Treatment of enteric fever (typhoid and paratyphoid fever) with cephalosporins.

BACKGROUND: Typhoid and paratyphoid (enteric fever) are febrile bacterial illnesses common in many low- and middle-income countries. The World Health Organization (WHO) currently recommends treatment with azithromycin, ciprofloxacin, or ceftriaxone due to widespread resistance to older, first-line antimicrobials. Resistance patterns vary in different locations and are changing over time. Fluoroquinolone resistance in South Asia often precludes the use of ciprofloxacin. Extensively drug-resistant strains of enteric fever have emerged in Pakistan. In some areas of the world, susceptibility to old first-line antimicrobials, such as chloramphenicol, has re-appeared. A Cochrane Review of the use of fluoroquinolones and azithromycin in the treatment of enteric fever has previously been undertaken, but the use of cephalosporins has not been systematically investigated and the optimal choice of drug and duration of treatment are uncertain. OBJECTIVES: To evaluate the effectiveness of cephalosporins for treating enteric fever in children and adults compared to other antimicrobials. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, the WHO ICTRP and ClinicalTrials.gov up to 24 November 2021. We also searched reference lists of included trials, contacted researchers working in the field, and contacted relevant organizations. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in adults and children with enteric fever that compared a cephalosporin to another antimicrobial, a different cephalosporin, or a different treatment duration of the intervention cephalosporin. Enteric fever was diagnosed on the basis of blood culture, bone marrow culture, or molecular tests. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were clinical failure, microbiological failure and relapse. Our secondary outcomes were time to defervescence, duration of hospital admission, convalescent faecal carriage, and adverse effects. We used the GRADE approach to assess certainty of evidence for each outcome. MAIN RESULTS: We included 27 RCTs with 2231 total participants published between 1986 and 2016 across Africa, Asia, Europe, the Middle East and the Caribbean, with comparisons between cephalosporins and other antimicrobials used for the treatment of enteric fever in children and adults. The main comparisons are between antimicrobials in most common clinical use, namely cephalosporins compared to a fluoroquinolone and cephalosporins compared to azithromycin. Cephalosporin (cefixime) versus fluoroquinolones Clinical failure, microbiological failure and relapse may be increased in patients treated with cefixime compared to fluoroquinolones in three small trials published over 14 years ago: clinical failure (risk ratio (RR) 13.39, 95% confidence interval (CI) 3.24 to 55.39; 2 trials, 240 participants; low-certainty evidence); microbiological failure (RR 4.07, 95% CI 0.46 to 36.41; 2 trials, 240 participants; low-certainty evidence); relapse (RR 4.45, 95% CI 1.11 to 17.84; 2 trials, 220 participants; low-certainty evidence). Time to defervescence in participants treated with cefixime may be longer compared to participants treated with fluoroquinolones (mean difference (MD) 1.74 days, 95% CI 0.50 to 2.98, 3 trials, 425 participants; low-certainty evidence). Cephalosporin (ceftriaxone) versus azithromycin Ceftriaxone may result in a decrease in clinical failure compared to azithromycin, and it is unclear whether ceftriaxone has an effect on microbiological failure compared to azithromycin in two small trials published over 18 years ago and in one more recent trial, all conducted in participants under 18 years of age: clinical failure (RR 0.42, 95% CI 0.11 to 1.57; 3 trials, 196 participants; low-certainty evidence); microbiological failure (RR 1.95, 95% CI 0.36 to 10.64, 3 trials, 196 participants; very low-certainty evidence). It is unclear whether ceftriaxone increases or decreases relapse compared to azithromycin (RR 10.05, 95% CI 1.93 to 52.38; 3 trials, 185 participants; very low-certainty evidence). Time to defervescence in participants treated with ceftriaxone may be shorter compared to participants treated with azithromycin (mean difference of -0.52 days, 95% CI -0.91 to -0.12; 3 trials, 196 participants; low-certainty evidence). Cephalosporin (ceftriaxone) versus fluoroquinolones It is unclear whether ceftriaxone has an effect on clinical failure, microbiological failure, relapse, and time to defervescence compared to fluoroquinolones in three trials published over 28 years ago and two more recent trials: clinical failure (RR 3.77, 95% CI 0.72 to 19.81; 4 trials, 359 participants; very low-certainty evidence); microbiological failure (RR 1.65, 95% CI 0.40 to 6.83; 3 trials, 316 participants; very low-certainty evidence); relapse (RR 0.95, 95% CI 0.31 to 2.92; 3 trials, 297 participants; very low-certainty evidence) and time to defervescence (MD 2.73 days, 95% CI -0.37 to 5.84; 3 trials, 285 participants; very low-certainty evidence). It is unclear whether ceftriaxone decreases convalescent faecal carriage compared to the fluoroquinolone gatifloxacin (RR 0.18, 95% CI 0.01 to 3.72; 1 trial, 73 participants; very low-certainty evidence) and length of hospital stay may be longer in participants treated with ceftriaxone compared to participants treated with the fluoroquinolone ofloxacin (mean of 12 days (range 7 to 23 days) in the ceftriaxone group compared to a mean of 9 days (range 6 to 13 days) in the ofloxacin group; 1 trial, 47 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Based on very low- to low-certainty evidence, ceftriaxone is an effective treatment for adults and children with enteric fever, with few adverse effects. Trials suggest that there may be no difference in the performance of ceftriaxone compared with azithromycin, fluoroquinolones, or chloramphenicol. Cefixime can also be used for treatment of enteric fever but may not perform as well as fluoroquinolones.  We are unable to draw firm general conclusions on comparative contemporary effectiveness given that most trials were small and conducted over 20 years previously. Clinicians need to take into account current, local resistance patterns in addition to route of administration when choosing an antimicrobial.

