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Typhoid fever: could dual antibiotic therapy be more effective?

Multi-arm, parallel, open-label comparative trial in Indian subcontinent.

Combination therapy of third-generation cephalosporins and azithromycin for patients with typhoid fever (TF) is better than monotherapy in terms of fever clearance time (FCT) and time to elimination of bacteraemia, according to recent study published in the journal PLoS.

Researchers evaluated 105 patients with TF, of which 54 hospitalised patients were randomly assigned to receive dual therapy (n=30; intravenous (IV) ceftriaxone+azithromycin) or monotherapy (n=24; IV ceftriaxone alone) and 51 outpatients were randomly assigned to receive dual therapy (n=24; oral azithromycin+cefixime) or monotherapy (n=27; oral azithromycin). FCT and bacteremia clearance time was assessed in all the four groups.

FCT was significantly shorter for patients who received dual combination therapy compared with patients who received monotherapy including both hospitalised and outpatient subgroups (88 vs 95 hours; P=.004). On day 3, proportionately more number of patients receiving monotherapy were detected with bacteraemia positive blood culture compared with patients on dual therapy (8/47 [17%] vs 2/51 [4%]; P=.045). No significant difference in FCT was observed in patients infected with S. typhi and S. paratyphi (all study arms together; P=.118). No adverse events reported in any of the groups.

"Findings from the study propose a new paradigm to the treatment of TF, which shortens the duration of the disease and can potentially prevent the emergence of resistance to antibiotics following a synergistic mode of action," the authors said.

References

Zmora N, Shrestha S, Neuberger A, Paran Y, Tamrakar R, Shrestha A, Madhup SK, Bedi TRS, Koju R, Schwartz E. Open label comparative trial of mono versus dual antibiotic therapy for Typhoid Fever in adults. PLoS Negl Trop Dis. 2018 Apr 23;12(4):e0006380.

Empirical colistin should be avoided!.

Background

Empirical colistin should be avoided. We aimed to evaluate the association between covering empirical antibiotics (EAT) and mortality for infections caused by carbapenem-resistant gram-negative bacteria (CRGNB).

Methods

This was a secondary analysis of a randomized controlled trial, including adults with bloodstream infections, pneumonia, or urosepsis caused by CRGNB. All patients received EAT followed by covering targeted therapy. The exposure variable was covering EAT in the first 48 hours. The outcome was 28-day mortality. We adjusted the analyses by multivariable regression analysis and propensity score matching.

Results

The study included 406 inpatients with severe CRGNB infections, mostly Acinetobacter baumannii (312/406[77%]). Covering EAT was given to 209 (51.5%) patients, mostly colistin (n = 200). Patients receiving noncovering EAT were older, more frequently unconscious and dependent, carrying catheters, and mechanically ventilated with pneumonia. Mortality was 84 of 197 (42.6%) with noncovering vs 96 of 209 (45.9%) with covering EAT (P = .504). Covering EAT was not associated with survival in the adjusted analysis; rather, there was a weak association with mortality (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.02–1.84). Results were similar for colistin monotherapy and colistin-carbapenem combination EAT. In the propensity score–matched cohort (n = 338) covering antibiotics were not significantly associated with mortality (OR, 1.42; 95% CI, .91–2.22). Similar results were obtained in an analysis of 14-day mortality.

Conclusions

Empirical use of colistin before pathogen identification, with or without a carbapenem, was not associated with survival following severe infections caused by CRGNBs, mainly A. baumannii.

(Clin Infect Dis. 2018 Nov 28;67(12):1815-1823.)

Infant Colic Represents Gut Inflammation and Dysbiosis

Objective

To dissect potential confounding effects of breast milk and formula feeding on crying + fussing, fecal calprotectin, and gut microbiota in babies with colic. We hypothesized that infant colic is associated with gut inflammation linked to intestinal dysbiosis.

Study design

A nested case-control design of 3 of our studies was used to analyze clinical and laboratory data at presentation, comparing babies with colic with controls. All investigators other than the biostatistician were blinded during data analysis. Subjects were recruited based on their age and crying + fussy time. We screened 65 infants, 37 with colic, as defined by Barr diary (crying + fussing time >3 hours daily), who were compared with 28 noncolicky infants.

