Effect of Bismuth Subsalicylate vs Placebo on Use of Antibiotics Among Adult Outpatients With Diarrhea in Pakistan: A Randomized Clinical Trial.

Importance: Many of the 4.5 billion annual episodes of diarrhea are treated unnecessarily with antibiotics; prevalence of antibiotic resistance among diarrheal pathogens is increasing. Knowledge-based antibiotic stewardship interventions typically yield little change in antibiotic use. Objective: To compare antibiotic use among adult outpatients with diarrhea given bismuth subsalicylate (BSS) or placebo. Design, Setting, and Participants: This randomized clinical trial took place from April to October 2014. Participants were patients aged 15 to 65 years with acute, nonbloody diarrhea from 22 outpatient clinics in Karachi, Pakistan. Participants were interviewed about symptoms and health care utilization during the 5 days after enrollment. Group assignment was concealed from participants, field staff, and the statistician. Primary analysis occurred from August to September 2015. Interventions: Participants were randomly assigned (1:1) to receive BSS or placebo for 48 hours or less. Main Outcomes and Measures: Use of systemic antibiotics within 5 days of enrollment. Secondary outcomes included measures of duration and severity of illness. Results: Among eligible patients, 39 declined to participate, 440 enrolled, and 1 enrolled participant was lost to follow-up, for a total of 439 patients included in the analysis. Median (interquartile range) participant age was 32 (23-45) years and 187 (43%) were male. Two hundred twenty patients were randomized to BSS and 220 were randomized to placebo. Overall, 54 participants (12%) used systemic antibiotics (16% in the placebo group and 9% in the BSS group); all antibiotic use followed consultation with a physician. Use of any antibiotic was significantly lower in the BSS group (20 of 220 vs 34 of 219 patients; odds ratio [OR], 0.54; 95% CI, 0.30-0.98), as was use of fluoroquinolones (8 of 220 vs 20 of 219 patients; OR, 0.38; 95% CI, 0.16-0.88). Rates of care seeking and hospitalization were similar between groups and no difference was detected in timing of diarrhea resolution. However, those in the BSS group less commonly received intravenous rehydration (14 of 220 vs 27 of 219 patients; OR, 0.48; 95% CI, 0.25-0.95) and missed less work (median [interquartile range], 0 [0-1] vs 1 [0-1] day; P = .04) during follow-up. Conclusions and Relevance: This study found less antibiotic use among participants given BSS for acute diarrhea in a setting where antibiotics are commonly used to treat diarrhea. Encouraging health care professionals in such settings to recommend BSS as frontline treatment for adults with diarrhea, and promoting BSS for diarrhea self-management, may reduce antibiotic use and rates of antibiotic resistance globally. Trial Registration: ClinicalTrials.gov identifier: NCT02047162.

What Happens When "Germs Don't Get Killed and They Attack Again and Again": Perceptions of Antimicrobial Resistance in the Context of Diarrheal Disease Treatment Among Laypersons and Health-Care Providers in Karachi, Pakistan.

In south Asia, where diarrhea is common and antibiotics are accessible without prescription, antimicrobial resistance is an emerging and serious problem. However, beliefs and behaviors related to antimicrobial resistance are poorly understood. We explored laypersons' and health-care providers' (HCP) awareness and perceptions of antimicrobial resistance in the context of treatment of adult diarrheal disease in Karachi, Pakistan. In-depth, open-ended interviews were conducted with 40 laypersons and 45 HCPs in a lower-middle-class urban neighborhood. Interviews conducted in Urdu were audiotaped, transcribed, translated, and coded using applied thematic analysis. Slightly over half of laypersons and two-thirds of HCPs were aware that antimicrobial medication could lose effectiveness, but misperceptions were common. Laypersons and HCPs often believed that "the body becomes immune" or "bacteria attack more strongly" if medications are taken "improperly." Another prevalent theme was that causes and effects of antimicrobial resistance are limited to the individual taking the antimicrobial medication and to the specific diarrheal episode. Participants often attributed antimicrobial resistance to patient behaviors; HCP behavior was rarely discussed. Less than half of the HCPs were aware of treatment guidelines. To combat antimicrobial resistance in urban Pakistan, a health systems strategy and community-supported outreach campaigns on appropriate antimicrobial use are needed.