Right hip gonococcal septic arthritis treatment with successful transition to oral fluoroquinolone.

We present a case of gonococcal septic arthritis of the right hip diagnosed via synovial fluid cultures. Antimicrobial susceptibility testing of the synovial fluid demonstrated susceptibility to tetracycline, ciprofloxacin, cefixime and ceftriaxone. Our patient was initially treated with ceftriaxone and was successfully de-escalated to oral levofloxacin to complete the treatment. This case is interesting given the rarity of disseminated gonococcal infections in the 21st century and that most clinical isolates of Neisseria gonorrhoeae are increasingly resistant to fluoroquinolones.

Randomized controlled trial of the relative efficacy of high-dose intravenous ceftriaxone and oral cefixime combined with doxycycline for the treatment of Chlamydia trachomatis and Neisseria gonorrhoeae co-infection.

OBJECTIVES: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are the commonest bacterial causes of sexually transmitted infections in humans with high incidence of co-infection. Treatment with high doses of ceftriaxone (CRO) and cefixime (CFM) is strongly recommended due to the reduced drug susceptibility of NG. However, their safety and efficacy have not been confirmed. We compared the safety and efficacy of a single 1 g intravenous (IV) dose of ceftriaxone (CRO) plus doxycycline (DOX) versus a single 800 mg oral dose of cefixime (CFM) plus DOX for the treatment of NG-CT co-infection. METHODS: An open-label randomized controlled trial was conducted on 125 individuals aged > 18 years with untreated gonorrhea and chlamydia to compare a single 1 g intravenous dose of CRO + DOX and a single 800 mg oral dose of CFM + DOX. The primary outcome was the clearance of NG from all the initially infected sites. Secondary outcomes included symptom resolution, changes in the serum clearance levels, glomerular filtration rate, and antibiotic minimum inhibitory concentrations. RESULTS: Both regimens were highly effective in treating gonorrhea with success rates of 96.7% (95% confidence interval [CI] 88.8-99.1%) for CRO and 95.3% (95% CI 87.1-98.4%) for CFM. However, CRO + DOX was superior to CFM + DOX for the treatment of NG-CT co-infection (odds ratio 4.41, 95% CI 1.11-25.7). The safety profiles of the two regimens were similar. CONCLUSIONS: CRO + DOX was superior to CFM + DOX for the treatment of NG-CT co-infection. CFM + DOX may be indicated in patients with CRO allergy and in settings where CRO is unavailable. Trial registration ClinicalTrials.gov (NCT05216744) on 31/01/22.

Resistance-Guided Therapy for Neisseria gonorrhoeae.

Antimicrobial-resistant Neisseria gonorrhoeae infections are a threat to public health. Novel strategies for combating such resistance include the development of molecular assays to facilitate real-time prediction of antimicrobial susceptibility. Resistance to ciprofloxacin is determined by the presence of a single mutation at codon 91 of the gyrase A gene; molecular assays to guide therapy are commercially available. Resistance to cefixime is conferred via 1 of 6 critical mutations in either the mosaic penA gene or specific loci in the nonmosaic region. Resistance to ceftriaxone is conferred through mutations in 1 of 4 genes: penA, ponA, penB, and mtr; however, the ability to predict reduced susceptibility based on those genes varies by geographic region. Here, we highlight the work done toward the development of 3 such assays for ciprofloxacin, cefixime, and ceftriaxone, discuss the status of our current understanding and ongoing challenges, and suggest future directions.

