Cyrus H. Simanjuntak

Efficacy trial of single-dose live oral cholera vaccine CVD 103-HgR in North Jakarta, Indonesia, a cholera-endemic area

A randomized, double-blind, placebo-controlled efficacy trial of one dose of CVD 103-HgR live oral cholera vaccine was performed in Indonesia from 1993 to 1997. 67,508 persons aged 2-41 years ingested vaccine or placebo and were followed for four years, detecting cholera cases using hospital-based surveillance. A nested reactogenicity study (538 vaccinees, 535 controls) revealed no vaccine-attributable side effects. A nested immunogenicity study (N=657) showed vibriocidal seroresponses in 64-70% of vaccinees vs 1-2% of controls. Cholera incidence was lower than expected. 103 cases of Vibrio cholerae O1 El Tor diarrhea were detected, 93 evaluable for vaccine efficacy (43 vaccine, 50 placebo; efficacy=14%). A suggestion of protection was observed among persons with blood group O [P=0.12]. Only seven cases occurred within six months of vaccination, precluding assessment of short-term efficacy. In Jakarta, single-dose CVD 103-HgR did not confer long-term protection. Short-term protection from a single-dose and long-term protection from two doses have yet to be studied.

The burden of diarrhoea, shigellosis, and cholera in North Jakarta, Indonesia: findings from 24 months surveillance

BackgroundIn preparation of vaccines trials to estimate protection against shigellosis and cholera we conducted a two-year community-based surveillance study in an impoverished area of North Jakarta which provided updated information on the disease burden in the area.MethodsWe conducted a two-year community-based surveillance study from August 2001 to July 2003 in an impoverished area of North Jakarta to assess the burden of diarrhoea, shigellosis, and cholera. At participating health care providers, a case report form was completed and stool sample collected from cases presenting with diarrhoea.ResultsInfants had the highest incidences of diarrhoea (759/1 000/year) and cholera (4/1 000/year). Diarrhea incidence was significantly higher in boys under 5 years (387/1 000/year) than girls under 5 years (309/1 000/year; p < 0.001). Children aged 1 to 2 years had the highest incidence of shigellosis (32/1 000/year). Shigella flexneri was the most common Shigella species isolated and 73% to 95% of these isolates were resistant to ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol and tetracycline but remain susceptible to nalidixic acid, ciprofloxacin, and ceftriaxone. We found an overall incidence of cholera of 0.5/1 000/year. Cholera was most common in children, with the highest incidence at 4/1 000/year in those less than 1 year of age. Of the 154 V. cholerae O1 isolates, 89 (58%) were of the El Tor Ogawa serotype and 65 (42%) were El Tor Inaba. Thirty-four percent of patients with cholera were intravenously rehydrated and 22% required hospitalization. V. parahaemolyticus infections were detected sporadically but increased from July 2002 onwards.ConclusionDiarrhoea causes a heavy public health burden in Jakarta particularly in young children. The impact of shigellosis is exacerbated by the threat of antimicrobial resistance, whereas that of cholera is aggravated by its severe manifestations.

Spectrum of vibrio species associated with acute diarrhea in North Jakarta, Indonesia

Vibrio spp was isolated from 1024 (21.2%) of 4820 diarrhea patients admitted to a community hospital in North Jakarta from 1996 through 1998. Vibrio cholerae O1 (49.5%) and V. parahaemolyticus (30.1%) comprised the major species isolated, followed by V. cholerae non-O1 (16.9%), and V. fluvialis (9.4%). In 938 (19.4%) patients, Vibrio was found as single isolate. Multiple infections were detected in 86 (1.8%) patients. A small number of V. furnisii, V. metschnikovii, V. mimicus and V. hollisae were also isolated. No V. cholerae O139 was detected. The majority of patients with Vibrio spp. infections were adults between the ages of 20 to 45 years. No Vibrio spp. was isolated from infants <1 year old in this study. In vitro antibiotic susceptibility testing revealed no antibiotic resistance associated with the 507 V. cholerae O1 isolates tested, except for colistin (100%). These data implicate Vibrio spp. as a major cause of diarrhea in this region.

