Variation in human genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese.

The genetic basis for susceptibility to malaria has been studied widely in African populations but less is known of the contribution of specific genetic variants in Asian populations. We genotyped 67 single-nucleotide polymorphisms (SNPs) in 1030 severe malaria cases and 2840 controls from Vietnam. After data quality control, genotyping data of 956 cases and 2350 controls were analysed for 65 SNPs (3 gender confirmation, 62 positioned in/near 42 malarial candidate genes). A total of 14 SNPs were monomorphic and 2 (rs8078340 and rs33950507) were not in Hardy-Weinberg equilibrium in controls (P<0.01). In all, 7/46 SNPs in 6 genes (ICAM1, IL1A, IL17RC, IL13, LTA and TNF) were associated with severe malaria, with 3/7 SNPs in the TNF/LTA region. Genotype-phenotype correlations between SNPs and clinical parameters revealed that genotypes of rs708567 (IL17RC) correlate with parasitemia (P=0.028, r(2)=0.0086), with GG homozygotes having the lowest parasite burden. Additionally, rs708567 GG homozygotes had a decreased risk of severe malaria (P=0.007, OR=0.78 (95% CI; 0.65-0.93)) and death (P=0.028, OR=0.58 (95% CI; 0.37-0.93)) than those with AA and AG genotypes. In summary, variants in six genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese. Further replicative studies in independent populations will be necessary to confirm these findings.

Value of lipocalin 2 as a potential biomarker for bacterial meningitis.

OBJECTIVES: Central nervous system (CNS) infections are common causes of morbidity and mortality worldwide. We aimed to discover protein biomarkers that could rapidly and accurately identify the likely cause of the infections, essential for clinical management and improving outcome. METHODS: We applied liquid chromatography tandem mass spectrometry on 45 cerebrospinal fluid (CSF) samples from a cohort of adults with and without CNS infections to discover potential diagnostic biomarkers. We then validated the diagnostic performance of a selected biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS infections admitted to a referral hospital in Vietnam. RESULTS: In the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of bacterial meningitis (BM) other than tuberculous meningitis. The analysis of the validation cohort showed that LCN2 could discriminate BM from other CNS infections (including tuberculous meningitis, cryptococcal meningitis and virus/antibody-mediated encephalitis), with sensitivity of 0.88 (95% confident interval (CI), 0.77-0.94), specificity of 0.91 (95% CI, 0.88-0.94) and diagnostic odds ratio of 73.8 (95% CI, 31.8-171.4). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) commonly used in routine care worldwide. The combination of LCN2, CSF leukocytes, glucose, protein and lactate resulted in the highest diagnostic performance for BM (area under the receiver operating characteristics curve, 0.96; 95% CI, 0.93-0.99). Data are available via ProteomeXchange with identifier PXD020510. CONCLUSIONS: LCN2 is a sensitive and specific biomarker for discriminating BM from a broad spectrum of other CNS infections. A prospective study is needed to assess the diagnostic utility of LCN2 in the diagnosis and management of CNS infections.

Suboptimal Exposure to Anti-TB Drugs in a TBM/HIV+ Population Is Not Related to Antiretroviral Therapy.

A placebo-controlled trial that compares the outcomes of immediate vs. deferred initiation of antiretroviral therapy in HIV +ve tuberculous meningitis (TBM) patients was conducted in Vietnam in 2011. Here, the pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol were investigated in the presence and absence of anti-HIV treatment in 85 patients. Pharmacokinetic analyses show that HIV therapy has no significant impact on the pharmacokinetics of TB drugs in this cohort. The same population, however, displayed generally low cerebrospinal fluid (CSF) and systemic exposures to rifampicin compared to previously reported HIV -ve cohorts. Elevated CSF concentrations of pyrazinamide, on the other hand, were strongly and independently correlated with increased mortality and neurological toxicity. The findings suggest that the current standard dosing regimens may put the patient at risk of treatment failure from suboptimal rifampicin exposure, and potentially increasing the risk of adverse central nervous system events that are independently correlated with pyrazinamide CSF exposure.

Neuropathological assessment of artemether-treated severe malaria.