Gentamicin Susceptibility in Neisseria gonorrhoeae and Treatment Outcomes for Urogenital Gonorrhea After 25 Years of Sustained Gentamicin Use in Malawi.

BACKGROUND: Gentamicin has been used for the treatment of gonorrhea in Malawi since 1993. However, declining clinical cure rates have been suspected. We evaluated current Neisseria gonorrhoeae susceptibility to gentamicin in vitro and clinically. METHODS: Men with acute urethritis were recruited at the Bwaila District Hospital STI Clinic in Lilongwe, Malawi, between January 2017 and August 2019. All men provided urethral swabs for etiological testing at enrollment and test of cure (TOC), 1 week later, using Gram-stained microscopy and culture. We used Etest to determine minimum inhibitory concentrations (MICs) of gentamicin, azithromycin, cefixime, ceftriaxone, ciprofloxacin, and spectinomycin; disc diffusion for tetracycline susceptibility; and whole-genome sequencing (WGS) to verify/refute treatment failure. RESULTS: Among 183 N. gonorrhoeae culture-positive men enrolled, 151 (82.5%) had a swab taken for TOC. Of these 151 men, 16 (10.6%) had a positive culture at TOC. One hundred forty-one baseline isolates were tested for gentamicin susceptibility using Etest: 2 (1.4%), MIC = 2 µg/mL; 111 (78.7%), MIC = 4 µg/mL; and 28 (19.9%), MIC = 8 µg/mL. All isolates were susceptible to azithromycin, cefixime, ceftriaxone, and spectinomycin, whereas 63.1% had intermediate susceptibility or resistance to ciprofloxacin. Almost all (96.1%) isolates were resistant to tetracycline. All examined isolates cultured at TOC (n = 13) had gentamicin MICs ≤8 µg/mL. Ten men had pretreatment and posttreatment isolates examined by whole-genome sequencing; 2 (20%) were verified new infections (4119 and 1272 single-nucleotide polymorphisms), whereas 8 (80%) were confirmed treatment failures (0-1 single-nucleotide polymorphism). CONCLUSIONS: Gentamicin MICs poorly predict gonorrhea treatment outcome with gentamicin, and treatment failures are verified with gonococcal strains with in vitro susceptibility to gentamicin. The first-line treatment of gonorrhea in Malawi should be reassessed.

Open Label Randomized Controlled Comparison of Three Alternative Regimes of Ciprofloxacin, Azithromycin and Cefixime for Treatment of Uncomplicated Typhoid Fever in Bangladesh.

Multi-drug resistant Typhoid fever (resistant to previously used chloramphenicol, ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole) has been commonly described in the South East Asia region and a recent report suggests that the salmonella typhi have reduced response to fluoroquinolones (nalidixic acid-resistant). The optimum treatment protocol for this type of serovar has not been established. This study compared different antimicrobial regimens for the treatment of uncomplicated typhoid fever which was conducted in the medicine ward of Dhaka Medical College Hospital (DMCH) and outdoor setting in private practice in Dhaka metropolitan city, Mymensingh and Sylhet town from January 2017 to December 2017. Bangladeshi adults with uncomplicated typhoid fever were included in this an open-label randomized controlled trial. Ciprofloxacin (20mg/kg of body weight/day for 14 days), azithromycin (20mg/kg/day for 14 days), and Cefixime (16mg/kg/day for 14 days) were compared. Of the 81 enrolled patients, 62 were eligible for analysis (61 S. enterica serovar Typhi, 1 Salmonella enterica serovar paratyphi A). Of the S enterica serovar Typhi isolates, 88.7% (55/62) were MDR and 93.5% (58/62) were nalidixic acid resistant (NAR). The clinical cure rate was 62% (13/21) with ciprofloxacin, 71% (15/21) with Cefixime, and 85% (17/20) with azithromycin (p=0.053). The mean (95% confidence interval [CI]) fever clearance time for patients treated with azithromycin (5.8 days [5.1 to 6.5 days]) was shorter than that for patients treated with cefixime (7.1 days [6.2 to 8.1 days]) and ciprofloxacin (8.2 days [7.2 to 9.2 days]) (p<0.001). All three antibiotics were well tolerated. A 7-day course of azithromycin can be successfully used in uncomplicated typhoid fever due to isolates of MDR S enterica serovar Typhi.