Etiology of Acute, Non-Malaria, Febrile Illnesses in Jayapura, Northeastern Papua, Indonesia

We conducted a prospective, inpatient fever study in malaria-endemic Papua, Indonesia to determine non-malaria fever etiologies. Investigations included malaria blood films, blood culture, paired serologic samples analysis for dengue, Japanese encephalitis, leptospirosis, scrub typhus, murine typhus, and spotted fever group rickettsia. During 1997–2000, 226 patients (127 males and 99 females) 1–80 years of age (median age = 25 years) were enrolled. Positive blood cultures (n = 34, 15%) were obtained for Salmonella Typhi (n = 13), Escherichia coli (n = 8), Streptococcus pneumoniae (n = 6), Staphylococcus aureus (n = 5), Streptococcus pyogenes (n = 1), and Klebsiella pneumoniae (n = 1). Twenty (8.8%) patients were positive for leptospirosis by polymerase chain reaction. Eighty (35.4%) of 226 patients had ≥ 1 positive serology, diagnostic for 15 rickettsial and 9 dengue cases. Acid-fast bacilli–positive sputum was obtained from three patients. Most common confirmed (81 of 226, 35.8%)/suspected diagnoses were typhoid fever (n = 41), pneumonia (n = 29), leptospirosis (n = 28), urinary tract infections (n = 20), rickettsioses (n = 19), dengue (n = 17), and meningitis/encephalitis (n = 15). There were 17 deaths, 7 (46.7%) were caused by meningitis/encephalitis. Multiple positive serologic results and few confirmed diagnoses indicate the need for improved diagnostics.

Vibrio parahaemolyticus associated with cholera-like diarrhea among patients in North Jakarta, Indonesia

A diarrhea study was conducted in North Jakarta, Indonesia from December 1996 through December 1997. Vibrio parahaemolyticus was isolated from 333 (6.1%) of 5442 rectal swab samples collected from patients with cholera-like diarrhea. Vibrio cholerae O1 was isolated from 545 (10.0%) and V. cholerae non-O1 from 183 samples (3.4%), respectively. Patients positive for V. parahaemolyticus were mostly adults between 20 and 40 years of age, with males constituting 62%. A majority (65%) of these patients demonstrated watery diarrhea with a frequency of fewer than 10 episodes per 24 hour. A large number of the patients had abdominal pain (83%) and vomiting (76%) and were non-febrile (90%). The highest isolation rate (9.6%) of V. parahaemolyticus was found during the dry season (June, July) and the lowest (4.5%) in the rainy season (December, January, February). All of the V. parahaemolyticus isolates were hemolytic on human blood agar (positive Kanagawa) but none was urease positive. Disk diffusion antibiotic susceptibility tests performed on the isolates demonstrated resistance to ampicillin (98%), cephalothin (24%), kanamycin (15%), colistin (97%), neomycin (2%) and ceftriaxone (0.3%). All isolates (100%) were sensitive to chloramphenicol, tetracycline, trimethoprim-sulfamethoxazole, gentamicin, and ciprofloxacin.