In animals, high doses of intramuscular artemether and artemotil have been shown to cause an unusual pattern of selective damage to certain brainstem nuclei, especially those implicated in hearing and balance. We aimed to investigate whether a similar pattern arises in human adults. We examined the brainstems of adults who died after treatment with high dose artemether or quinine for severe falciparum malaria for evidence of a pattern of selective neuronal damage. Neuropathological findings were similar in recipients of quinine (n=15) and artemether (n=6; total artemether doses received 4-44 mg/kg). No evidence was recorded for artemether-induced neurotoxic effects.

Malaria in injection drug abusers in Vietnam.

A prospective case-control study was conducted in a referral hospital in Ho Chi Minh City, Vietnam, to compare the clinical and laboratory features and outcome of severe falciparum malaria in injection drug abusers (IDAs) with those of patients who had acquired malaria by mosquito bite. From 1991 to 1996, 70 IDAs were admitted to the hospital, of whom at least 32 had acquired malaria by needle sharing. Although IDAs were more likely than control patients with severe malaria to be malnourished and to have coincident hepatitis B, hepatitis C, and human immunodeficiency virus infections, the overall rates of mortality, complications, and recovery were similar in the 2 groups. The route of malaria acquisition did not affect the outcome of severe malaria. The management of severe malaria in IDAs is similar to that for other patients.

Clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain-stem function in Vietnamese patients.

The qinghaosu (artemisinin) group of drugs is the most important new class of antimalarials developed in the last fifty years. Although there has been no clinical evidence of neurotoxicity, an unusual pattern of damage to specific brain-stem nuclei has been reported in experimental animals receiving high doses of arteether or artemether. Detailed clinical examinations, audiometry, and brain stem auditory evoked potentials (BSAEPs) were assessed in 242 Vietnamese subjects who had previously received up to 21 antimalarial treatment courses of artemisinin or artesunate alone and 108 controls from the same location who had not received these drugs. There was no evidence of a drug effect on the clinical or neurophysiological parameters assessed. In this population there was no clinical or neurophysiological evidence of brain-stem toxicity that could be attributed to exposure to artemisinin or artesunate.

Isoniazid resistance, mycobacterial genotype and outcome in Vietnamese adults with tuberculous meningitis.

SETTING: Centre for Tropical Diseases, a 500-bed hospital for infectious diseases in Ho Chi Minh City, Vietnam. OBJECTIVE: The factors that determine outcome in adults with tuberculous meningitis are poorly understood. The objective of the study was to investigate the relationship between admission clinical features, HIV infection, drug resistance, mycobacterial genotype and outcome in adults with tuberculous meningitis. DESIGN: Clinical and laboratory data were recorded prospectively for 56 Vietnamese adults with tuberculous meningitis confirmed by culture of cerebrospinal fluid. Variables associated with in-hospital mortality, IV infection, drug resistance and microbial genotype were assessed by univariate and multivariate analysis. RESULTS: Admission coma score independently predicted death in hospital (OR 0.73, 95%CI 0.61-0.87, P = 0.001). HIV-infected adults with tuberculous meningitis were more likely to be infected with Mycobacterium tuberculosis resistant to isoniazid (P = 0.011) and streptomycin (P = 0.002). Isoniazid resistance, streptomycin resistance, HIV infection and microbial genotype were not associated with increased in-hospital mortality. CONCLUSION: Treatment of tuberculous meningitis before the onset of coma saves lives. Resistance to isoniazid and/or streptomycin does not appear to affect outcome.

An open randomized comparison of intravenous and intramuscular artesunate in severe falciparum malaria.

An open paired randomized comparison of intramuscular and intravenous artesunate was conducted in 28 adult patients with severe falciparum malaria. The dose regimen in both groups was 2 mg/kg given immediately followed by 1 mg/kg at 12 and 24 h, and then daily until the patient could swallow. Both routes of administration were well tolerated and there was no evidence of toxicity. One patient in each treatment group died. Clinical and parasitological measures of recovery in survivors were similar in the 2 groups with mean fever clearance times of 37.3 h (standard deviation [SD] = 26.1 h) and 31.5 h (SD = 24.2 h) and mean parasite clearance times of 33.4 h (SD = 13.9 h) and 29.4 h (SD = 12.7 h) in the intravenous and intramuscular groups respectively. Artesunate is equally effective and well tolerated when given by the intravenous or intramuscular routes.

Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria.

