Treatment Response in Enteric Fever in an Era of Increasing Antimicrobial Resistance: An Individual Patient Data Analysis of 2092 Participants Enrolled into 4 Randomized, Controlled Trials in Nepal.

BACKGROUND.: Enteric fever, caused by Salmonella Typhi and Salmonella Paratyphi A, is the leading cause of bacterial febrile disease in South Asia. METHODS.: Individual data from 2092 patients with enteric fever randomized into 4 trials in Kathmandu, Nepal, were pooled. All trials compared gatifloxacin with 1 of the following comparator drugs: cefixime, chloramphenicol, ofloxacin, or ceftriaxone. Treatment outcomes were evaluated according to antimicrobial if S. Typhi/Paratyphi were isolated from blood. We additionally investigated the impact of changing bacterial antimicrobial susceptibility on outcome. RESULTS.: Overall, 855 (41%) patients had either S. Typhi (n = 581, 28%) or S. Paratyphi A (n = 274, 13%) cultured from blood. There were 139 (6.6%) treatment failures with 1 death. Except for the last trial with ceftriaxone, the fluoroquinolone gatifloxacin was associated with equivalent or better fever clearance times and lower treatment failure rates in comparison to all other antimicrobials. However, we additionally found that the minimum inhibitory concentrations (MICs) against fluoroquinolones have risen significantly since 2005 and were associated with increasing fever clearance times. Notably, all organisms were susceptible to ceftriaxone throughout the study period (2005-2014), and the MICs against azithromycin declined, confirming the utility of these alternative drugs for enteric fever treatment. CONCLUSION.: The World Health Organization and local government health ministries in South Asia still recommend fluoroquinolones for enteric fever. This policy should change based on the evidence provided here. Rapid diagnostics are urgently required given the large numbers of suspected enteric fever patients with a negative culture.

Evaluation of antibiotic sensitivity pattern in cases of enteric fever in north west Rajasthan.

A total of 50 cases of blood culture proved enteric fever were studied for clinical response to the treatment and compared with in vivo antibiotic sensitivity pattern. Out of 50 Salmonella strains isolated, 37 were S typhi and 13 S paratyphi A. All S typhi isolates were sensitive in vitro to gentamicin and ceftriaxone while sensitivity to ciprofloxacin was 73%, ampicillin 29.7%, chloromphenicol 27%, tetracycline 27% and co-trimoxazole 13.5%. Multidrug resistance (Ampicillin, Chloramphenicol, Cotrimoxazale and Tetracycline) was observed in 62% isolates. All Sparatyphi A isolates were sensitive to all the antibiotics. Clinical response to the antibiotic therapy was as follows: Group I--Ampicillin + Gentamicin: 15 cases, clinical response (CR), 9.1% (S typhi) and 75% (S paratyphi A), mean day of defervescence 5.33 days. Group II--Ciprofloxacin: 29 cases, clinical response 47.6% (S typhi) and 75% (S paratyphi A), mean day of defervescence--5.22 days. Group--III Ceftriaxone: 30 cases, clinical response 100% in all, mean day of defervescence--4.93 days. Thus we observed highly significant discrepancy in antibiotic sensitivity pattern of the isolates and clinical response. Most importantly we observed significantly delayed clinical response to the ceftriaxone. This may be indicative of evolving resistance to ceftriaxone.

A case report and review of the literature: ciprofloxacin resistant Salmonella enterica serovar Typhi in India.

BACKGROUND: Enteric fever is a major public health problem in India. The current treatment of choice is the fluoroquinolones. METHODS: The minimum inhibitory concentration (MIC) of ciprofloxacin was determined by E-test, HIMEDIA HiComb MIC test and agar dilution. RESULTS: An isolate of Salmonella enterica serovar Typhi (S. Typhi) from a case of enteric fever gave a ciprofloxacin MIC of 64 microg/ml. CONCLUSIONS: To our knowledge there have been no reports of such high-level resistance to ciprofloxacin in S. Typhi from southern India. HIMEDIA HiComb MIC test method is an alternative to the E-test. Ciprofloxacin resistant typhoid fever responds to treatment with ceftriaxone.