Associations between antimicrobial susceptibility/resistance of Neisseria gonorrhoeae isolates in European Union/European Economic Area and patients' gender, sexual orientation and anatomical site of infection, 2009-2016.

BACKGROUND: The emergence and spread of antimicrobial resistance (AMR) in Neisseria gonorrhoeae, nationally and internationally, is a serious threat to the management and control of gonorrhoea. Limited and conflicting data regarding the epidemiological drivers of gonococcal AMR internationally have been published. We examined the antimicrobial susceptibility/resistance of gonococcal isolates (n = 15,803) collected across 27 European Union/European Economic Area (EU/EEA) countries in 2009-2016, in conjunction to epidemiological and clinical data of the corresponding patients, to elucidate associations between antimicrobial susceptibility/resistance and patients' gender, sexual orientation and anatomical site of infection. METHODS: In total, 15,803 N. gonorrhoeae isolates from the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP), 2009-2016, were examined. Associations between gonococcal susceptibility/resistance and patients' gender, sexual orientation and anatomical site of infection were investigated using univariate and multivariate logistic regression analysis. Statistical significance was determined by Pearson χ2-test or Fisher's exact test with two-tailed p-values of < 0.05 indicating significance. RESULTS: The overall gonococcal resistance from 2009 to 2016 was 51.7% (range during the years: 46.5-63.5%), 7.1% (4.5-13.2%), 4.3% (1.8-8.7%), and 0.2% (0.0-0.5%) to ciprofloxacin, azithromycin, cefixime, and ceftriaxone, respectively. The level of resistance combined with decreased susceptibility to ceftriaxone was 10.2% (5.7-15.5%). Resistance to cefixime and ciprofloxacin, and resistance combined with decreased susceptibility to ceftriaxone were positively associated with urogenital infections and heterosexual males, males with sexual orientation not reported and females (except for ciprofloxacin), i.e. when compared to men-who-have-sex-with-men (MSM). Azithromycin resistance was positively associated with heterosexual males, but no association was significant regarding anatomical site of infection. CONCLUSIONS: Overall, sexual orientation was the main variable associated with gonococcal AMR. Strongest positive associations were identified with heterosexual patients, particularly males, and not MSM. To provide evidence-based understanding and mitigate gonococcal AMR emergence and spread, associations between antimicrobial susceptibility/resistance and patients' gender, sexual orientation and anatomical site of infection need to be further investigated in different geographic settings. In general, these insights will support identification of groups at increased risk and targeted public health actions such as intensified screening, 3-site testing using molecular diagnostics, sexual contact tracing, and surveillance of treatment failures.

External quality assessment (EQA) of Neisseria gonorrhoeae antimicrobial susceptibility testing in primary laboratories in Germany.

BACKGROUND: Worldwide, an increase in antimicrobial resistance (AMR) of Neisseria gonorrhoeae has been observed. Until now, no protocol for an external quality assessment (EQA) has been available for Germany. The German gonococcal resistance network (GORENET) performed an EQA of primary laboratories in Germany in order to assess quality of antibiotic susceptibility testing, to gain information about laboratory procedures and to assess the impact of these procedures on test results. METHODS: Laboratories assessed drug susceptibility to cefixime, ceftriaxone, azithromycin, penicillin and ciprofloxacin for five N. gonorrhoeae strains, using their standard laboratory protocols. Minimal inhibitory concentrations (MICs) were compared to World Health Organisation (WHO) consensus results (or, if not available, reference laboratory results), while deviation by +/- one doubling dilution was accepted. Data on laboratory procedures were collected via a standardised questionnaire. Generalized linear models and conditional inference trees (CTREE) were used to assess relationships between laboratory procedures and testing outcomes. RESULTS: Twenty-one primary laboratories participated in the EQA in June 2018. 96% of ciprofloxacin MICs were reported within accepted deviations, as well as 88% for cefixime, 85% for ceftriaxone, 79% for penicillin and 70% for azithromycin. The use of interpretation standards and general laboratory procedures like agar base, incubation settings or the use of control strains strongly differed between laboratories. In statistical analysis, incubation time of cultures < 24 h was associated with correct measurements. Additionally, a 5% CO2 concentration was associated with correct results regarding azithromycin compared to 3%. CTREE analysis showed that incubation time, humidity and CO2 concentration had the greatest influence on the average deviation from consensus results. CONCLUSIONS: In conclusion, we report the development of a protocol for N. gonorrhoeae antimicrobial susceptibility testing in Germany. While testing results were in accordance with the expected consensus results in 70-96%, depending on the antibiotic agent, laboratory methodology was heterogeneous and may significantly affect the testing quality. We therefore recommend the development of a standard operating procedure (SOP) for N. gonorrhoeae susceptibility testing in Germany.

