The drug sensitivity and transmission dynamics of human malaria on Nias Island, North Sumatra, Indonesia.

Nias Island, off the north-western coast of Sumatra, Indonesia, was one of the first locations in which chloroquine-resistant Plasmodium vivax malaria was reported. This resistance is of particular concern because its ancient megalithic culture and the outstanding surfing conditions make the island a popular tourist destination. International travel to and from the island could rapidly spread chloroquine-resistant strains of P. vivax across the planet. The threat posed by such strains, locally and internationally, has led to the routine and periodic re-assessment of the efficacy of antimalarial drugs and transmission potential on the island. Active case detection identified malaria in 124 (17%) of 710 local residents whereas passive case detection, at the central health clinic, confirmed malaria in 77 (44%) of 173 cases of presumed 'clinical malaria'. Informed consenting volunteers who had malarial parasitaemias were treated, according to the Indonesian Ministry of Health's recommendations, with sulfadoxine-pyrimethamine (SP) on day 0 (for P. falciparum) or with chloroquine (CQ) on days 0, 1 and 2 (for P. vivax). Each volunteer was then monitored for clinical and parasite response until day 28. Recurrent parasitaemia by day 28 treatment was seen in 29 (83%) of the 35 P. falciparum cases given SP (14, 11 and four cases showing RI, RII and RIII resistance, respectively). Recurrent parasitaemia was also observed, between day 11 and day 21, in six (21%) of the 28 P. vivax cases given CQ. Although the results of quantitative analysis confirmed only low prevalences of CQ-resistant P. vivax malaria, the prevalence of SP resistance among the P. falciparum cases was among the highest seen in Indonesia. When the parasites present in the volunteers with P. falciparum infections were genotyped, mutations associated with pyrimethamine resistance were found at high frequency in the dhfr gene but there was no evidence of selection for sulfadoxine resistance in the dhps gene. Night-biting mosquitoes were surveyed by human landing collections and tested for sporozoite infection. Among the five species of human-biting anophelines collected, Anopheles sundaicus was dominant (68%) and the only species found to be infective--two (1.2%) of 167 females being found carrying P. vivax sporozoites. The risk of malarial infection for humans on Nias was considered high because of the abundance of asymptomatic carriers, the reduced effectiveness of the available antimalarial drugs, and the biting and infection 'rates' of the local An. sundaicus.

Chloroquine-resistant Plasmodium vivax in transmigration settlements of West Kalimantan, Indonesia.

Malariometric surveys were conducted during July 1996 in native Dayak villages and predominantly Javanese transmigration settlements in Ketapang district of West Kalimantan, Indonesia. Malaria prevalence ranged from 0.9% to 2.7% in Dayak villages and from 1% to 20% in the transmigration settlements. Plasmodium falciparum accounted for 67% of the cases among Dayaks but P. vivax was dominant among transmigrants, accounting for more than 72% of the infections. Chloroquine sensitivity/resistance was assessed by 28-day in vivo testing of uncomplicated malaria infections and measurement of chloroquine blood levels in cases where parasitemias reappeared within the 28-day test period. Resistance was based on the appearance of asexual parasites against chloroquine plus desethylchloroquine levels exceeding the minimally effective whole blood concentrations proposed for sensitive parasite strains (P. vivax, 100 ng/ml; P. falciparum, 200 ng/ml). All parasitemias cleared initially within four days of beginning supervised chloroquine therapy (25 mg base/kg over a 48-hr period), but asexual parasites reappeared within 28 days in 27 of 52 P. vivax and three of 12 P. falciparum cases. Chloroquine blood levels at the time of recurrent parasitemias revealed resistance in 12 of the 27 P. vivax cases and in one of the three P. falciparum cases. Genotypes of nine of the 12 recurrent P. vivax isolates matched with their primary isolates and ruled out reinfection. These findings establish the presence of chloroquine-resistant P. vivax on the island of Borneo. The pattern of malaria and the high frequency of chloroquine resistance by P. vivax at the West Kalimantan location may relate to demographic, ecologic, agricultural, and socioeconomic changes associated with transmigration.

Whole blood chloroquine concentrations with Plasmodium vivax infection in Irian Jaya, Indonesia.

Whole blood concentrations of self-administered chloroquine (CQ) and its metabolite desethylchloroquine (DCQ) were measured in 168 patients with microscopically confirmed infection by Plasmodium vivax in northeastern Irian Jaya, Indonesia. The study consisted of both survey and passive case detection in four separate villages between 1992 and 1994. The subjects were Javanese people 4-51 years old who had lived in the Arso region for up to two years. The sum of CQ and DCQ ranged from 0 to 8,342 ng/ml of whole blood, and 122 subjects (73%) had > or = 100 ng/ml of CQ plus DCQ, the estimated minimally effective concentration (MEC) in whole blood against chloroquine-sensitive P. vivax. Among 56 subjects reporting to a clinic with symptoms of malaria, 53 (95%) had ordinarily effective levels of chloroquine in blood. Among 109 largely asymptomatic malaria patients found by survey case detection, 69 (63%) had chloroquine blood levels greater than the MEC. Virtually all clinical and most subclinical vivax malaria in this region occurs despite ordinarily effective levels of chloroquine in blood.