Effect of recent diarrhoeal episodes on risk of pneumonia in children under the age of 5 years in Karachi, Pakistan.

BACKGROUND: We assessed the association between the duration of diarrhoea and the risk ofpneumonia incidence among children <5 years of age. METHODS: We analysed data from a cluster randomized controlled trial in Karachi, Pakistan, which assessed the effect of promoting hand washing with soap (antibacterial and plain) on child health. Field workers visited households with children <5 years of age weekly and asked primary caregivers if their child had diarrhoea, cough or difficulty breathing in the preceding week. We used the WHO clinical case definitions for diarrhoea and pneumonia.We used adjusted time-to-event analyses with cumulative diarrhoea prevalence over the previous 2 and 4 weeks as exposure and pneumonia as outcome. We calculated the attributable risk of pneumonia due to recent diarrhoea across the intervention groups. RESULTS: 873 households with children <5 years were visited. Children had an increased risk of pneumonia for every additional day of diarrhoea in the 2 weeks (1.06, 95% CI: 1.03-1.09) and 4 weeks (1.04, 95% CI: 1.03-1.06) prior to the week of pneumonia onset. The attributable risk of pneumonia cases due to recent exposure to diarrhoea was 6%. A lower associated pneumonia risk following diarrhoea was found in the control group: (3%) compared with soap groups (6% in antibacterial soap, 9% in plain soap). CONCLUSION: Children <5 years of age are at an increased risk of pneumonia following recent diarrhoeal illness. Public health programmes that prevent diarrhoea may also reduce the burden of respiratory illnesses.

Sustained improvements in handwashing indicators more than 5 years after a cluster-randomised, community-based trial of handwashing promotion in Karachi, Pakistan.

OBJECTIVE: To evaluate handwashing behaviour 5 years after a handwashing intervention in Karachi, Pakistan. METHODS: In 2003, we randomised neighbourhoods to control, handwashing promotion, or handwashing promotion and water treatment. Intervention households were given soap +/- water treatment product and weekly handwashing education for 9 months. In 2009, we re-enrolled 461 households from the three study groups: control (160), handwashing (141), and handwashing + water treatment (160) and assessed hygiene-related outcomes, accounting for clustering. RESULTS: Intervention households were 3.4 times more likely than controls to have soap at their handwashing stations during the study visit [293/301 (97%) vs. 45/159 (28%), P < 0.0001]. While nearly all households reported handwashing after toileting, intervention households more commonly reported handwashing before cooking [relative risk (RR) 1.2 (95% confidence interval (CI) 1.0-1.4)] and before meals [RR 1.7 (95% CI, 1.3-2.1)]. Control households cited a mean of 3.87 occasions for washing hands; handwashing households, 4.74 occasions; and handwashing + water treatment households, 4.78 occasions (P < 0.0001). Households reported purchasing a mean of 0.65 (control), 0.91 (handwashing) and 1.1 (handwashing + water treatment) bars of soap/person/month (P < 0.0001). CONCLUSIONS: Five years after receiving handwashing promotion, intervention households were more likely to have soap at the household handwashing station, know key times to wash hands and report purchasing more soap than controls, suggesting habituation of improved handwashing practices in this population. Intensive handwashing promotion may be an effective strategy for habituating hygiene behaviours and improving health.

Association between intensive handwashing promotion and child development in Karachi, Pakistan: a cluster randomized controlled trial.

OBJECTIVE: To evaluate associations between handwashing promotion and child growth and development. DESIGN: Cluster randomized controlled trial. SETTING: Informal settlements in Karachi, Pakistan. PARTICIPANTS: A total of 461 children who were enrolled in a trial of household-level handwashing promotion in 2003 and were younger than 8 years at reassessment in 2009. INTERVENTIONS: In 2003, neighborhoods were randomized to control (n = 9), handwashing promotion (n = 9), or handwashing promotion and drinking water treatment (n = 10); intervention households received free soap and weekly handwashing promotion for 9 months. MAIN OUTCOME MEASURES: Anthropometrics and developmental quotients measured with the Battelle Developmental Inventory II at 5 to 7 years of age. RESULTS: Overall, 24.9% (95% CI, 20.0%-30.6%) and 22.1% (95% CI, 18.0%-26.8%) of children had z scores that were more than 2 SDs below the expected z scores for height and body mass index for age, respectively; anthropometrics did not differ significantly across study groups. Global developmental quotients averaged 104.4 (95% CI, 101.9-107.0) among intervention children and 98.3 (95% CI, 93.1-103.4) among control children (P = .04). Differences of similar magnitude were measured across adaptive, personal-social, communication, cognitive, and motor domains. CONCLUSIONS: Although growth was similar across groups, children randomized to the handwashing promotion during their first 30 months of age attained global developmental quotients 0.4 SDs greater than those of control children at 5 to 7 years of age. These gains are comparable to those of at-risk children enrolled in publicly funded preschools in the United States and suggest that handwashing promotion could improve child well-being and societal productivity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01538953.