Seventy-nine comatose cerebral malaria patients given standard supportive treatment were randomized to receive specific antimalarial chemotherapy of intravenous quinine, intravenous artesunate, or artemisinin suppositories. Artesunate and artemisinin reduced peripheral asexual parasitaemia significantly more rapidly than quinine (90% clearance time 16 h, 18.9 h and 34.5 h respectively), but did not significantly reduce the duration of coma or mortality. The rapid lowering of peripheral parasitaemia may not ameliorate complications already present. These results demonstrate that artemisinin suppositories are as effective as artesunate and quinine given intravenously, and have economic and practical advantages for the treatment of severe malaria in areas remote from major medical centres. However, large numbers of patients will need to be studied if differences in mortality between the 3 treatment groups are to be demonstrated.

Reactive nitrogen intermediates and outcome in severe adult malaria.

The role of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in the pathophysiology of severe falciparum malaria remains unclear. We conducted a retrospective case-control study of Vietnamese adults with severe malaria to determine the relationship between outcome and admission plasma reactive nitrogen intermediates (RNI), the stable metabolites of NO. The study was designed to take into account the potential confounders of recent dietary nitrogen intake and renal function. Seventy-six patients who died from severe malaria were matched for age and sex with 76 survivors from a prospectively studied series of 560 patients. Median untransformed unadjusted plasma RNI levels were slightly higher in fatal cases (45 mumol/L, range 0-482) than in survivors (24.1 mumol/L, range 1.4-466) (P = 0.031, Wilcoxon signed-rank). There was a significant positive correlation between RNI levels and plasma creatinine (Spearman's rho = 0.35, P < 0.0001), and the addition of plasma creatinine as a covariate in a multivariate analysis abolished the trend towards higher RNI levels in fatal cases (P for the coefficient for RNI = 0.96). There was no association between RNI levels and either depth of coma on admission or time to regain consciousness. These findings do not support a pivotal role for systemic generation of NO in the pathogenesis of severe malaria in general, or cerebral malaria in particular.

An evaluation of the usefulness of neuroimaging for the diagnosis of Japanese encephalitis.

Japanese encephalitis virus (JEV) is estimated to cause 30­50,000 cases of encephalitis every year. The disease occurs mainly in rural Asia and is transmitted to humans from birds and pigs by mosquitoes of the genus Culex. JE is diagnosed with antibody testing of the serum and CSF, but this is not available in many hospitals. Neuroimaging abnormalities, particularly thalamic hypodensity on computed tomography (CT) and hyperintensity on T2 weighted magnetic resonance imaging (MRI) have been described in case studies, but their usefulness for diagnosing JE is not known. We have therefore evaluated the usefulness of neuroimaging (CT and MRI) for the diagnosis of JE. The findings of thalamic lesions were compared with the final serological diagnosis in a cohort of 75 patients (children and adults) with suspected CNS infections in Southern Vietnam, a JEV endemic area. Thalamic lesions on CT and/or MRI combined had sensitivity 23% (95% confidence interval 12.9­33.1%), specificity 100%, positive predictive value 100% and negative predictive value 42.1% (95% confidence interval 30.2­53.8%) for a diagnosis of JE in this cohort. Over time, the thalamic lesions resolved in some patients. One patient showed disappearance of lesions on CT followed by reappearance of the lesions some time later, known as the fogging effect. In this setting, the presence of thalamic abnormalities suggested the diagnosis of JE, but their absence did not exclude it.

Cerebral calpain in fatal falciparum malaria.

Disruption of axonal transport may represent a final common pathway leading to neurological dysfunction in cerebral malaria (CM). Calpains are calcium (Ca2+)-activated cysteine proteases which have been implicated in axonal injury in neurological diseases of various aetiologies. In this study we examined the association between mu- and m-calpain, the specific inhibitor calpastatin, and axonal injury in post mortem brain tissue from patients who died from severe malaria. Calpains were associated with axons labelled for the beta-amyloid precursor protein that detects impaired axonal transport. Elevated levels of calpastatin were rarely observed in injured axons. There were increased numbers of neurones with mu-calpain in the nuclear compartment in severe malaria cases compared with non-neurological controls, and increased numbers of glia with nuclear mu-calpain in CM patients compared with non-CM malaria cases and non-neurological controls. There was marked redistribution of calpastatin in the sequestered Plasmodium falciparum-infected erythrocytes. Responses specific to malaria infection were ascertained following analysis of brain samples from fatal cases with acute axonal injury, HIV encephalitis, and progressive multifocal leucoencephalopathy. Our findings implicate a role for calpains in the modulation of disease progression in CM.

