobocytopenia and renal failure),toxic megacolon, hypoglycaemia, hyponatraemia, protein los-ing enteropathy, arthritis, arthralgia and conjunctivitis. Thisreview will focus on the role of antibiotic, the usefulness ofrehydration therapy and the problem of antibiotic resistancein shigellosis case management.
2. Goal of therapy
There are five main goals of therapy in the treatment of shig-ellosis. First, to confirm the clinical diagnosis with labora-tory support, where necessary. Second, to provideappropriate antibiotic therapy for all shigellosis cases. Third,to use rehydration solution for prevention or treatment ofdehydration, if any. Fourth, to ensure appropriate feedingduring and after dysentery to prevent malnutrition espe-cially among young children. Finally, we should also aim toprevent complications whenever possible. In this review,however, we do not propose to discuss the management ofcomplications of shigellosis.
3. Available therapy
3.1 Confirmation of diagnosis: role of laboratory supportFrom the typical presenting clinical features described above,it is not very difficult to diagnose a case of shigellosis. How-ever, in some cases, it may be necessary to get a stool culturedone. This will also help to determine the antibiotic suscepti-bility pattern of the infecting Shigella spp. isolate. SinceS. dysenteriae type 1 strains are frequently multi-drug resist-ant, this may help in the rationalisation of antibiotic treat-ment once a diagnosis of shigellosis is made and its antibioticsusceptibility pattern has been determined. It may not be nec-essary to do stool culture and susceptibility testing in all casesin the same area. However, from time to time, a review of theantibiotic susceptibility pattern is recommended becauseS. dysenteriae type 1 rapidly changes resistance patterns attimes because of drug pressure.
3.2 Antibiotic therapyNumerous clinical studies have amply demonstrated that theuse of an appropriate antibiotic for the treatment of shigellosisdefinitely decreases the duration of fever, shortens the dura-tion of diarrhoea and dysentery as well as shortens the dura-tion of excretion of pathogen. Certain antibiotics also showgreat in vitro susceptibility against shigella but are ineffectivein vivo, e.g., furazolidone and amoxycillin.
3.2.1 The problem of drug resistanceAs previously mentioned, multi-drug resistance is a serious prob-lem for the treatment of shigellosis, particularly those caused byS. dysenteriae type 1. Sulfonamides, which were highly effectivein the 1940s, had little practical value by the 1950s (100%resistance). Later in the 1960s, tetracycline, followed by ampicil-lin and co-trimoxazole, were found to be highly beneficial [18].Resistance to these three drugs became high (75 – 90%) in thelate 1960s through to the 1980s [19]. In the early 1980s,nalidixic acid was found to be very useful (100% sensitive) [13],however, when in the early 1990s, resistance to nalidixic acidbecame widespread (30 – 100% resistance) [20], norfloxacin [21]
and ciprofloxacin [22] came to the rescue, until recently, whenresistance (100%) to these drugs was reported [23-25]. It has beenshown in West African epidemics that S. dysenteriae type 1 hasthe propensity to acquire multi-drug resistance at high levels. Infact, in Senegal in 1998, > 95% of S. dysenteriae type 1 strainswere resistant to tetracycline, ampicillin, co-trimoxazole, chlo-ramphenicol and ∼ 90% of strains had uniform sensitivity to thenewer quinolones and ceftriaxone [ 26].
3.2.2 Antibiotics of choiceAntibiotics remain the cornerstone for the treatment of shigel-losis. A large number of antibiotics are effective against Shig-ella spp. (Table 1). Ampicillin may be given at a dose of100 mg/kg/day q.i.d. for children and for adults 1 g q.i.d. for
Table 1. Antimicrobials used to treat shigellosis.
Antibiotic of choice* Dose
Ampicillin
Children 25 mg/kg q.i.d. for 5 days
Adults 1 g q.i.d. for 5 days
TMP-SMX
Children TMP 5 mg/kg and SMX 25 mg/kg b.i.d. for 5 days
Adults TMP 160 mg and SMX 800 mg b.i.d. for 5 days
Nalidixic acid
Children 15 mg/kg q.i.d. for 5 days
Adults 1 g q.i.d. for 5 days
Norfloxacin§ 400 mg b.i.d. for 3 – 5 dayssingle dose 800 mg‡
Ciprofloxacin§ 500 mg b.i.d. for 3 – 5 dayssingle dose 1 g‡
Ofloxacin§ 200 mg b.i.d. for 3 – 5 days
*Choice of antibiotic depends on drug resistance pattern of locally circulating Shigella isolates. ‡May not be effective for the treatment of S. dysenteriae type 1 infection. §These drugs are currently not recommended for use in children and pregnant women.SMX: Sulfamethoxazole; TMP: Trimethoprim.