The variability of childhood diarrhea in Karachi, Pakistan, 2002-2006.

Diarrhea burden is often estimated using cross-sectional surveys. We measured variability in diarrhea prevalence among children < 5 years of age living in squatter settlements in central Karachi, Pakistan. We pooled data from non-intervention control households from studies conducted from 2002 through 2006. The prevalence of diarrhea varied on average by 29% from one week to the next, by 37% from one month to the next, and during peak diarrhea season by 32% from one year to the next. During 24 months when the same nine neighborhoods were under surveillance, each month the prevalence of diarrhea varied by at least an order of magnitude from the lowest to the highest prevalence neighborhood, and each neighborhood recorded the highest diarrhea prevalence during at least one month. Cross-sectional surveys are unreliable measures of diarrhea prevalence.

Difficulties in maintaining improved handwashing behavior, Karachi, Pakistan.

In an earlier study in Karachi, Pakistan, households that received free soap and handwashing promotion for 9 months reported 53% less diarrhea than controls. Eighteen months after the intervention ended, these households were enrolled in a follow-up study to assess sustainability of handwashing behavior. Upon re-enrollment, mothers in households originally assigned to the intervention were 1.5 times more likely to have a place with soap and water to wash hands (79% versus 53%, P = 0.001) and when asked to wash hands were 2.2 times more likely to rub their hands together at least three times (50% versus 23%, P = 0.002) compared with controls. In the ensuing 14 months, former intervention households reported a similar proportion of person-days with diarrhea (1.59% versus 1.88%, P = 0.66) as controls. Although intervention households showed better handwashing technique after 2 years without intervention, their soap purchases and diarrhea experience was not significantly different from controls.

Field trial of a low cost method to evaluate hand cleanliness.

OBJECTIVE: To evaluate a simple low cost method for measuring hand contamination as an objective assessment of handwashing practices. METHOD: As part of a larger randomized controlled trial of handwashing promotion with soap conducted in squatter settlements of Karachi, Pakistan, a randomly selected subset of 52 mothers in households receiving soap and handwashing promotion and 28 mothers in control households directly pressed three fingers of their right hand onto MacConkey agar plates on weekly unannounced visits from April to September 2002, and monthly from October 2002 to March 2003. The MacConkey plates were incubated at 44 degrees C for 24 h, and evaluated for growth of thermotolerant coliform bacteria. RESULTS: The proportion of samples that had detectable thermotolerant coliforms (50%) was similar in households that received soap and control households (52%, P = 0.40). In the week after evaluation of the mothers' hands, the proportion of households that reported diarrhoea was similar regardless of whether or not the mother had thermotolerant coliforms detected by direct finger imprint (18.6%vs. 19.1%, Relative Risk 0.99, 95% CI 0.96, 1.03). CONCLUSIONS: A three finger direct imprint test using MacConkey agar for thermotolerant coliforms was not a useful method to assess regular handwashing practices with soap in Karachi. Developing better measures of handwashing behaviour remains an important research priority.

No evidence for prolonged excretion of polioviruses in persons with residual paralytic poliomyelitis in Ethiopia, Pakistan and Guatemala.