Diagnosis of resistance to chloroquine by Plasmodium vivax: timing of recurrence and whole blood chloroquine levels.

To develop criteria for the diagnosis of resistance to chloroquine using an in vivo test, we examined published records of early clinical trials of quinine and chloroquine against Plasmodium vivax. These data established the timing of relapse by tropical P. vivax relative to therapy by these drugs. The first relapse occurred 17 days after initiating and three days after terminating quinine therapy. The median day of relapse was day 23, and 59% of the patients had relapsed by day 30 (n = 333). In contrast, no relapse occurred until day 36 following chloroquine treatment (n = 256). Data from our laboratory may help explain this difference; among 91 Indonesian patients with malaria, the mean whole blood levels of chloroquine (CQ) and desethylchloroquine (DCQ) were 141 ng/ml (95% confidence interval = 115-167) on day 28 after initiating standard therapy (25 mg base/kg in three doses over a 48-hr period). This exceeds the estimated minimal effective concentration of chloroquine (100 ng/ml of whole blood). Thus, chloroquine lingering in the blood for at least 28 days after starting standard therapy was sufficient to eliminate or at least suppress chloroquine-sensitive tropical P. vivax. We conclude that a parasitemia by P. vivax recurring in the 28 days after full compliance to standard chloroquine therapy demonstrates resistance. If the recurrence appears before day 16, it is almost certainly a recrudescence and between days 17 and 28 it may be either a recrudescence or a relapse by chloroquine-resistant parasites. Recurrences beyond day 28 could be relapse by chloroquine-sensitive P. vivax.

In vivo resistance to chloroquine by Plasmodium vivax and Plasmodium falciparum at Nabire, Irian Jaya, Indonesia.

A survey of resistance to chloroquine by Plasmodium vivax and P. falciparum was conducted during May 1995 at three mesoendemic villages 30 km southeast of Nabire, near the central northern coast of Irian Jaya, Indonesia. The prevalence of malaria at Urusumu (n = 157), Margajaya (n = 573), and Topo (n = 199) was 18%. 9%, and 9%, respectively, with spleen rates among children of 79%, 10%, and 27%. Infected patients among those screened formed a study population of 64 subjects eligible for a 28-day in vivo test of resistance to chloroquine. Sixty-three patients successfully completed the test; 45 males and 18 females 1-60 years of age, of whom 29 were Javanese transmigrants of five years residence in Irian Jaya and 34 were native to Irian Jaya. The seven-day day cumulative incidence of therapeutic failure for P. vivax and P. falciparum was 15% (n = 34) and 30% (n = 37). The 14- and 28-day estimates of cumulative incidence were 45% and 64% for P. vivax and 58% and 89% for P. falciparum. Almost all recurrences appeared in the face of ordinarily effective levels of chloroquine and its major metabolite, desethylchloroquine, in whole blood (> or = 100 ng/ml). Four infections by P. malariae in subjects enrolled in this study cleared by day 2 and none reappeared within 28 days. Chloroquine no longer provides effective therapy for falciparum or vivax malaria along the northern coast of Irian Jaya, Indonesia.

Survey of in vivo sensitivity to chloroquine by Plasmodium falciparum and P. vivax in Lombok, Indonesia.

A malariometric survey was conducted in 14 villages of Sekotong district, in Lombok, Indonesia during October 1994. Point prevalence of malaria ranged from 0% to 15% in the surveyed villages, averaging 6% overall, and Plasmodium falciparum accounted for 63% of the infections. Forty-nine patients with uncomplicated malaria and parasite counts ranging from 40 to 10,800 asexual forms/microliter were enrolled in a 28-day in vivo test of chloroquine sensitivity. All subjects received a supervised therapeutic regimen of chloroquine (25 mg base/kg over a 48-hr period) and parasitemia and symptoms were closely monitored for 28 days. Asexual parasites were eliminated within four days in the 29 P. falciparum and 20 P. vivax study patients enrolled. The cumulative incidence of therapeutic failure (recurrent symptomatic parasitemia) among P. falciparum cases at days 7, 14, and 28 was 7%, 10%, and 14% (4 of 29), respectively. However in all four cases, parasitemias recurred against chloroquine blood levels below the minimally effective concentration (MEC) of 200 ng/ml and do not confirm chloroquine resistance. All 20 P. vivax parasitemias were sensitive to chloroquine and the blood remained clear, with the exception of one case in which an asymptomatic parasitemia appeared on day 28. Parasitemias by P. falciparum and P. vivax that were observed before supervised therapy, but in the presence of whole blood chloroquine above normally suppressive MEC levels, suggest resistance to suppressive or prophylactic regimens of chloroquine.