The effects of dopamine and adrenaline infusions on acid-base balance and systemic haemodynamics in severe infection.

BACKGROUND: Adrenaline is used increasingly in the management of septic shock, but its efficacy and safety are uncertain. METHODS: In an open, randomised, crossover study we compared the effects of stepped doses of adrenaline 0.1 to 0.5 microgram/kg per min and dopamine 2.5 to 10 micrograms/kg per min on the haemodynamic and acid-base status of 23 patients critically ill with severe sepsis (n = 10) or severe malaria (n = 13). FINDINGS: All patients completed the dopamine study whereas in 16 (84%) patients the adrenaline infusion had to be terminated before reaching, or during, the maximum dose because of lactic acidosis (p < 0.0002). Adrenaline was associated with a mean (95% CI) increase in plasma lactate of 3.2 (2.6 to 3.8) mmol/L, and mean falls in arterial pH of 0.052 (0.035-0.068) pH units and base excess of 3.8 (2.8-4.7) mmol/L. The geometric mean (95% CI) lactate increment per unit adrenaline dose was 8.2 (5.8-10.5) mmol/L per microgram/kg per min. In contrast dopamine was associated with a fall in lactate of 1.0 (0.4-1.5) mmol/L, a rise in base excess of 1.4 (0.7 to 2.0) mmol/L (p < 0.0001 in each case), and no effect on arterial pH. Both drugs induced significant increases in cardiac index and oxygen delivery with smaller increases in oxygen consumption and falls in systemic vascular resistance which were similar in severe malaria and severe sepsis (p > 0.1 in each case) [corrected]. INTERPRETATION: Infusion of inotropic doses of adrenaline in severe infections causes lactic acidosis.

Age-related changes in microvascular permeability: a significant factor in the susceptibility of children to shock?

During studies of the pathogenesis of dengue shock syndrome, a condition largely confined to childhood and characterized by a systemic increase in vascular permeability, we observed that healthy controls, age-matched to children with dengue shock syndrome, gave high values of filtration capacity (K(f)), a factor describing vascular permeability. We hypothesized that K(f) might be age dependent. Calf K(f) was studied in 89 healthy Vietnamese subjects aged 5 to 77 years. The K(f) was highest in the youngest children [7. 53 (1.96-15.46) K(f)U; median (range); where the units of K(f), K(f)U=ml.min(-1).100 ml(-1).mmHg(-1)]. Values were 3- to 4-fold lower towards the end of the second decade [4.69 (1.91-7.06) K(f)U]. Young mammals are known to have a larger microvascular surface area per unit volume of skeletal muscle than adults. During development the proportion of developing vessels is greater. Moreover, the novel microvessels are known to be more permeable to water and plasma proteins than when mature. These factors may explain why children more readily develop hypovolaemic shock than adults in dengue haemorrhagic fever and other conditions characterized by increased microvascular permeability.

A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain.

Microvascular sequestration was assessed in the brains of 50 Thai and Vietnamese patients who died from severe malaria (Plasmodium falciparum, 49; P. vivax, 1). Malaria parasites were sequestered in 46 cases; in 3 intravascular malaria pigment but no parasites were evident; and in the P. vivax case there was no sequestration. Cerebrovascular endothelial expression of the putative cytoadherence receptors ICAM-1, VCAM-1, E-selectin, and chondroitin sulfate and also HLA class II was increased. The median (range) ratio of cerebral to peripheral blood parasitemia was 40 (1.8 to 1500). Within the same brain different vessels had discrete but different populations of parasites, indicating that the adhesion characteristics of cerebrovascular endothelium change asynchronously during malaria and also that significant recirculation of parasitized erythrocytes following sequestration is unlikely. The median (range) ratio of schizonts to trophozoites (0.15:1; 0.0 to 11.7) was significantly lower than predicted from the parasite life cycle (P < 0.001). Antimalarial treatment arrests development at the trophozoite stages which remain sequestered in the brain. There were significantly more ring form parasites (age < 26 hours) in the cerebral microvasculature (median range: 19%; 0-90%) than expected from free mixing of these cells in the systemic circulation (median range ring parasitemia: 1.8%; 0-36.2%). All developmental stages of P. falciparum are sequestered in the brain in severe malaria.