Persons who have developed acute flaccid paralysis following infection with wild-type polioviruses or vaccine-associated paralytic poliomyelitis usually excrete polioviruses for only a few weeks. However, some patients with paralytic poliomyelitis have had prolonged excretion of polioviruses for periods of up to 10 years after onset of disease. Most prolonged excretors have been identified in industrialized countries. We studied 348 patients 2-28 years old in Ethiopia, Pakistan and Guatemala with residual paralytic poliomyelitis to determine if they had IgA or IgG deficiency or persistent poliomyelitis excretion at least 1 year after onset of disease. None of the 348 affected individuals had IgG deficiency or persistent poliovirus excretion. One child had borderline low serum IgA concentration. Since we did not study children under 2 years of age, persons born with IgG deficiency disorders may have died in developing countries where replacement immunoglobulin therapy is not readily available. Nevertheless, persistent poliovirus excretion among persons 2 years of age and older with residual paralytic poliomyelitis is uncommon in developing countries.

Combining drinking water treatment and hand washing for diarrhoea prevention, a cluster randomised controlled trial.

OBJECTIVES: To evaluate the effectiveness of point of use water treatment with flocculent-disinfectant on reducing diarrhoea and the additional benefit of promoting hand washing with soap. METHODS: The study was conducted in squatter settlements of Karachi, Pakistan, where diarrhoea is a leading cause of childhood death. Interventions were randomly assigned to 47 neighbourhoods. Households in 10 neighbourhoods received diluted bleach and a water vessel; nine neighbourhoods received soap and were encouraged to wash hands; nine neighbourhoods received flocculent-disinfectant water treatment and a water vessel; 10 neighbourhoods received disinfectant-disinfectant water treatment and soap and were encouraged to wash hands; and nine neighbourhoods were followed as controls. Field workers visited households at least once a week from April to December 2003 to promote use of the interventions and to collect data on diarrhoea. RESULTS: Study participants in control neighbourhoods had diarrhoea on 5.2% of days. Compared to controls, participants living in intervention neighbourhoods had a lower prevalence of diarrhoea: 55% (95% CI 17%, 80%) lower in bleach and water vessel neighbourhoods, 51% (95% CI 12%, 76%) lower in hand washing promotion with soap neighbourhoods, 64% lower (95% CI 29%, 90%) in disinfectant-disinfectant neighbourhoods, and 55% (95% CI 18%, 80%) lower in disinfectant-disinfectant plus hand washing with soap neighbourhoods. CONCLUSIONS: With an intense community-based intervention and supplies provided free of cost, each of the home-based interventions significantly reduced diarrhoea. There was no benefit by combining hand washing promotion with water treatment.

Effect of handwashing on child health: a randomised controlled trial.

BACKGROUND: More than 3.5 million children aged less than 5 years die from diarrhoea and acute lower respiratory-tract infection every year. We undertook a randomised controlled trial to assess the effect of handwashing promotion with soap on the incidence of acute respiratory infection, impetigo, and diarrhoea. METHODS: In adjoining squatter settlements in Karachi, Pakistan, we randomly assigned 25 neighbourhoods to handwashing promotion; 11 neighbourhoods (306 households) were randomised as controls. In neighbourhoods with handwashing promotion, 300 households each were assigned to antibacterial soap containing 1.2% triclocarban and to plain soap. Fieldworkers visited households weekly for 1 year to encourage handwashing by residents in soap households and to record symptoms in all households. Primary study outcomes were diarrhoea, impetigo, and acute respiratory-tract infections (ie, the number of new episodes of illness per person-weeks at risk). Pneumonia was defined according to the WHO clinical case definition. Analysis was by intention to treat. FINDINGS: Children younger than 5 years in households that received plain soap and handwashing promotion had a 50% lower incidence of pneumonia than controls (95% CI (-65% to -34%). Also compared with controls, children younger than 15 years in households with plain soap had a 53% lower incidence of diarrhoea (-65% to -41%) and a 34% lower incidence of impetigo (-52% to -16%). Incidence of disease did not differ significantly between households given plain soap compared with those given antibacterial soap. INTERPRETATION: Handwashing with soap prevents the two clinical syndromes that cause the largest number of childhood deaths globally-namely, diarrhoea and acute lower respiratory infections. Handwashing with daily bathing also prevents impetigo.

Delayed effectiveness of home-based interventions in reducing childhood diarrhea, Karachi, Pakistan.