Phase II trial evaluating the clinical efficacy of cefixime for treatment of active syphilis in non-pregnant women in Brazil (CeBra).

BACKGROUND: Syphilis is a sexually and vertically transmitted infection caused by the bacteria Treponema pallidum for which there are few proven alternatives to penicillin for treatment. For pregnant women infected with syphilis, penicillin is the only WHO-recommended treatment that will treat the mother and cross the placenta to treat the unborn infant and prevent congenital syphilis. Recent shortages, national level stockouts as well as other barriers to penicillin use call for the urgent identification of alternative therapies to treat pregnant women infected with syphilis. METHODS: This prospective, randomized, non-comparative trial will enroll non-pregnant women aged 18 years and older with active syphilis, defined as a positive rapid treponemal and a positive non-treponemal RPR test with titer ≥1:16. Women will be a, domized in a 2:1 ratio to receive the oral third generation cephalosporin cefixime at a dose of 400 mg two times per day for 10 days (n = 140) or benzathine penicillin G 2.4 million units intramuscularly based on the stage of syphilis infection (n = 70). RPR titers will be collected at enrolment, and at three, six, and nine months following treatment. Participants experiencing a 4-fold (2 titer) decline by 6 months will be considered as having an adequate or curative treatment response. DISCUSSION: Demonstration of efficacy of cefixime in the treatment of active syphilis in this Phase 2 trial among non-pregnant women will inform a proposed randomized controlled trial to evaluate cefixime as an alternative treatment for pregnant women with active syphilis to evaluate prevention of congenital syphilis. TRIAL REGISTRATION: Trial identifier: www.Clinicaltrials.gov, NCT03752112. Registration Date: November 22, 2018.

An exploratory pilot study evaluating the supplementation of standard antibiotic therapy with probiotic lactobacilli in south African women with bacterial vaginosis.

BACKGROUND: To reduce acquisition and relapse of bacterial vaginosis (BV), lactobacilli must be maintained in the vaginal microbiome. Probiotic lactobacilli may aid this purpose. We investigated whether vaginal probiotics (containing Lactobacillus rhamnosus DSM 14870 and Lactobacillus gasseri DSM 14869) would result in vaginal colonisation with lactobacilli in women with and without BV. METHODS: This prospective, partially randomised, exploratory pilot study was conducted in Soweto, South Africa. Thirty-nine sexually-active, HIV negative women were enrolled from October 2014 to May 2016 into three arms. Women who did not have BV (Group 1, n = 13) self-administered probiotic capsules vaginally once daily for 30 days, then once a week until Day 190. Women diagnosed with BV were randomized into Group 2 (n = 12) or Group 3 (n = 14) and treated with the triple oral antibiotic combination for vaginal discharge syndrome per South African guidelines (cefixime 400 mg stat, doxycycline 100 mg BD for 7 days and metronidazole 2 g stat). Immediately after antibiotic treatment, women in Group 2 self-administered probiotic capsules vaginally once daily for 30 days then vaginally once a week until Day 190. Women in Group 3 were not given lactobacilli. RESULTS: During the study, L. rhamnosus DSM 14870 or L. gasseri DSM 14869, were isolated in 5/13 (38.5%) women in Group 1 compared to 10/12 (83.3%) women in Group 2 (p = 0.041). The 1-month and 6-month BV cure rates were similar (P >  0.05) between Group 2 (42 and 25%) compared to Group 3 (36 and 25%). In Group 2, no correlation was observed between the frequency of isolation of the two Lactobacillus strains and the 1-month or 6-month cure rate. CONCLUSIONS: Supplementation with vaginal probiotic capsules resulted in colonisation of the vagina by the Lactobacillus strains (L. rhamnosus DSM 14870 and L. gasseri DSM 14869) contained in the capsules. We observed low initial cure rates of BV after a stat dose of metronidazole and that the probiotic did not improve BV cure rates or alleviate recurrence which could be due to treatment failure or very limited power of the study. TRIAL REGISTRATION: Registered at the Pan African Clinical Trial Registry ( www.pactr.org ) on April 13, 2018 (retrospectively registered). Trial identification number: PACTR201804003327269.

