[Show abstract][Hide abstract] ABSTRACT: Background: Streptococcus suis infection, an emerging zoonosis, is an increasing public health problem across South East Asia and the most common cause of acute bacterial meningitis in adults in Vietnam. Little is known of the risk factors underlying the disease.
[Show abstract][Hide abstract] ABSTRACT: Streptococcus suis infection, an emerging zoonosis, is an increasing public health problem across South East Asia and the most common cause of acute bacterial meningitis in adults in Vietnam. Little is known of the risk factors underlying the disease.
A case-control study with appropriate hospital and matched community controls for each patient was conducted between May 2006 and June 2009. Potential risk factors were assessed using a standardized questionnaire and investigation of throat and rectal S. suis carriage in cases, controls and their pigs, using real-time PCR and culture of swab samples. We recruited 101 cases of S. suis meningitis, 303 hospital controls and 300 community controls. By multivariate analysis, risk factors identified for S. suis infection as compared to either control group included eating "high risk" dishes, including such dishes as undercooked pig blood and pig intestine (OR(1) = 2.22; 95%CI = [1.15-4.28] and OR(2) = 4.44; 95%CI = [2.15-9.15]), occupations related to pigs (OR(1) = 3.84; 95%CI = [1.32-11.11] and OR(2) = 5.52; 95%CI = [1.49-20.39]), and exposures to pigs or pork in the presence of skin injuries (OR(1) = 7.48; 95%CI = [1.97-28.44] and OR(2) = 15.96; 95%CI = [2.97-85.72]). S. suis specific DNA was detected in rectal and throat swabs of 6 patients and was cultured from 2 rectal samples, but was not detected in such samples of 1522 healthy individuals or patients without S. suis infection.
This case control study, the largest prospective epidemiological assessment of this disease, has identified the most important risk factors associated with S. suis bacterial meningitis to be eating 'high risk' dishes popular in parts of Asia, occupational exposure to pigs and pig products, and preparation of pork in the presence of skin lesions. These risk factors can be addressed in public health campaigns aimed at preventing S. suis infection.
PLoS ONE 01/2011; 6(3):e17604. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The emergence of drug resistant typhoid fever is a major public health problem, especially in Asia. An oral single dose typhoid vaccine would have major advantages. M01ZH09 is a live oral single dose candidate typhoid vaccine containing Salmonella enterica serovar Typhi (Ty2 aroC(-)ssaV(-)) ZH9 with two independently attenuating deletions. Studies in healthy adults demonstrated immunogenicity and an acceptable safety profile.
We conducted a randomised placebo controlled, single-blind trial to evaluate the safety and immunogenicity of M01ZH09 in healthy Vietnamese children aged 5 to 14 years.
Subjects were randomly assigned to receive either a nominal dose of 5x10(9) CFU of M01ZH09 or placebo and were followed up for 28 days. The primary safety outcome was the proportion of subjects with any adverse event attributed to M01ZH09. The primary immunogenicity endpoint was the proportion of subjects who showed a positive immune response to M01ZH09 in the Salmonella Typhi lipopolysaccharide (LPS) specific serum IgA and IgG ELISA.
One hundred and fifty-one children were enrolled, 101 subjects received M01ZH09 and 50 subjects received placebo. An intention to treat analysis was conducted. There were no serious adverse events and no bacteraemias. In the M01ZH09 group, 26 (26%; 95% CI, 18-5%) of 101 subjects experienced adverse events compared to 11 (22%; 95% CI, 12-36%) of 50 subjects in the placebo group (odds ratio (OR) [95%CI] = 1.23 [0.550-2.747]; p = 0.691). Faecal shedding of S. Typhi (Ty2 aroC(-)ssaV(-)) ZH9 was detected in 51 (51%; 95% CI, 41-61%) of 100 M01ZH09 subjects. No shedding was detected beyond day 3. A positive immune response, defined as 70% increase (1.7 fold change) in LPS specific serum IgG (day 14 or 28) and/or 50% increase (1.5 fold change) in LPS specific serum IgA (day 7 or 14) from baseline was detected in 98 (97%; 95% CI, 92-99%) of 101 M01ZH09 recipients and 8 (16%; 95% CI, 7-29%) of 50 placebo recipients. Twenty-eight (100%; 95% CI, 88-100%) of 28 vaccine recipients who were evaluated in the LPS specific IgA ELISPOT assay showed a positive response compared to none of the 14 placebo recipients tested.
This was the first phase II trial of a novel oral candidate typhoid vaccine in children in an endemic country. M01ZH09 had an appropriate safety profile and was immunogenic in children.
PLoS ONE 01/2010; 5(7):e11778. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug resistant typhoid fever is a major clinical problem globally. Many of the first line antibiotics, including the older generation fluoroquinolones, ciprofloxacin and ofloxacin, are failing.
We performed a randomised controlled trial to compare the efficacy and safety of gatifloxacin (10 mg/kg/day) versus azithromycin (20 mg/kg/day) as a once daily oral dose for 7 days for the treatment of uncomplicated typhoid fever in children and adults in Vietnam.