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Expert Opin. Pharmacother. (2003) 4(8) 1317
5 days [27]. Trimethoprim-sulphamethoxazole combinationdose for children includes trimethoprim 5 mg/kg and sul-phamethoxazole 25 mg/kg b.i.d. and that for adults includetrimethoprim 160 mg and sulphamethoxazole 800 mg b.i.d.for 5 days [28]. Alternatively, nalidixic acid 55 mg/kg/day infour divided doses (for children) and 1 g q.i.d. (for adults) for5 days may be used [13].
Norfloxacin 400 mg b.i.d. (alternatively, a single dose of800 mg [29], ciprofloxacin 500 mg b.i.d. [30] (alternatively, asingle dose of 1 g) or ofloxacin 200 mg b.i.d. for 3 – 5 days,may be used. However, a single dose may not be effective forthe treatment of S. dysenteriae type 1 infection. Althoughthese drugs are currently not recommended for children andpregnant women, there is growing evidence that they willprove safe [31]. Pivmecillinum [32] in a dose of 400 mg p.o.every 6 h for 5 days has been shown in Bangladesh to be aseffective as ampicillin and may be used as a useful drug for thetreatment of shigellosis. Recently, azithromycin [33,34] hasbeen shown to be effective in the treatment of shigellosis.
Although for the treatment of shigellosis, oral use of antibi-otics is always preferred, in those patients who may have nau-sea and vomiting and therefore, cannot tolerate oralantibiotics, parenteral (intramuscular or intravenous) admin-istration of antibiotics may be required. As fluoroquinolonesare not recommended for children and pregnant women,third-generation cephalosporins, especially ceftriaxone, mayhave to be given parenterally. Of course, such treatment ismuch more expensive.
According to the WHO guidelines [35], when a presumptivediagnosis of shigellosis is made (based on clinical features andepidemiological setting), all such patients should be treatedwith an antibiotic, the choice being decided by the antimicro-bial susceptibility pattern of locally circulating shigella strains.If after 2 days of therapy, the patient condition improves, thena full course for 5 days should be given. On the other hand, ifthe patient does not improve, the antibiotic should bechanged. If improvement is seen after 2 days, it should becontinued for a total of 5 days. If, even with the second anti-biotic, the patient does not show signs of improvement, thediagnosis must be reviewed and stool microscopy and culturesusceptibility testing should be carried out, keeping in mindthe possibility of acute amoebic dysentery and other causes ofbloody diarrhoea.
3.3 Rehydration therapyWhereas antibiotic treatment is the pivot of therapy ofshigellosis patients, rehydration therapy may be required inthose cases which are associated with dehydration. Dehy-dration is not a conspicuous feature in the majority of shig-ellosis cases. They are usually associated with mild-to-moderate dehydration, which should be corrected with oralrehydration salt (ORS) solution recommended by theWHO and UNICEF (United Nations Children's Fund)[35]. Such a solution contains sodium chloride 3.5 g, triso-dium citrate, dihydrate 2.9 g or sodium bicarbonate 2.5 g,
potassium chloride 1.5 g and glucose anhydrous 20 g dis-solved in 1 l of drinking water. Rarely, cases of shigellosiswho may present with severe dehydration because of frankwatery diarrhoea, should be rehydrated with intravenousRinger’s Lactate.
3.4 The Role of other drugsAntimotility agents such as tincture of opium, paregoric anddiphenoxylate with atropine are strictly contraindicated in thetreatment of shigellosis [36]. The use of such agents may pro-long duration of fever and excretion of shigella. Commonantidiarrhoeal preparations such as pectin-kaolin formulae,bismuth salicylate, lactobacilli, sour milk or yoghurt have nobeneficial effect on the outcome of shigellosis.
3.5 Feeding during shigellosisOwing to anorexia, patients with shigellosis particularly chil-dren, may refuse to take food. However, it is important toprovide nutritious food to all shigellosis patients. With effec-tive antimicrobial therapy, appetite usually improves and atthis stage, patients should be encouraged to take small mealsat frequent intervals. Mothers should continue to breast feedtheir infants and young children. Appropriate feeding duringand after an attack of shigellosis helps prevent malnutrition.
3.6 Prevention of complicationsEarly treatment with an appropriate antibiotic, timely rehy-dration therapy and proper nutritional management may helpthe prevention of some of the complications. A high index ofsuspicion of complications will help their detection at theearly stage and appropriate management should be institutedas soon as possible.