A hospital-based study of bloodstream infections in febrile patients in Dhulikhel Hospital Kathmandu University Teaching Hospital, Nepal.

The etiology of bloodstream infections in febrile patients remain poorly characterized in Nepal. A retrospective study of febrile patients presenting to Dhulikhel Hospital Kathmandu University Teaching Hospital from July 2002 to June 2004 was performed to evaluate the etiology of bloodstream infections and the drug sensitivity patterns of cultured organisms. The medical and laboratory records of all febrile patients with an axillary temperature > or = 38 degrees C who had a blood culture taken (n = 1,774) were retrieved and analyzed. Of these, 122 (6.9%) patients had positive blood cultures, of which 40.1% were age 11 to 20 years. The male to female ratio was 1.7:1. Antibiotics had been taken prior to hospital presentation by 39 (32%) patients. Salmonella enterica serovar Typhi and serovar Paratyphi A were isolated in 50 (41.0%) and 13 (10.7%) cases, respectively. All S. Typhi and S. Paratyphi isolates were susceptible to ceftriaxone, while susceptibility to ciprofloxacin and chloramphenicol was recorded in 94.8% and 94.5% of cases, respectively. Cephalexin and amoxicillin had the lowest rates of susceptibility (64.2% and 54.1%, respectively). Salmonella spp were usually sensitive to chloramphenicol. These findings provide clinicians in this region of Nepal with a better understanding of the spectrum of pathogens causing bloodstream infections and will help guide empiric antibiotic choice.

Multidrug-resistant typhoid fever.

One hundred children (consecutive) with positive blood culture for Salmonella typhi were studied for clinical profile and complications. The common clinical features were fever (100%), vomiting (58%), abdominal pain (48%), cough (22%) and loose stools (14%) and the Widal test was positive in 75% patients. Eighty per cent of the salmonella isolates were resistant to amoxycillin, chloramphenicol and co-trimoxazole drugs, but all were sensitive to ciprofloxacin and ceftriaxone. Forty patients developed complications: encephalopathy (18), melaena (12), haematemesis (10), epistaxis (4), hepatitis (4), acalculous cholecystitis (4), bowel perforation (3) and nephritis (2). Complications were more frequent in children with multidrug-resistant typhoid. The final antibiotic required to render the children afebrile included ciprofloxacin (80), ceftriaxone, amoxycillin (4), chloramphenicol (4), amoxycillin and gentamicin (4), amoxycillin with chloramphenicol (2), and furazolidone (2). The defervesence time was least with ceftriaxone and greatest with amoxycillin. All the affected children made a complete recovery.

Ciprofloxacin for treatment of severe typhoid fever in children.

Eighteen children with bacteriologically confirmed severe typhoid fever were initially treated intravenously with ciprofloxacin (10 mg/kg of body weight per day). Clinical cure with eradication of multiresistant Salmonella typhi infection was observed in 17 patients (94.4%; 95% confidence interval [CI], 84 to 100%). Children regained normal consciousness within an average of 2 days (95% CI, 1.8 to 2.2 days). The temperatures of the children returned to normal within 3.3 days (95% CI, 3.1 to 3.5 days). Complications were not observed during the hospital stay or a 3-month follow-up period. Relapse and carrier state were also not encountered during the follow-up period.

Clinical profile and outcome in enteric fever.

Sixty five blood culture positive cases of S. typhi were studied for clinical profile. A total of 64.6% were multidrug resistant and 35.4% were chloramphenicol sensitive. In patients with multidrug resistant S. typhi the age was higher (p < 0.01), and incidence of complications such as shock (35.7%), encephalopathy (42.9%), myocarditis (14.3%) and gastric hemorrhage (4.7%) were more frequent, compared to chloramphenicol sensitive group. Cases with multidrug resistant S. typhi (MDRST) were treated with oral ciprofloxacin; the period of defervescence of fever was significantly less (p < 0.05) compared to the chloramphenicol group. Our study suggests the use of ciprofloxacin in the treatment of MDRST without any side effects.