Surveillance of bacterial pathogens of diarrhea disease in Indonesia

Emerging or reemerging infections due to bacterial disease may be a local, regional or global problem. Bacterial acute gastroenteritis is a potential cause of substantial morbidity in travelers and deployed U.S. military personnel. A surveillance study was conducted over a two-year period in Indonesia among 6760 patients with debilitating diarrheal diseases. Of the 6,760 patients, 587 (9%) of the patient stools were positive for bacteria. The proportions of bacteria isolated from the 587 patients were: Shigella flexneri (39%), Salmonella spp. (26%), Vibrio spp. (17%), S. sonnei (7%), Campylobacter jejuni (4.4%), Salmonella typhi (3%) and S. dysenteriae (2.3%). Shigella flexneri was the most prevalent pathogen isolated, over Vibrio spp. No V. cholerae was isolated in the cities of Pontianak, Padang or Batam in Indonesia. Shigella dysenteriae reemergence was noted in Bali, Kalimantan, Batam and Jakarta after an absence of 15 years. Isolation of a high proportion of S. flexneri, and Vibrio spp. occurred during the rainy months. All bacterial isolates were susceptible to quinolones, with the exception of C. jejuni and Salmonella spp., which were resistant to ciprofloxacin, norfloxacin and nalidixic acid. Our findings highlight the decline of V. cholerae, the rise of S. flexneri and the reemergence of S. dysenteriae in Indonesia. The study also documents the emergence of quinolone-resistant Campylobacter spp. in the Indonesia archipelago.

A multi-country cluster randomized controlled effectiveness evaluation to accelerate the introduction of Vi polysaccharide typhoid vaccine in developing countries in Asia : rationale and design

Phase‐III vaccine efficacy trials typically employ individually randomized designs intended to ensure that measurements of vaccine protective efficacy reflect only direct vaccine effects. As a result, decisions about introducing newly licensed vaccines into public health programmes often fail to consider the substantially greater protection that may occur when a vaccine is deployed in public health programmes, due to the combination of direct plus indirect vaccine protective effects. Vaccine total protection can be better evaluated with cluster randomized trials. Such a design was considered to generate policy relevant data to accelerate the rationale introduction of the licensed typhoid fever Vi polysaccharide (PS) vaccine in Asia by the Diseases of the Most Impoverished (DOMI) typhoid fever programme. The DOMIs programme multi‐country study is one of the largest cluster randomized vaccine trials ever mounted in Asia, which includes approximately 200 000 individuals. Its main objective is to determine the effectiveness of a licensed Vi PS vaccine. The rationale and design of this study are discussed. Preliminary results are presented that determined the final planning of the trial before immunization. Important methodological and practical issues regarding vaccine cluster randomized designs are illustrated.

Prevalence of enterotoxigenic Escherichia coli (ETEC) in hospitalized acute diarrhea patients in Denpasar, Bali, Indonesia

The relationship between enterotoxigenic Escherichia coli (ETEC) and hospitalized patients with acute diarrhea was examined in a study conducted in two hospitals from June 2000 to May 2001 in Denpasar, Bali, Indonesia. A total of 489 hospitalized patients with acute diarrhea were enrolled, and their rectal swabs were screened for enteric bacterial pathogens. Toxins, colonization factor antigens (CFAs), in vitro antimicrobial susceptibility and seasonal distribution patterns associated with ETEC were ascertained. The diagnosis of ETEC infection and CFAs association were performed with GM-1 ELISA and Dot blot immunoassays. Enterotoxigenic Escherichia coli was isolated from the rectal swabs of 14.9% of the patients. The distribution of toxins among the ETEC strains found was ST in 51 (69.9%), while LT and ST/LT were found in 28.8% and 1.3% respectively. The highest isolation rate for ETEC was found among children between the ages of 1 and 15 years. Colonization factor antigens were identified in 28.8% of the ETEC strains. A high prevalence of CFA was found among the rectal swabs of patients with ST isolates. High frequency of resistance to ampicillin, trimethoprim/sulfamethoxazole, chloramphenicol, tetracycline and cephalothin was displayed among the ETEC strains. All ETEC strains were susceptible to norfloxacin, ciprofloxacin and nalidixic acid. The results of this study document the prevalence of ETEC in hospitalized patients with acute diarrhea in Denpasar, Bali, Indonesia. Data generated in this study depicts the prevalence of ETEC diarrhea and CFA types among diarrhea patients in the tourist city of Denpasar, Bali, Indonesia.