We introduced home drinking water disinfection and handwashing with soap in Karachi squatter settlements to evaluate their effect on diarrhea. In April 2000, 150 households received soap, 76 received dilute bleach and a water storage vessel, and 76 were enrolled as controls. In 2000, among households wealthy enough to own a refrigerator, children in households that received bleach and a vessel had a 73% lower incidence of diarrhea than controls; those that received soap had a 56% lower incidence. There was no reduction in diarrhea in intervention households without a refrigerator. In 2001, households that received bleach and a vessel had a 71% lower incidence of diarrhea and children in households that received soap had a 35% lower incidence than controls. In 2001, the interventions were equally effective in households that had a refrigerator and those that did not. Both of these home-based interventions were ultimately effective in preventing diarrhea, but only households of slightly higher socioeconomic status changed their behavior quickly enough to benefit during the first summer.

Effect of intensive handwashing promotion on childhood diarrhea in high-risk communities in Pakistan: a randomized controlled trial.

CONTEXT: Washing hands with soap prevents diarrhea, but children at the highest risk of death from diarrhea are younger than 1 year, too young to wash their own hands. Previous studies lacked sufficient power to assess the impact of household handwashing on diarrhea in infants. OBJECTIVE: To evaluate the effect of promoting household handwashing with soap among children at the highest risk of death from diarrhea. DESIGN, SETTING, AND PARTICIPANTS: A cluster randomized controlled trial of 36 low-income neighborhoods in urban squatter settlements in Karachi, Pakistan. Field workers visited participating households at least weekly from April 15, 2002, to April 5, 2003. Eligible households located in the study area had at least 2 children younger than 15 years, at least 1 of whom was younger than 5 years. INTERVENTIONS: Weekly visits in 25 neighborhoods to promote handwashing with soap after defecation and before preparing food, eating, and feeding a child. Within intervention neighborhoods, 300 households (1523 children) received a regular supply of antibacterial soap and 300 households (1640 children) received plain soap. Eleven neighborhoods (306 households and 1528 children) comprised the control group. MAIN OUTCOME MEASURE: Incidence density of diarrhea among children, defined as the number of diarrheal episodes per 100 person-weeks of observation. RESULTS: Children younger than 15 years living in households that received handwashing promotion and plain soap had a 53% lower incidence of diarrhea (95% confidence interval [CI], -65% to -41%) compared with children living in control neighborhoods. Infants living in households that received handwashing promotion and plain soap had 39% fewer days with diarrhea (95% CI, -61% to -16%) vs infants living in control neighborhoods. Severely malnourished children (weight for age z score, <-3.0) younger than 5 years living in households that received handwashing promotion and plain soap had 42% fewer days with diarrhea (95% CI, -69% to -16%) vs severely malnourished children in the control group. Similar reductions in diarrhea were observed among children living in households receiving antibacterial soap. CONCLUSION: In a setting in which diarrhea is a leading cause of child death, improvement in handwashing in the household reduced the incidence of diarrhea among children at high risk of death from diarrhea.

Elevated blood lead levels among children living in a fishing community, Karachi, Pakistan.

Lead is a widespread environmental contaminant worldwide and is associated with adverse outcomes in children, including impaired neurobehavioral development and learning difficulties. A cross-sectional survey of 53 young children was conducted in a fishing village on an island adjacent to Karachi, Pakistan. Whole blood from each individual was tested for lead levels. Also tested were samples of cooked food, house dust, and drinking water from 36 households. Laboratory determinations were made by the Pakistan Council for Scientific and Industrial Research with quality control by the United States Centers for Disease Control and Prevention. Fifty-two subjects (98%) had blood lead levels above 10 microg/dl (mean 21.60 microg/dl), an internationally recognized threshold for potential neurotoxicity. The mean concentration was 3.90 microg/g in cooked food, 4.02 microg/l in drinking water, and 91.30 microg/g in house dust. These findings indicate possible major health concerns and suggest significant environmental contamination in this community as well as the need to identify locally relevant early childhood exposures.

Determinants of therapeutic injection overuse among communities in Sindh, Pakistan.