Randomized prospective study comparing two dosage regimens of ciprofloxacin for the treatment of typhoid fever.

Sixty-two patients with blood culture-proven typhoid fever were randomly assigned to receive either 500 or 750 mg of ciprofloxacin orally, twice daily for 7 days or for two days following defervescence, whichever was greater. Thirty-four and 28 patients received 500 mg and 750 mg respectively. Strains of Salmonella typhi resistant to ampicillin, chloramphenicol and co-trimoxazole were isolated from the blood of 27 patients (43.5%). No resistance to ciprofloxacin was encountered. Both regimens were equally effective; fever subsided in mean times of 4.9 +/- 1.7 days in the 500 mg group and 5.2 +/- 2.2 days in the 750 mg group (P = 0.54). All patients were cured, although one patient in the 750 mg group experienced a presumed relapse two months following completion of therapy. Ciprofloxacin administered for 7-10 days was adequate treatment for 57 of the 62 patients (92%); only five patients required therapy for more than 10 days. Patients with pretreatment symptoms of > or = 10 days duration defervesced in a mean of 5.7 +/- 2.3 days compared with 4.5 +/- 1.3 days (P = 0.01) for those with symptoms of shorter duration. We conclude that 500 mg of ciprofloxacin taken orally twice daily is adequate treatment for typhoid fever.

Participation of Hageman factor dependent pathways in human disease states.

Abnormalities of Hageman factor dependent pathways have been described in a wide variety of human disease states. Congenital deficiencies of factor XII (Hageman trait) prekallikrein (Fletcher trait) and high molecular weight kininogen (Williams, Fitzgerald and Flaujeac traits) although resulting in profound in vitro changes, do not cause in vivo difficulties. In contrast, deficiency of C1 esterase inhibitor (hereditary angioedema) results in significant morbidity and mortality. Acquired diseases may exhibit decreased synthesis of these three proteins in cirrhosis and dengue fever. In vivo activation of factor XII initiated pathways occur in septic shock, disseminated or localized intravascular coagulation, typhoid fever, polycythemia vera, hyperbetalipoproteinemia, coronary artery disease, nephrotic syndrome, transfusion reactions, hemodialysis and extracorporeal bypass. Activation of both the intrinsic system and tissue mediators contribute to the vasomotor phenomena in carcinoid syndrome and postgastrectomy dumping. Roles for factor XII, prekallikrein and kininogen have been suggested in gouty arthritis, allergic disorders and cystic fibrosis but the evidence is not yet convincing in these disorders.

Antibiotics and the Aberdeen typhoid outbreak in 1964.

This paper gives an abbreviated account of part of a research programme which followed the Aberdeen typhoid outbreak in 1964. Chloramphenicol, the main antibiotic used in treatment, was shown to have a minimum inhibitory concentration (MIC) of between 5 and 2-5 mug./ml. for the S. typhi phage type 34 of the outbreak. The MIC for methacycline was between 5 and 2-5 and 2 mug./ml. Whereas the deep and shallow broth techniques used gave similar results with these antibiotics, the MIC for ampicillin, and also cephaloridine, was less in the deep than in the shallow broths. Serum assays in patients given ampicillin or cephaloridine yielded abnormally high concentrations of both antiboitics when S. typhi phage type 34 was the test organism whereas, with other test organisms, the concentrations were within expectation. These abnormally high values fell within expected values when the sera under investigation had first been heated to 56 degrees C. for 30 min. before assay against the S. typhi of the outbreak. The findings with ampicillin suggested that dosages given were satisfactory. With cephaloridine the concentrations found in patients' sera seemed to show that twice daily doses of 0-5 g. fell short of adequacy.