Safety and immunogenicity of combined diphtheria-tetanus-pertussis (whole cell and acellular): Haemophilus influenzae-b conjugate vaccines administered to Indonesian children

A randomized double-blind trial was conducted to evaluate the safety and immunogenicity of vaccines comprised of diphtheria (D) and tetanus (T) toxoids combined with either a whole cell (P) or an acellular (aP) pertussis component and Haemophilus influenzae type b polyribosylphosphate (PRP) tetanus toxoid conjugate (PRP-T) in Indonesian infants. Three doses of either DTaP, DTaP-PRP-T, or DTP-PRP-T were administered to 930 infants approximately 2-3 months of age and at 2 month intervals thereafter. A booster dose of either DTP-PRP-T or DTaP-PRP-T was administered at 15-18 months of age. Both local and systemic reactions occurred at a significantly (p < 0.001-0.026) higher rate in the group that received whole cell pertussis vaccine versus groups which were immunized with aP containing vaccines. There was no significant difference (p > 0.05) in the rate of adverse events between groups immunized with DTaP or DTaP PRP T. One month after the third dose of vaccine, 99% of subjects had achieved > or =0.1 IU of anti-D and anti-T antibody per ml of serum. The geometric mean titer (GMT) to D was significantly (p < 0.001) higher in the group immunized with DTaP versus the other two groups whereas the anti-T GMT was significantly (p < 0.006) higher for the group immunized with DTP-PRP-T. Both the anti-pertussis toxin (PT) and anti-filamentous hemagglutinin (FHA) antibody levels were significantly (p < 0.001) higher in recipients of acellular versus whole cell pertussis vaccine. In contrast, the anti-B. pertussis agglutinating antibody response was significantly (p < 0.0001) higher in the group immunized with whole cell pertussis vaccine. The anti-PRP GMTs (microg antibody/ml) at 7 months were 0.096, 3.35 and 6.11 for groups immunized with DTaP, DTaP-PRP-T and DTP-PRP-T, respectively. The GMT for those immunized with DTP-PRP-T was significantly (p < 0.001) higher compared to recipients of DTaP-PRP-T. The percent of children who attained > or =0.15 or > or =1 microg/ml after immunization was 18 and 2% for the DTaP group, 93 and 76% for the DTaP-PRP-T group and 97 and 88% for the DTP-PRP-T group. At the > or =1 microg/ml level the difference between the DTaP-PRP0-T and DTP-PRP-T groups was significant (p < 0.01). Children immunized with either DTaP, DTaP-PRP-T, or DTP-PRP-T were reimmunized with DTaP-PRP-T whereas a portion of children immunized with DTP PRP T where also boosted with this vaccine at 15-18 months of age. There was a vigorous anamnestic response to the D and T components with all children possessing > or =0.1 IU/ml. There was also a substantial increase in anti-PT, anti-FHA and B. pertussis agglutinating antibodies. The poorest anti-PT response was seen among children receiving DTP-PRP-T for both primary and reimmunization while the highest agglutinating antibody response followed receipt of 4 doses of DTP-PRP-T. Greater than 80% of children immunized with either DTP PRP T or DTaP-PRP-T possessed > or =0.15 microg/ml before boosting versus 38% for those vaccinated with DTaP (p < 0.001). Primary immunization with DTP-PRP-T resulted in a significantly (p < 0.05) higher percentage (72%) maintaining > or =1 microg/ml compared to those immunized with DTaP-PRP-T (46%). Prior to reimmunization, the anti-PRP GMT was significantly (p < 0.005) higher for children immunized with 3 doses of DTP-PRP-T versus DTaP-PRP-T. Subsequent to reimmunization, > or =95% of subjects attained > or =1 microg/ml.

Streptokinase clot culture compared with whole blood culture for isolation of Salmonella typhi and S. paratyphi A from patients with enteric fever

The sensitivities of whole blood and clot cultures were compared in 155 patients with typhoid or paratyphoid fever. Salmonella typhi or S. paratyphi A were isolated from 98.7% of 5 ml 1:10 blood:broth ratio blood cultures and 94.8% of 5 ml streptokinase clot cultures (P greater than 0.05). There was no difference in the speed of isolation. Whole blood culture and clot culture were of nearly equal sensitivity in this group of patients.