An open-label multi-centre randomised trial with pre-specified per protocol analysis and intention to treat analysis was conducted. The primary outcome was fever clearance time, the secondary outcome was overall treatment failure (clinical or microbiological failure, development of typhoid fever-related complications, relapse or faecal carriage of S. typhi).
We enrolled 358 children and adults with suspected typhoid fever. There was no death in the study. 287 patients had blood culture confirmed typhoid fever, 145 patients received gatifloxacin and 142 patients received azithromycin. The median FCT was 106 hours in both treatment arms (95% Confidence Interval [CI]; 94-118 hours for gatifloxacin versus 88-112 hours for azithromycin), (logrank test p = 0.984, HR [95% CI] = 1.0 [0.80-1.26]). Overall treatment failure occurred in 13/145 (9%) patients in the gatifloxacin group and 13/140 (9.3%) patients in the azithromycin group, (logrank test p = 0.854, HR [95% CI] = 0.93 [0.43-2.0]). 96% (254/263) of the Salmonella enterica serovar Typhi isolates were resistant to nalidixic acid and 58% (153/263) were multidrug resistant.
Both antibiotics showed an excellent efficacy and safety profile. Both gatifloxacin and azithromycin can be recommended for the treatment of typhoid fever particularly in regions with high rates of multidrug and nalidixic acid resistance. The cost of a 7-day treatment course of gatifloxacin is approximately one third of the cost of azithromycin in Vietnam.
PLoS ONE 02/2008; 3(5):e2188. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is uncertain whether all adults with bacterial meningitis benefit from treatment with adjunctive dexamethasone.
We conducted a randomized, double-blind, placebo-controlled trial of dexamethasone in 435 patients over the age of 14 years who had suspected bacterial meningitis. The goal was to determine whether dexamethasone reduced the risk of death at 1 month and the risk of death or disability at 6 months.
A total of 217 patients were assigned to the dexamethasone group, and 218 to the placebo group. Bacterial meningitis was confirmed in 300 patients (69.0%), probable meningitis was diagnosed in 123 patients (28.3%), and an alternative diagnosis was made in 12 patients (2.8%). An intention-to-treat analysis of all the patients showed that dexamethasone was not associated with a significant reduction in the risk of death at 1 month (relative risk, 0.79; 95% confidence interval [CI], 0.45 to 1.39) or the risk of death or disability at 6 months (odds ratio, 0.74; 95% CI, 0.47 to 1.17). In patients with confirmed bacterial meningitis, however, there was a significant reduction in the risk of death at 1 month (relative risk, 0.43; 95% CI, 0.20 to 0.94) and in the risk of death or disability at 6 months (odds ratio, 0.56; 95% CI, 0.32 to 0.98). These effects were not found in patients with probable bacterial meningitis. Results of multivariate analysis indicated that dexamethasone treatment for patients with probable bacterial meningitis was significantly associated with an increased risk of death at 1 month, an observation that may be explained by cases of tuberculous meningitis in the treatment group.
Dexamethasone does not improve the outcome in all adolescents and adults with suspected bacterial meningitis; a beneficial effect appears to be confined to patients with microbiologically proven disease, including those who have received prior treatment with antibiotics. (Current Controlled Trials number, ISRCTN42986828 [controlled-trials.com] .).
New England Journal of Medicine 01/2008; 357(24):2431-40. · 51.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Infections with community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) are emerging worldwide. We investigated an outbreak of severe CA-MRSA infections in children following out-patient vaccination.
We carried out a field investigation after adverse events following immunization (AEFI) were reported. We reviewed the clinical data from all cases. S. aureus recovered from skin infections and from nasal and throat swabs were analyzed by pulse-field gel electrophoresis, multi locus sequence typing, PCR and microarray. In May 2006, nine children presented with AEFI, ranging from fatal toxic shock syndrome, necrotizing soft tissue infection, purulent abscesses, to fever with rash. All had received a vaccination injection in different health centres in one District of Ho Chi Minh City. Eight children had been vaccinated by the same health care worker (HCW). Deficiencies in vaccine quality, storage practices, or preparation and delivery were not found. Infection control practices were insufficient. CA-MRSA was cultured in four children and from nasal and throat swabs from the HCW. Strains from children and HCW were indistinguishable. All carried the Panton-Valentine leukocidine (PVL), the staphylococcal enterotoxin B gene, the gene complex for staphylococcal-cassette-chromosome mec type V, and were sequence type 59. Strain HCM3A is epidemiologically unrelated to a strain of ST59 prevalent in the USA, although they belong to the same lineage.
We describe an outbreak of infections with CA-MRSA in children, transmitted by an asymptomatic colonized HCW during immunization injection. Consistent adherence to injection practice guidelines is needed to prevent CA-MRSA transmission in both in- and outpatient settings.