Effective Oral Combination Treatment for Extended-Spectrum Beta-Lactamase-Producing Escherichia coli.

Background: Extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) is increasing worldwide. The drugs of choice for treatment of ESBLs are parenteral carbapenems. The aim of this study was to evaluate the in vitro and in vivo efficacy of a new combination of oral cephalosporins and amoxicillin/clavulanate in treatment of ESBL-EC. Methods: A total of 150 ESBL-EC samples were collected over 1 year from two referral centers. Synergistic studies of cephalosporins and amoxicillin/clavulanate were performed in vitro using disk approximation and disk replacement methods. Combination treatment was assessed in vivo on 20 ESBL-EC urinary tract infection (UTI) patients. Results: ESBL-EC isolates were confirmed in 150 patients with a mean age of 46.67 years, 75.2% of them being women. Antibiotic susceptibility testing of isolates indicated high resistance rate to oral antibiotics. The frequency of positive synergy and mean distance of synergy between cephalosporins and amoxicillin/clavulanate was significantly higher with cefotaxime and cefixime compared with cefpodoxime, cefdinir, and ceftazidime using disk approximation and disk replacement methods (p < 0.05). Addition of amoxicillin/clavulanate enhanced the susceptibility rate with cefixime from 8.6% to 86.3%, significantly higher than with other cephalosporins (p < 0.0005). Cefixime and amoxicillin/clavulanate synergy was not affected by age, gender, hospital, department, sample type, or bacterial load. Eighteen of 20 ESBL-EC-positive UTI patients had a positive in vitro synergy test and complete clinical and microbiological resolution after completion of cefixime and amoxicillin/clavulanate oral treatment course. Conclusions: Cefixime and amoxicillin/clavulanate combination therapy could be an effective oral outpatient treatment option for ESBL-EC. In vitro synergistic testing is simple and predictive of successful treatment.

A case of Raoultella ornithinolytica urinary tract infection in a pediatric patient.

Raoultella ornithinolytica is a Gram-negative, non-motile, encapsulated, biofilm producing, facultative aerobic bacillus and is found in natural environment. Human infections with R.ornithinolytica is rare in children with only five cases having been reported previously. The present case report describes an urinary tract infection caused by R. ornithinolytica that was identified by MALDI-TOF MS and successfully treated with antibiotic therapy in a 6.5-year-old female child.

Stably high azithromycin resistance and decreasing ceftriaxone susceptibility in Neisseria gonorrhoeae in 25 European countries, 2016.

BACKGROUND: The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) performs annual sentinel surveillance of Neisseria gonorrhoeae susceptibility to therapeutically relevant antimicrobials across the European Union/European Economic Area (EU/EEA). We present the Euro-GASP results from 2016 (25 countries), linked to patient epidemiological data, and compared with data from previous years. METHODS: Agar dilution and minimum inhibitory concentration (MIC) gradient strip methodologies were used to determine the antimicrobial susceptibility (using EUCAST breakpoints) of 2660 N. gonorrhoeae isolates from 25 countries across the EU/EEA. Significance of differences compared with Euro-GASP results in previous years was analysed using Z-tests. RESULTS: No isolates with resistance to ceftriaxone (MIC > 0.125 mg/L) were detected in 2016 (one in 2015). However, the proportion of isolates with decreased susceptibility to ceftriaxone (MICs from 0.03 mg/L to 0.125 mg/L) increased significantly (p = 0.01) from 2015 to 2016. There were 14 (0.5%) isolates with ceftriaxone MICs 0.125 mg/L (on the resistance breakpoint), of which one isolate was resistant to azithromycin and four showed intermediate susceptibility to azithromycin. Cefixime resistance was detected in 2.1% of isolates in 2016 compared with 1.7% in 2015 (p = 0.26) and azithromycin resistance in 7.5% in 2016 compared with 7.1% in 2015 (p = 0.74). Seven (0.3%) isolates from five countries displayed high-level azithromycin resistance (MIC≥256 mg/L) in 2016 compared with five (0.2%) isolates in 2015. Resistance rate to ciprofloxacin was 46.5% compared with 49.4% in 2015 (p = 0.06). No isolates were resistant to spectinomycin and the MICs of gentamicin remained stable compared with previous years. CONCLUSIONS: Overall AMR rates in gonococci in EU/EEA remained stable from 2015 to 2016. However, the ceftriaxone MIC distribution shifted away from the most susceptible (≤0.016 mg/L) and the proportion of isolates with decreased susceptibility to ceftriaxone increased significantly. This development is of concern as current European gonorrhoea management guideline recommends ceftriaxone 500 mg plus azithromycin 2 g as first-line therapy. With azithromycin resistance at 7.5%, the increasing ceftriaxone MICs might soon threaten the effectiveness of this therapeutic regimen and requires close monitoring.