Cellular stress and injury responses in the brains of adult Vietnamese patients with fatal Plasmodium falciparum malaria.

Immunohistochemical techniques have been used to investigate specific patterns of potentially reversible cellular injury, DNA damage, and apoptosis in the brainstems of Vietnamese patients who died of severe Plasmodium falciparum malaria. The degree and pattern of neuronal and glial stress responses were compared between patients with cerebral and non-cerebral malaria (CM), and appropriate non-malaria infected controls. The following markers were examined: (i) heat shock protein 70 (HSP70), for reversible injury; (ii) heme oxygenase-1, for oxidative stress; (iii & iv) two DNA-repair proteins, poly(ADP) ribose polymerase (PARP) and DNA-dependent protein kinase catalytic subunit; (v) poly(ADP) ribose, an end-product of PARP activity; and (vi) caspase-3-active, for apoptosis. Stress responses were found in a range of cell types as reflected by the widespread expression of HSP70. Oxidative stress predominated in the vicinity of vessels and haemorrhages. Some degree of DNA damage was found in the majority of malaria patients, but the distribution and frequency of the damage was much less than that observed in controls with irreversible neuronal injury. Similarly, caspase-3-active expression, as a measure of apoptosis, was no higher in the majority of malaria patients than the negative control cases, although 40% of CM cases expressed caspase-3-active in a small number of neurones of the pontine nuclei or within swollen axons of the pontocerebellar and corticospinal tracts. In conclusion, cells within the brainstem of all patients who died from severe malaria showed staining patterns indicative of considerable stress response and reversible neuronal injury. There was no evidence for a specific pattern of widespread irreversible cell damage in those patients with cerebral malaria.

The pathophysiologic and prognostic significance of acidosis in severe adult malaria.

OBJECTIVE: To investigate the pathophysiology and prognostic significance of acidosis in severe adult malaria. DESIGN: Cohort study. SETTING: The intensive care unit of an infectious diseases hospital in southern Vietnam. PATIENTS: Three hundred forty-six consecutive adult patients with severe falciparum malaria. INTERVENTIONS: Measurements of baseline venous lactate and pyruvate concentrations and an extensive range of clinical and laboratory variables were made, and patients were followed up carefully until death or discharge from the hospital. Admission arterial blood pH and gas tensions were recorded in 296 patients, and hepatic venous sampling was done in 12 patients. MEASUREMENTS AND MAIN RESULTS: Overall, 198 (67%) patients were acidotic (standard base deficit [SBD], >3.3 mmol/L [n = 196], or arterial Pco2, >45 torr [6 kPa] [n = 3]). Hyperlactatemia (plasma lactate, >4 mmol/L) occurred in 120 (35%) of the 346 patients and was associated significantly with acidosis (p < .0001). The hepatosplanchnic lactate extraction ratio was negatively correlated with mixed venous plasma lactate (r2 = .50; p = .006). Hyperlactatemia, metabolic acidosis (SBD, >3.3), and acidemia (pH <7.35) were strongly positively associated with a fatal outcome (relative risks [95% confidence interval], 4.3 [range, 1.8-10.6], 5.0 [range, 3.0-8.1], and 2.7 [range, 1.8-4.1], respectively). The SBD was the single best clinical or laboratory predictor of fatal outcome. The overall median lactate/pyruvate ratio was raised at 30.6 (range, 20.6-62.3; normal range, <15), suggesting hypoxia and anaerobic glycolysis, and was significantly higher in fatal cases (p < .0001). In an additive multivariate model, the two main independent contributors to metabolic acidosis were plasma creatinine, as a measure of renal dysfunction, and venous plasma lactate, together accounting for 63% of the variance in SBD. In univariate analyses, they contributed 29% and 38%, respectively. CONCLUSIONS: These results confirm the importance of acidosis in the pathophysiology of severe adult malaria and suggest a multifactorial origin involving tissue hypoxia, liver dysfunction, and impaired renal handling of bicarbonate.

Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria.