[Show abstract][Hide abstract] ABSTRACT: One of the most serious complications of typhoid fever is intestinal perforation. Of 27 patients admitted to a provincial hospital in the Mekong Delta region of Vietnam who had gastrointestinal perforation secondary to suspected typhoid fever, 67% were male, with a median age of 23 years and a median duration of illness of 10 days. Salmonella enterica subspecies enterica serotype Typhi (S. Typhi) was isolated from 11 (41%) of 27 patients; of 27 patients, only 4 (15%) had positive cultures from gut biopsies. S. Typhi DNA was detected by polymerase chain reaction for all perforation biopsy samples. Detailed histological examination of the gastrointestinal mucosa at the site of perforation in all cases showed a combination of discrete acute and chronic inflammation. Acute inflammation at the serosal surface indicated additional tissue damage after perforation. Immunohistochemical results showed that the predominant infiltrating cell types at the site of perforation were CD68+ leukocytes (macrophages) or CD3+ leukocytes (T lymphocytes).
[Show abstract][Hide abstract] ABSTRACT: Enteric fever is the only bacterial infection of humans for which bone marrow examination is routinely recommended. A prospective study of the concentrations of bacteria in the bone marrow and their relationship to clinical features was conducted with 120 Vietnamese patients with suspected enteric fever, of whom 89 had confirmed typhoid fever. Ninety-three percent of the Salmonella enterica serovar Typhi samples isolated were resistant to ampicillin, chloramphenicol, and co-trimoxazole. For 81 patients with uncomplicated typhoid and satisfactory bone marrow aspirates, the number of serovar Typhi CFU in bone marrow aspirates was a median value of 9 (interquartile range [IQR], 1 to 85; range, 0.1 to 1,580) compared to 0.3 (IQR, 0.1 to 10; range, 0.1 to 399) CFU/ml in simultaneously sampled blood. The ratio of individual blood counts to bone marrow counts was 10 (IQR, 2.3 to 97.5). The number of bacteria in blood but not bone marrow was correlated inversely with the duration of preceding fever. Thus, with increasing duration of illness the ratio of bone marrow-to-blood bacterial concentrations increased; the median ratio was 4.8 (IQR, 1 to 27.5) during the first week compared with 158 (IQR, 60 to 397) during the third week. After lysing the host cells, the median ratio of viable bone marrow to blood increased, reflecting the higher concentration of intracellular serovar Typhi in the bone marrow. Effective antibiotic pretreatment had a significantly greater effect in reducing blood counts compared to bone marrow counts (P < 0.001). Thus, bacteria in the bone marrow of typhoid patients are less affected by antibiotic treatment than bacteria in the blood. The numbers of bacteria in bone marrow correlated negatively with the white blood cell (R = -0.3, P = 0.006) and platelet counts (R = -0.32, P = 0.01) and positively with fever clearance time after treatment (R = 0.4, P < 0.001). The bacterial load in bone marrow therefore may reflect the clinical course of the infection, and high levels may suppress neutrophil proliferation.
Journal of Clinical Microbiology 04/2001; 39(4):1571-6. · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Typhoid fever continues to be a major public health problem in tropical countries, exacerbated in recent years by the spread of multi-drug resistant strains of Salmonella typhi. Short treatment courses of fluoroquinolones are effective, and have the advantage of reduced cost and increased compliance, but the optimal length of treatment is unknown. In an open, randomized comparison, 107 adults with uncomplicated enteric fever (95 of whom had positive blood cultures for S. typhi and 5 for S. paratyphi) were treated with oral ofloxacin, 15 mg/kg/d for 2 d or 10 mg/kg/d for 3 d. Mean fever clearance times were the same in the 2 treatment groups (97 h). There were 7 treatment failures, one in the 2 d group and 6 in the 3 d group (P = 0.07). Three of the 5 patients infected with nalidixic acid resistant strains of S. typhi had treatment failures, compared with 4 of 90 with nalidixic acid sensitive isolates (P < 0.0001; relative risk 13.5, 95% confidence interval 4.1-43%). Treatment with ofloxacin for 2 or 3 d is equally effective in adults with uncomplicated enteric fever caused by nalidixic acid sensitive strains of S. typhi. The epidemiology and management of nalidixic acid resistent typhoid needs further investigation.
Transactions of the Royal Society of Tropical Medicine and Hygiene 01/1997; 91(3):347-9. · 1.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In recent years, multiresistant strains of Salmonella typhi have emerged in many tropical countries. These strains remain highly sensitive to the fluoroquinolone antibiotics, although use of these drugs by children is considered contraindicated because of their reported toxicity in the cartilage of experimental animals. In a paired, open, randomized study during an epidemic of multidrug-resistant typhoid in southern Vietnam, two short-course ofloxacin regimens (15 mg/kg daily for 3 days and 10 mg/kg daily for 5 days) were compared for the treatment of uncomplicated typhoid fever. Of 438 patients enrolled (of whom 286 were < or = 14 years old), 228 had blood cultures positive for Salmonella species (S. typhi, 207; S. paratyphi A, 19; and S. choleraesuis, 2). There was one treatment failure in a patient who took only one dose of ofloxacin. Otherwise, both regimens were completely effective; there were no proven carriers, and there was no evidence of toxicity, particularly in children. A 3-day course of ofloxacin proved to be safe and highly effective in the treatment of uncomplicated, multidrug-resistant typhoid fever.