Results

Fecal calprotectin was elevated in babies with colic. For each mode of infant feeding (breast milk, formula, or breast + formula), infants' fecal calprotectin was higher in babies with colic. Infants with colic had similar levels of fecal alpha diversity (richness) when compared with controls, and alpha diversity was lower in breast-fed babies. Beta diversity at the phylum level revealed significant differences in microbial population. A phylum difference resulted from reduced Actinobacteria (95% of which are Bifidobacilli) in babies with colic. Species significantly associated with colic were Acinetobacter and Lactobacillus iners.

Conclusions

Colic is linked with gut inflammation (as determined by fecal calprotectin) and dysbiosis, independent of mode of feeding, with fewer Bifidobacilli.

(J. Marc Rhoads, in The Journal of Pediatrics, December 2018Volume 203, Pp 55–61.e3)

Probiotics do not prevent gastroenteritis symptoms in children, studies show

Stephen B. Freedman

Probiotics did not provide beneficial effects in children with gastroenteritis in EDs in the United States and Canada, according to a pair of studies recently published in The New England Journal of Medicine.

The researchers wrote that gastroenteritis accounts for approximately 1.7 million visits by children to the ED in the U.S. each year but that data to support the use of probiotics are lacking.

In the first study, researchers conducted a randomized trial of 886 children aged 3 to 48 months with gastroenteritis who presented to six pediatric EDs in Canada. The study participants received a 5-day course of a combination probiotic product containing Lactobacillus rhamnosus R0011 and Lactobacillushelveticus R0052 twice daily or placebo.

The researchers reported that within 14 days of enrollment, 26.1% of the probiotic-assigned cohort and 24.7% of the placebo-assigned cohort experienced moderate-to-severe gastroenteritis (OR = 1.06: 95% CI, 0.77-1.46). After they adjusted for trial site, age, detection of rotavirus in stool and frequency of diarrhea and vomiting before enrollment, the researchers reported that assignment to a certain trial group did not predict moderate-to-severe gastroenteritis (OR = 1.06; 95% CI, 0.76-1.49).

We analyzed numerous secondary outcomes including the duration of diarrhea and vomiting, and the percentage of children who had unscheduled physician visits, and we failed to identify any benefits among those who received probiotics as it relates to these outcomes as well,"Stephen B. Freedman, MDCM, MSc, an associate professor of pediatrics at Alberta Children's Hospital and Research Institute, University of Calgary, told Infectious Diseases in Children. "We found no benefits associated with the administration of a Lactobacillus rhamnosus R0011 and L. helveticus R0052 combination probiotic product in children with infectious diarrhea."

In the second study, Freedman and colleagues studied 971 children aged 3 to 48 months who presented to 10 pediatric EDs with acute gastroenteritis. The children received a 5-day course of L. rhamnosus GG twice daily or placebo. The researchers conducted follow-up surveys daily for 5 days and at 14 days and 1 month after enrollment.

Nine hundred forty-three patients (97.1%) completed the study, with a median age of 1.4 years. The researchers reported there were no significant differences between the two treatment cohorts in duration of diarrhea (median, 49.7 hours in the L rhamnosus GG cohort and 50.9 hours in the placebo cohort), duration of vomiting(median, 0 hours in both groups), day care absenteeism (median, 2 days in both groups) or rate of household transmission (10.6% in the L rhamnosus GG cohort and 14.1% in the placebo cohort).

We found that probiotic administration did not prevent the development of moderate-to-severe gastroenteritis within 14 days after enrollment,” Freedman, who was a researcher on both studies, said. “We analyzed numerous secondary outcomes including the duration and frequency of diarrhea and vomiting, the duration of day care absenteeism, and the household transmission rate, and we failed to identify any benefits among those who received probiotics as it relates to these outcomes as well. We found no benefits associated with the administration of L.rhamnosus GG in children with infectious diarrhea." - by Bruce Thiel

(Citations: Freedman SB, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1802597. Schnadower D, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1802598.)

UTI prophylaxis increases likelihood of multidrug-resistant infection

Although children with vesicoureteral reflux are at increased risk of UTIs, prescribing antibiotics to prevent these infections may result in a higher likelihood of developing multidrug-resistant infections.

Children with vesicoureteral reflux, a condition in which urine flows backward from the bladder to the kidneys, are at increased risk for urinary tract infections; however, those who receive prophylaxis are 6.4 times more likely to develop multidrug-resistant infections, according to a recent meta-analysis.