The first-dose pharmacokinetic properties of intramuscular (i.m.) artesunate (ARTS; 2.4 mg/kg immediately [stat], followed by 1.2 mg/kg i.m. daily) and artemether (ARM; 3.2 mg/kg i.m. stat, followed by 1.6 mg/kg i.m. daily) were compared in Vietnamese adults with severe falciparum malaria. A total of 19 patients were studied; 9 received ARTS, and 10 received ARM. ARTS was absorbed very rapidly; concentrations in plasma peaked between 1,362 and 8,388 nmol/liter (median, 5,710 nmol/liter) within 20 min of injection and then declined with a median (range) half-life (t(1/2)) of 30 (3 to 67) min. ARTS was hydrolyzed rapidly and completely to the biologically active metabolite dihydroartemisinin (DHA). Peak DHA concentrations in plasma ranged between 1,718 and 7,080 nmol/liter (median, 3,060 nmol/liter) and declined with a t(1/2) of 52 (26 to 69) min. In contrast, ARM was slowly and erratically absorbed. The absorption profile appeared biphasic. Maximum ARM concentrations in plasma ranged between 67 nmol/liter (a value close to the 50% inhibitory concentration for some Plasmodium falciparum isolates) and 1,631 nmol/liter (median, 574 nmol/liter) and occurred at a median (range) of 10 (1.5 to 24) h. There was relatively little conversion to DHA. After i.m. injection in cases of severe malaria, absorption of the water-soluble ARTS is rapid and extensive, whereas the oil-based ARM is slowly and erratically absorbed, with relatively little conversion to the more active DHA. On the basis of this pharmacological study, parenteral ARTS is preferable to ARM as an initial antimalarial therapy, particularly in the most seriously ill patients. These findings should be formally assessed by a randomized clinical trial.

Acute renal failure in patients with severe falciparum malaria.

Since 1988 in this referral center for severe cases of malaria for South Vietnam, a specialist team has managed malaria-associated renal failure (MARF) with peritoneal dialysis, and the mortality rate of MARF has fallen from 75% (78 of 104) to 26% (27 of 104) (P < .0002). Sixty-four patients with MARF (of whom 12 died) were compared to 66 patients with severe malaria whose serum creatinine levels remained < 250 mumol/L (six died). MARF had the clinical and biochemical features of acute tubular necrosis and was significantly associated with liver dysfunction (P < .05). A fatal outcome was associated significantly with anuria, a short history of illness, multisystem involvement, and high parasitemia. Most patients died from complications related to renal failure. Recovery of renal function was unrelated to parasitemia or hemoglobinuria; the median (range) time until urine output exceeded 20 mL/(kg.d) was 4 (0-19) days, and the time (mean +/- SD) for serum creatinine level to return to normal was 17 +/- 6 days. MARF can be managed effectively by prompt and careful peritoneal dialysis, but more effective dialysis or diafiltration might reduce the mortality rate further.

Nasal carriage in Vietnamese children of Streptococcus pneumoniae resistant to multiple antimicrobial agents.

Resistance to antimicrobial agents in Streptococcus pneumoniae is increasing rapidly in many Asian countries. There is little recent information concerning resistance levels in Vietnam. A prospective study of pneumococcal carriage in 911 urban and rural Vietnamese children, of whom 44% were nasal carriers, was performed. Carriage was more common in children <5 years old than in those >/=5 years old (192 of 389 [49.4%] versus 212 of 522 [40.6%]; P, 0.01). A total of 136 of 399 isolates (34%) had intermediate susceptibility to penicillin (MIC, 0.1 to 1 mg/liter), and 76 of 399 isolates (19%) showed resistance (MIC, >1.0 mg/liter). A total of 54 of 399 isolates (13%) had intermediate susceptibility to ceftriaxone, and 3 of 399 isolates (1%) were resistant. Penicillin resistance was 21.7 (95% confidence interval, 7.0 to 67.6) times more common in urban than in rural children (35 versus 2%; P, <0.001). More than 40% of isolates from urban children were also resistant to erythromycin, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline. Penicillin resistance was independently associated with an urban location when the age of the child was controlled for. Multidrug resistance (resistance to three or more antimicrobial agent groups) was present in 32% of isolates overall but in 39% of isolates with intermediate susceptibility to penicillin and 86% of isolates with penicillin resistance. The predominant serotypes of the S. pneumoniae isolates were 19, 23, 14, 6, and 18. Almost half of the penicillin-resistant isolates serotyped were serotype 23, and these isolates were often multidrug resistant. This study suggests that resistance to penicillin and other antimicrobial agents is common in carriage isolates of S. pneumoniae from children in Vietnam.