4. Current best practices
4.1 AntibioticsCurrently, effective antibiotics, which should only be givenorally, can be decided by determining the antimicrobial sus-ceptibility pattern of the local shigella isolates. Recommendedantibiotics include norfloxacin 400 mg or ciprofloxacin500 mg or ofloxacin 200 mg b.i.d. for 3 – 5 days. However,these drugs are not yet approved for the treatment of childrenor pregnant women. There is growing evidence, however, thatthey will prove safe in the future [30].
4.2 Rehydration therapy and feedingMild-to-moderate dehydration should be treated withWHO/UNICEF recommended ORS. Generally, all patientswith shigellosis should be encouraged to take ORS, which isusually helpful. Although shigellosis patients, particularlychildren, may initially refuse to take food because of ano-rexia, they should be encouraged to take frequently small,easily digestible meals. The task becomes easier with effec-tive antibiotic treatment for 1 – 2 days. Antimotility agentsare contraindicated.
An evaluation of current shigellosis treatment
1318 Expert Opin. Pharmacother. (2003) 4(8)
5. Factors influencing choice of therapy
All cases of shigellosis should be treated with an effective anti-biotic, and oral antibiotics are useful and well tolerated. How-ever, shigellosis cases particularly those caused byS. dysenteriae type 1, are multi-drug resistant and may pose areal therapeutic challenge (drug resistance). When resistanceto existing drugs assumes high level (mostly because of indis-criminate use to treat many different presumptive infectiveconditions and as a prophylaxis for other conditions), epi-demics of shigellosis, particularly caused by S. dysenteriaetype 1, break out and such outbreaks are difficult to controlunless we have, at that point of time, a new effective drug.
On many occasions, clinicians use various combinations ofantibiotics and even parenterally without any additional bene-fit (combinations and parenteral administration).
Sometimes, shigellosis is confused with acute amoebic dysen-tery and large doses of anti-amoebic drugs such as metronidazoleor tinidazole, are used unsuccessfully. Moreover, antiamoebicdrugs generally aggravate anorexia and may produce nausea andvomiting (causing confusion concerning the diagnosis).
6. Expert opinion
Multi-drug resistant S. dysenteriae type 1 has known to pro-duce protracted epidemics and have also caused pandemics inthe past. At the beginning of any shigellosis epidemic, generalpractitioners and clinicians who often encounter the casesfirst, are confused about the diagnosis and appropriate man-agement. Being unaware of the drug of choice, they randomlyuse various combinations of antibiotics and anti-amoebics.This is not only irrational but also causes side effects andincreases the cost of treatment. It is, therefore, recommendedthat in a given situation when large number of bloody diar-rhoea cases are being encountered, stool culture and determi-nation of antibiotic susceptibility pattern of the shigellaisolates should be carried out. Such practice will not only helpconfirm the diagnosis, but also streamline the treatment andprevent the spread of the infection.
The WHO guidelines for the treatment of shigellosis asmentioned previously, may be difficult to strictly followbecause of the problem of wide-spread drug resistance. Manyof the drugs, which were very useful at one time, have nowbecome totally infective and hence, it is sometimes very diffi-cult to decide on the drug of choice.
Asymptomatic shigella carriers, seen particularly in chil-dren, are a potential source in perpetuating endemic shigel-losis in the community and could trigger outbreaks. As ameasure of the control strategy, identification methods ofcarriers, coupled with evaluation of their treatment policy,is essential.
7. Conclusion
If rational case management is followed, all cases of shigellosisshould recover within 1 week unless complications develop.As multi-drug resistance is a serious problem in shigellosiscase management, it is imperative that cost-effective preven-tive measures should be adopted to interrupt direct faeco-oraltransmission and thereby, the horizontal transmission of thedisease. Hand-washing with plenty of water and soap has beenshown to be of great benefit in interrupting infection causedby direct contact with people. Disposal of excreta frominfected patients should be done scrupulously. In developingcountries, the human excreta may be buried under the soil.Exclusive breast feeding during the first 6 months of lifeshould be encouraged. Emphasis should be given on improv-ing domestic and food hygiene.
Efforts for an effective vaccine against shigellosis havebeen ongoing for the past 30 years. Considerable advancesin our understanding of the molecular mechanism of viru-lence of shigella, has helped to develop candidates for live,attenuated Shigella spp. vaccines. Nevertheless, as most vac-cine development efforts have been serotype-specific, it willbe difficult to produce a single vaccine to protect against allthe circulating serotypes globally [1]. The priority is todevelop vaccines against S. dysenteriae type 1 and S. flexneritype 2a.
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AffiliationSujit Kumar Bhattacharya† & Dipika Sur†Author for correspondenceNational Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata – 700 010, IndiaTel: +91 33 2350 1176;Fax: +91 33 2350 5066 or +91 33 2353 2524;E-mail: [email protected]