Survey of resistance to chloroquine by Plasmodium vivax in Indonesia.

In February 1995 we surveyed to chloroquine among patients with Plasmodium vivax malaria at Nias Island, in the Indian Ocean near north-western Sumatra, Indonesa. The subjects, 21 indigenous males and females (6-50 years old) infected with > 40 asexual blood stage parasites of P. vivax per microliter of blood, had mild symptoms or none at all. Seven of these patients had > 100 ng/mL whole blood chloroquine levels before the first supervised dose of chloroquine (3 doses of 10 mg/kg, 10 mg/kg, 5 mg/kg of base given at 24 h intervals). Whole blood chloroquine levels on the last day of dosing confirmed normal absorption (range 413-3248, mean 1141, SD 616 ng/mL). Blood films were examined on days 0, 2, 4, 7, 11, 14, 18, 21 and 28 after initiating therapy. Three patients had recurrent asexual P. vivax parasitaemias between days 14 and 18, despite effective levels of chloroquine in whole blood (> or = 100 ng/mL) at the time of recurrence. Resistance to standard chloroquine therapy by P. vivax appeared in 14% of infections among residents of Nias.

Treatment of chloroquine-resistant Plasmodium vivax with chloroquine and primaquine or halofantrine.

Optimal therapy for infection by chloroquine-resistant Plasmodium vivax has not been established. From 1992 to 1994 during three separate studies, 147 Javanese residents of Irian Jaya infected by P. vivax were treated with either chloroquine (25 mg of base/kg during 3 days or 10 mg of base/kg in one dose) plus primaquine (10 mg/kg during 28 days or 2.5 mg/kg during 3 days) (n = 78), chloroquine plus placebo (n = 50), or halofantrine (24 mg base/kg in 12 h; n = 19). There was no difference in tolerance to or side effects of any of the regimens. Within 14 days of starting therapy, therapeutic failure among these patients was 44% for chloroquine, 5% for chloroquine plus primaquine (P < .001), and 0 for halofantrine (P < .001). After 28 days, therapeutic failure was 78%, 15%, and 6%, respectively. Thus, chloroquine plus primaquine in combination and halofantrine alone are effective therapies for chloroquine-resistant P. vivax.

Primaquine for prophylaxis against malaria among nonimmune transmigrants in Irian Jaya, Indonesia.

A comparison of primaquine versus chloroquine for prophylaxis among nonimmune transmigrants from Java and Bali in the hyperendemic Arso region of Irian Jaya, Indonesia was conducted. Forty-five subjects received 0.5 mg of primaquine base/kg of body weight every other day, and 54 people in the same village received weekly 5 mg of chloroquine base/kg for 16-19 weeks beginning in December 1992. Plasmodium falciparum accounted for 18 of 30 infections with chloroquine, and four of five infections among subjects receiving primaquine. Plasmodium vivax was found in 12 people taking chloroquine but in just one person taking primaquine. The risk of malaria among people taking chloroquine relative to that among subjects taking primaquine was 3.96 (P = 0.014) for P. falciparum and 10.56 (P = 0.012) for P. vivax. Primaquine was better tolerated than chloroquine. The minimal protective efficacy for primaquine prophylaxis was 74% against P. falciparum and 90% against P. vivax among nonimmune children and adults living in Irian Jaya. These findings require confirmation with randomized, double-blinded, and placebo-controlled trials.

Evidence for specific suppression of gametocytemia by Plasmodium falciparum in residents of hyperendemic Irian Jaya.

An epidemiologic study of hyperendemic malaria in Arso PIR, a village in northeastern Irian Jaya (Indonesian New Guinea), revealed evidence suggesting suppression of gametocytemia independent of immune control of the asexual parasitemia. A total of 240 people, representing ages between 2 and 60 years, were followed by biweekly blood film examination for 16 weeks beginning in November 1987. Two distinct subpopulations were represented--1) life-long residents of Irian Jaya, and 2) transmigrants from Java who arrived in Irian Jaya 20 months before the surveillance effort began. Twenty-five percent of blood films from natives and 31% from Javanese were positive for falciparum malaria; of these, the rate of gametocytemia was 21% for natives, and 42% for the Javanese transmigrants (P less than 0.001). This difference could not be explained by differences in the frequency or grade of parasitemia, illness, or by known patterns of antimalarial consumption. Similarly, in Wor, a village near Arso PIR, the gametocyte rate for P. falciparum diminished from 83% to 25% in transmigrants from Java between their eleventh and twenty-fifth month of residence in Irian Jaya, a period during which the falciparum malaria rate remained stable between 30% and 50%. An immunofluorescent antibody test using whole, acetone-fixed gametocytes as substrate revealed correlation between antibody titer and protection from gametocytemia among the semi-immune natives of Arso PIR, but not among the Javanese. Specific immune suppression of gametocytes, independent of immune control of asexual parasites, can explain all of these observations.