Antimicrobial misuse in pediatric urinary tract infections: recurrences and renal scarring.

BACKGROUND: In children, urinary tract infection (UTI) is one of a common bacterial infection. This study was conducted to detect the uropathogen, antimicrobial susceptibility, pathogen associated with recurrences and renal scarring in children initially taken care from general practitioners and later presented to tertiary care. METHODS: Every inward UTI episode, culture and antimicrobial susceptibility was done while on past 6-month, history of infections and use of antimicrobials was collected using clinical records and demonstration of antimicrobials. Children with recurrent pyelonephritis was followed and in vitro bio film formation was assessed. RESULTS: Frequency of UTI was significantly high among infants (p = 0.03). Last 6-month, all (220) were exposed to antimicrobials. Cefixime was the commonly prescribed antimicrobial (p = 0.02). In current UTI episode, 64.5% (142/220) of children with UTI were consulted GPs' prior to seek treatment from tertiary care pediatric unit (p = 0.02). While on follow up child who developed UTI, found urine culture isolates were significantly shifted from E. coli and K. pneumoniae to extended spectrum of beta-lactamase (ESBL) E. coli and K. pneumoniae. Out of 208 participants, 36 of them had re-current pyelonephritis (R-PN). Renal scarring (RS) was detected in 22 out of 70 patients with pyelonephritis following dimercaptosuccinic acid scan. Following each episodes of recurrent pyelonephritis 11% of new scar formation was detected (p = 0.02). Bio film forming E. coli and K. pneumoniae was significantly associated in patients with R-PN (p = 0.04). DISCUSSION: Medical care providers often prescribe antimicrobials without having an etiological diagnosis. While continuing exposure of third generation cephalosporin and carbapenem leads to development of ESBL and CRE microbes in great. The empiric uses of antimicrobials need to be stream lined with local epidemiology and antimicrobial susceptibility pattern. R-PN in childhood leads to RS. In great, bio film formation act as the focus for such recurrences.

Antimicrobial susceptibility pattern of Shigella spp. isolated from children under 5 years of age attending tertiary care hospitals, Nepal along with first finding of ESBL-production.

BACKGROUND: Shigella is an important cause of bacterial gastroenteritis in resource-poor countries. The treatment of shigellosis mostly requires antibiotics. However, the increase of multidrug resistance along with emergence of extended-spectrum ß-lactamase and ciprofloxacin resistance among Shigella spp. has challenged the situation. This study was conducted to determine the distribution of species and antibiotic susceptibility pattern of Shigella species isolated from stool specimen among children less than 5 years of age in Nepal. RESULTS: Out of total 717 stool samples collected, 15 cases of Shigella spp. was isolated which includes 12 S. flexneri and 3 S. sonnei. Multidrug resistance was found among 13(86%) of the isolates. One of the isolates of S. flexneri was found to be ESBL-producer with MIC >256 mg/L for cefixime. CONCLUSION: The high occurrence of multidrug resistance among Shigella spp. along with a case of ESBL-production for the first time in Nepal alarms the concerns about dissemination of the resistant isolates. So, systemic monitoring of the antimicrobial susceptibility pattern of Shigella spp. is becoming crucial to guide therapy.

Changes in Bacterial Resistance Patterns of Pediatric Urinary Tract Infections and Rationale for Empirical Antibiotic Therapy.