"Children being treated with prolonged administration of antibiotics have been found to have an increased risk of resistance,"Rachel E. Selekman, MD, a urology clinical fellow at the University of California, San Francisco, and colleagues wrote. “In addition to causing uropathogen resistance to the prophylactic agent used for UTI prevention, the development of antibiotic multidrug resistance may also occur."

The researchers examined results from randomized controlled trials in which pediatric patients no older than 18 years of age were treated with uninterrupted prophylaxis regimens for the prevention of UTIsresulting from vesicoureteral reflux. The outcomes of these patients were compared with those of patients who received no treatment or placebos. The studies included in the analysis had information regarding antibiotic susceptibility profiles.

Of the 1,299 children included in the review, 224 had UTIs. Approximately one-third (33%) had multidrug-resistant infections when treated with prophylaxis. This percentage was significantly smaller - 6% - in children who did not receive prophylaxis. Additionally, those who regularly received antibiotics for preventing UTIs had a higher likelihood of being prescribed broad-spectrum antibiotics (68% vs. 49%).

According to Selekman and colleagues, children receiving prophylaxis were 6.4 times more likely to develop multidrug-resistant infections (95% CI, 2.7-15.6). These infections were also frequent, with one multidrug-resistant infection reported for every 21 patients with vesicoureteral reflux receiving prophylaxis.

"We recognize that oral broad-spectrum antibiotics are often appropriate empirical choices for the management of recurrent UTIs given the risk for multidrug resistance," Selekman and colleagues wrote. “However, use of broad-spectrum antibiotics may potentiate the cycle of resistance because antibiotic use is a major risk factor for the development of antibiotic resistance." – by Katherine Bortz

(Reference: Selekman RE, et al. Pediatrics. 2018;doi:10.1542/peds.2018-0119.)

Circumcision in infants with hydronephrosis tied to lower UTI risk

Infant boys with hydronephrosis who received newborn circumcision had a significantly decreased risk of urinary tract infections, according to recently published research in Pediatrics.

"Hydronephrosis, often discovered antenatally, is a common newborn diagnosis that impacts 1% to 3% of all live births,"Jonathan S. Ellison, MD, assistant professor of urology at Seattle Children's Hospital, and colleagues wrote. “Boys with hydronephrosis are at an increased risk of urinary tract infections (UTIs), especially early in life. Circumcision is known to provide a small yet significant risk reduction of early UTIs in healthy boys."

Ellison and colleagues identified boys diagnosed with hydronephrosis or a hydronephrosis-related diagnosis within the first 30 days of life by using MarketScan, an employer-based claims database. Researchers compared UTI rates within the first year of life between circumcised boys and uncircumcised boys - the study's primary outcome. Geographic region of care, insurance type, year of birth and infant comorbidity also were included.

The study included 5,560 boys aged younger than 1 year with hydronephrosis within the first month of life and 11,120 healthy boys of the same age range. According to the researchers, 42.9% of boys with hydronephrosis and 51.9% of healthy controls underwent circumcision within 28 days. There was an association between circumcision and a significantly decreased risk for UTI in boys with hydronephrosis (OR = 0.36; 95% CI, 0.29-0.44) and healthy boys (OR = 0.32; 95% CI, 0.21-0.48), they found.

There was an occurrence of UTIs in 12% of boys with hydronephrosis, compared with 1% of the healthy cohort. Ten boys with hydronephrosis would need to undergo circumcision, compared with 83 healthy boys, to prevent one UTI, the researchers said.

Among specific hydronephrosis diagnoses, there were associations between circumcision and a reduced risk for UTI in boys with isolated hydronephrosis (OR = 0.35; 95% CI, 0.26-0.46), vesicoureteral reflux (OR = 0.35; 95% CI, 0.23-0.54) and ureteropelvic junction obstruction (OR = 0.35; 95% CI, 0.2-0.61) when compared with uncircumcised boys.

In this nationally representative sample of insured children, circumcision was associated with a significantly decreased risk for UTI among both healthy boys and those with a diagnosis of hydronephrosis in infancy," the researchers wrote.

"The associated benefit of newborn circumcision was greater for boys with hydronephrosis than healthy controls,” Ellison and colleagues concluded. "Importantly, this associative benefit was consistent across different underlying hydronephrosis diagnoses. These results are hypothesis generating and may guide future prospective studies for this population." – by Bruce Thiel

(Reference: Ellison JS, et al. Pediatrics. 2018;doi:10.1542/peds.2017.3703.)