A penicillinase test incorporated in the rapid carbohydrate fermentation method for rapid detection of beta-lactamase producing Neisseria gonorrhoeae.

A modification of the acidometric (phenol red) test for penicillinase producing N. gonorrhoeae was incorporated into the rapid fermentation method for rapid screening and identification of PPNG strains. Two hundred and twenty-four non-penicillinase-producing N. gonorrhoeae, 55 penicillinase-producing N. gonorrhoeae, 87 N. meningitidis and 89 N. lactamica were included in this study. Results of the modified test were comparable with the iodometric and penicillin disk diffusion susceptibility and were obtainable within 1 to 5 minutes.

In vitro growth inhibition of Plasmodium falciparum by sera from tropical splenomegaly syndrome patients.

Sera from tropical splenomegaly syndrome (TSS) and non-TSS patients from the same village were examined for their ability to inhibit the in vitro growth of Plasmodium falciparum. Using synchronized malaria cultures, sera from both groups inhibited parasite development only if added before merozoite reinvasion of erythrocytes had occurred. There was no significant difference in the degree or apparent mechanism of inhibition caused by TSS and non-TSS sera. These results suggest that the aberrant immune response that results in TSS may not be associated with the elaboration of unique serum factors that differentially inhibit growth of the parasite in vitro.

The Widal slide agglutination test, a valuable rapid diagnostic test in typhoid fever patients at the Infectious Diseases Hospital of Jakarta.

The Widal slide agglutination test was evaluated as a rapid diagnostic test in typhoid fever patients at the Infectious Diseases Hospital, Jakarta, Indonesia from 1980-1982. The results of the test can be available within 45 minutes of patient admission. The study showed that, among 229 patients with Salmonella typhi-positive typhoid fever and 179 control fever patients, when the Widal O antibody titer was greater than or equal to 1:20 the sensitivity was 53%, the specificity 98%, the positive predictive value 96%, and the negative predictive value 68%. A negative Widal test (O antibody titer less than 1:20) does not provide useful information, but when the O antibody titer is greater than or equal to 1:20 the clinician at the Infectious Diseases Hospital of Jakarta can be 96% certain that the patient has typhoid fever.

Susceptibility of Neisseria gonorrhoeae isolates from Jakarta, Indonesia, to antibiotics.

The minimum inhibitory concentration (MIC) of penicillin, tetracycline and spectinomycin was determined for 6 beta-lactamase (PPNG) and 73 non beta-lactamase producing Neisseria gonorrhoeae isolates from Jakarta, Indonesia. All PPNG were resistant to greater than or equal to 128 micrograms/ml penicillin. Forty-six percent of the non-PPNG strains were inhibited by less than or equal to 1.0 microgram/ml of penicillin and 97% by less than or equal to 4 micrograms/ml. Most of the PPNG and non-PPNG isolates (90%) were inhibited by less than or equal to 4 micrograms/ml tetracycline and less than or equal to 16 micrograms/ml spectinomycin. Two non-PPNG strains were resistant to 64 micrograms/ml of tetracycline, 8 micrograms/ml penicillin and 32 micrograms/ml spectinomycin. The non-PPNG strains generally were more resistant to penicillin and tetracycline compared to strains tested from other parts of the world in previously reported studies.

Neisseria gonorrhoeae and penicillinase producing N. gonorrhoeae among some patients in Jakarta Indonesia.

Neisseria gonorrhoeae was isolated from 14 out of 50 (28%) of one group and 35 out of 60 (58%) of a second group of females in different areas of Jakarta, Indonesia. four (7%) of the patients in the second group were infected with penicillinase producing Neisseria gonorrhoeae (PPNG). This may be the first reported isolation of PPNG in Indonesia.

A survey of scrub and murine typhus in the Ancol section of Jakarta, Indonesia.

Rickettsia tsutsugamushi was isolated from L. (L.) arenicola chiggers and three species of rats in an area of scrub and sedge along the Bay of Jakarta. This is the only finding in Indonesia of a cycle of the agent of scrub typhus associated with L. (L.) arenicola. A serologic survey of nearly 300 persons living in two kampungs near the site at which rickettsiae were recovered revealed one individual with antibodies to R. tsutsugamushi. Murine typhus, with a seropositivity rate of 6.5%, may be endemic at low levels.