BACKGROUND: The causative agent spectrum and resistance patterns of urinary tract infections in children are affected by many factors. AIMS: To demonstrate antibiotic resistance in urinary tract infections and changing ratio in antibiotic resistance by years. STUDY DESIGN: Retrospective cross-sectional study. METHODS: We analysed antibiotic resistance patterns of isolated Gram (-) bacteria during the years 2011-2014 (study period 2) in children with urinary tract infections. We compared these findings with data collected in the same centre in 2001-2003 (study period 1). RESULTS: Four hundred and sixty-five uncomplicated community-acquired Gram (-) urinary tract infections were analysed from 2001-2003 and 400 from 2011-2014. Sixty-one percent of patients were female (1.5 girls : 1 boy). The mean age of children included in the study was 3 years and 9 months. Escherichia coli was the predominant bacteria isolated during both periods of the study (60% in study period 1 and 73% in study period 2). Bacteria other than E. coli demonstrated a higher level of resistance to all of the antimicrobials except trimethoprim-sulfamethoxazole than E. coli bacteria during the years 2011-2014. In our study, we found increasing resistance trends of urinary pathogens for cefixime (from 1% to 15%, p<0.05), amikacin (from 0% to 4%, p<0.05) and ciprofloxacin (from 0% to 3%, p<0.05) between the two periods. Urinary pathogens showed a decreasing trend for nitrofurantoin (from 17% to 7%, p=0.0001). No significant trends were detected for ampicillin (from 69% to 71%), amoxicillin-clavulanate (from 44% to 43%), cefazolin (from 39% to 32%), trimethoprim-sulfamethoxazole (from 32% to 31%), cefuroxime (from 21% to 18%) and ceftriaxone (from 10% to 14%) between the two periods (p>0.05). CONCLUSION: In childhood urinary tract infections, antibiotic resistance should be evaluated periodically and empiric antimicrobial therapy should be decided according to antibiotic sensitivity results.

Genetic Resistance Determinants for Cefixime and Molecular Analysis of Gonococci Isolated in Italy.

A strictly defined subset of gonococci (n = 65) isolated in Italy from 2011 to 2014 was characterized by antimicrobial susceptibility for cefixime (CFM) and ceftriaxone (CRO) and by sequencing of resistance determinant genes (penA, mtrR, porB1b, ponA) for extended-spectrum cephalosporins and Neisseria gonorrhoeae multiantigen sequence typing (NG-MAST). The penA mosaic alleles XXXIV and XXXV were found in all resistant (R) and decreased susceptibility (DS) gonococci to CFM, except for one. They were associated with an adenine deletion in the mtrR promoter plus amino acid substitutions, H105Y or G45D, in the coding region and ponA L421P. The penA mosaic allele XXXIV, and one variant, was found exclusively among genogroup (G) 1407 and its closely related sequence types (STs), as in CFM-DS as well as in CFM-R isolates. Single or combined mutation patterns in penA, mtrR, porB1b, and ponA genes were associated with different CFM susceptibility patterns and NG-MAST STs. Genotyping and antimicrobial resistance (AMR) determinant analyses can be valuable to enhance the gonococcal AMR surveillance.

Studies on the therapeutic effect of propolis along with standard antibacterial drug in Salmonella enterica serovar Typhimurium infected BALB/c mice.

BACKGROUND: Antibiotic resistance is an emerging public health problem. Centers for Disease Control and Prevention (CDC) has described antibiotic resistance as one of the world's most pressing health problems in 21st century. WHO rated antibiotic resistance as "one of the three greatest threats to human health". One important strategy employed to overcome this resistance is the use of combination of drugs. Many plants, natural extracts have been shown to exhibit synergistic response with standard drugs against microorganisms. The present study focused on the antibacterial potential of propolis in combination with the standard antibiotic Cefixime against the typhoid causing bacteria i.e. Salmonella. METHODS: Ethanolic extract of propolis was taken for the present work. For the experiment BALB/c mice were taken as animal model and divided into ten groups. Along with normal and infected control groups, four different combinations of cefixime and propolis were used. Biochemical, hematological and histopathological indices were studied by following the standard protocols. RESULTS: In BALB/c mice, Salmonella causes severe biochemical, hematological and histopathological alterations by 5th day of infection. Ethanolic extract of propolis at a dose of 300 mg/kg body weight of mice when used alone to treat Salmonella infection in mice gave significant results by 30th day of treatment. Similarly, when cefixime (4 mg/kg body weight of mice) was used to treat infection in mice, significant results as compared to infected control were observed after 5th day. But when propolis and cefixime were used together in different concentrations in combination therapy, evident results were observed after 5 days of treatment. The levels of various liver and kidney function enzymes, blood indices and the histopathology of liver, spleen and kidney were restored to near normal after 5 days of treatment and at much lower doses as compared to the effective dose when used alone. CONCLUSION: The study confirmed that significant results were observed in three combinations of cefixime and propolis as compared to infected controls. Propolis acted synergistically with cefixime and enhanced the efficacy of antibiotic and reduced its effective dose in combined therapy.