BACKGROUND: Unsafe injections including reuse of disposable syringe is very common in developing countries including Pakistan. Healthcare providers unnecessarily prescribe injections to patients suggesting that patients ask for injections. We conducted this qualitative study to determine the reasons of overuse of therapeutic injections by the communities in Sindh province of Pakistan. METHODS: Using field-tested focus group guides of World Health Organization, eighteen focus group discussions (FGDs) were conducted with community members of rural Sindh, peri-urban and urban Karachi during January-February 2001. RESULTS: Injections are overused in Sindh, Pakistan, because patients prefer them, believing that they provide quick relief, and perceive them as a therapeutic norm and standard practice. According to community members initiative of prescription of injections are taken by doctors. Overuse of injections is of particular concern as patients are not aware of the risks associated with reuse of injection equipment. Doctors and television are considered as the most credible source of providing healthcare information. CONCLUSION: There is a need to educate communities regarding rationale use of therapeutic injections. Open discussion and frequent communication between doctors and patient should be encouraged. Mass media could play a vital role in educating communities about risks of unsafe injections.

Serological response and poliovirus excretion following different combined oral and inactivated poliovirus vaccines immunization schedules.

A controlled study was conducted in Karachi, Pakistan to compare humoral and mucosal immune responses against polioviruses in infants who received oral poliovirus vaccine (OPV) at birth and at 6, 10, and 14 weeks according to the Expanded Program on Immunization (EPI) with infants who received either three doses of inactivated poliovirus vaccine (IPV) at 6, 10, and 14 weeks together with OPV or one additional dose of IPV at 14 weeks together, with the last dose of OPV. A total of 1429 infants were enrolled; 24-week serum specimens were available for 898 infants (63%). They all received a challenge dose of OPV type 3 at 24 weeks of age. The addition of three doses of IPV to three doses of OPV induced a significantly higher percentage of seropositive children at 24 weeks of age for polio 1 (97% versus 89%, P<0.001) and polio 3 (98% versus 92%) compared to the EPI schedule. However, the one supplemental dose of IPV at 14 weeks did not increase the serological response at 24 weeks. Intestinal immunity against the challenge dose was similar in the three groups. Combined schedules of OPV and IPV in the form of diphtheria-pertussis-tetanus-IPV vaccine (DPT-IPV) may be useful to accelerate eradication of polio in developing countries.

Factors associated with elevated blood lead concentrations in children in Karachi, Pakistan.

OBJECTIVES: To confirm whether blood lead concentrations in Karachi were as high as reported in 1989 and to identify which types of exposure to lead contribute most to elevated blood lead concentrations in children in Karachi. METHODS: A total of 430 children aged 36-60 months were selected through a geographically stratified design from the city centre, two suburbs, a rural community and an island situated within the harbour at Karachi. Blood samples were collected from children and a pretested questionnaire was administered to assess the effect of various types of exposure. Cooked food, drinking-water and house dust samples were collected from households. FINDINGS: About 80% of children had blood lead concentrations 10 g/dl, with an overall mean of 15.6 g/dl. At the 5% level of significance, houses nearer to the main intersection in the city centre, application of surma to children's eyes, father's exposure to lead at workplace, parents' illiteracy and child's habit of hand- to-mouth activity were among variables associated with elevated lead concentrations in blood. CONCLUSION: These findings are of public health concern, as most children in Karachi are likely to suffer some degree of intellectual impairment as a result of environmental lead exposure. We believe that there is enough evidence of the continuing problem of lead in petrol to prompt the petroleum industry to take action. The evidence also shows the need for appropriate interventions in reducing the burden due to other factors associated with this toxic element.

The effect of antibacterial soap on impetigo incidence, Karachi, Pakistan.

We conducted a study to determine if soap containing 1.2% triclocarban would be effective in reducing the incidence of impetigo. We randomized 162 households in a low-income neighborhood of Karachi, Pakistan, to receive a regular supply of 1.2% triclocarban-containing soap (n = 81) or an identically appearing placebo (n = 81); 79 households in a nearby neighborhood were enrolled as standard practice controls. After adjustment for household clustering and covariates, the incidence of impetigo among children living in households receiving triclocarban-containing soap (1.10 episodes per 100 person-weeks) was 23% lower than in households receiving placebo soap (P = 0.28) and 43% lower than the standard habit and practice controls (P = 0.02). The routine use of triclocarban-containing soap by children living in a community with a high incidence of impetigo was associated with a reduced incidence of impetigo.