Methenamine hippurate to prevent recurrent urinary tract infections in older women: protocol for a randomised, placebo-controlled trial (ImpresU).

INTRODUCTION: Methenamine hippurate is a urinary antiseptic used as preventive treatment for recurrent urinary tract infections (UTIs) in some Scandinavian countries. However, the scientific evidence for the preventive effect and safety for longer-term use is limited. The aim of this study is to assess whether methenamine hippurate can reduce the incidence of UTIs in older women with recurrent UTIs. METHODS AND ANALYSIS: The ImpresU consortium is a collaboration between Norway, Sweden, Poland and the Netherlands. The study is a randomised, controlled, triple-blind phase IV clinical trial. Women ≥70 years with recurrent UTIs are screened for eligibility in a general practice setting. We aim to include 400 women in total, with 100 recruited from each collaborating country. The participants are randomised to treatment with methenamine hippurate 1 g or placebo tablets two times per day for a treatment period of 6 months, followed by a drug-free follow-up period of 6 months. The primary outcome is number of antibiotic treatments for UTIs during the treatment period. The secondary outcomes include number of antibiotic treatments for UTIs during the follow-up period and self-reported symptom of severity and duration of UTI episodes. Differences in complications between the treatment groups are measured as safety outcomes. We also aim to investigate whether strain characteristics or phylogenetic subgroups of Escherichia coli present in the urine culture at inclusion have a modifying effect on the outcomes. ETHICS AND DISSEMINATION: Ethical approvals are obtained in all participating countries. The results will be communicated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04077580); EudraCT: 2018-002235-15.

An immunosuppressed woman in her sixties with a high fever. / En immunsupprimert kvinne i 60-årene med høy feber.

Investigation of fever in immunosuppressed patients can be challenging. Rapid and correct microbiological test results are essential for steering the investigation in the right direction. Our patient was eventually diagnosed with a condition that was initially suspected, but the time to reach a laboratory-confirmed diagnosis was unusually long.

The efficacy of pivmecillinam in oral step-down treatment in hospitalised patients with E. coli bacteremic urinary tract infection; a single-arm, uncontrolled treatment study.

BACKGROUND: The role of oral beta-lactam antibiotics in treating febrile urinary tract infections (UTI) is not yet definite. Today, fluoroquinolones together with trimethoprim-sulfamethoxazole (TMP-MTX) are considered standard of care and often the only available evidence-based oral treatment for febrile UTI. This study clarifies the efficacy and safety of pivmecillinam (PIV) used as step-down therapy for bacteremic urinary tract infection (UTI). METHODS: A single-arm, uncontrolled treatment trial was conducted in the period September 2017-March 2020. Candidates for inclusion were men and women suffering from E. coli bacteremia due to UTI and were consecutively included in a Norwegian hospital. Exclusion criteria were among others: other ongoing bacterial infection, septic shock, pyonephrosis/abscess and pregnancy. After 3 days of parenteral antibiotic, the treatment was converted to the study drug; oral PIV 400 mg QID for 1 week. Primary endpoint was a combination of three elements; afebrility, no need for retreatment and improvement in self-reported health status. Test Of Cure (TOC) was 1 week post-treatment. Secondary endpoints included among others microbiological efficacy and CRP value < 30 mg/L. RESULTS: Of 476 screened subjects, 53 patients were included. Median age was 67 years, 28 (56%) were women. 50 patients were evaluated for per-protocol analysis. 44 of 50 patients (88%) (95% CI [75.7-95.5]) reached the primary endpoint on TOC. 14 of 48 patients (29.2%) had significant growth (> 103 CFU/mL) of E.coli on TOC. CRP-level was strongly associated to treatment outcome, (OR 0.006 [95% CI 0.00-0.11], p < 0.001). CONCLUSIONS: This trial documents that PIV 400 mg QID given for 1 week following 3 days of parenteral antibiotics, is a suitable treatment option in patients suffering from bacteremic UTI due to E. coli. Randomised clinical trials studying the efficacy of PIV vs standard of care of febrile UTI are warranted. Trial registration The trial was registered at ClinicalTrials.gov under the identifier: NCT03282006 13/09/2017 and approved by The Regional Committees for Medical Research Ethics South East Norway (2015/2384/REK sør-øst) and the Norwegian Medicines Agency (SLV; reference No 16/06018-09; EudraCT No 2016-000984-18) before initiation.

Low prevalence of tick-borne encephalitis virus antibodies in Norwegian blood donors.

BACKGROUND: Tick-borne encephalitis (TBE) constitutes a public health concern in Europe. Certain coastal municipalities in southern Norway are considered TBE risk areas and in the last two years, there have been increasing numbers of TBE cases. Since the majority of infections are claimed to be asymptomatic, the aim of the current study was to assess the seroprevalence of antibodies to tick-borne encephalitis virus (TBEV) among unvaccinated adults living in a TBE endemic area in Norway. METHODS: One thousand one hundred and twenty-three blood donors living in Vestfold and Telemark county were included and associated sera were analysed for TBEV IgG antibodies. Information regarding tick bites, previous flavivirus exposure and knowledge regarding TBE and TBE prevention were obtained through a questionnaire. RESULTS: Fifty-eight samples were reactive by ELISA, of which 21 (36.2%) were confirmed by a TBEV-specific serum neutralization test. Of the 21 blood donors with neutralizing TBEV antibodies detected, 17 reported previous TBE vaccination. Thus, only four blood donors (0.4%) had TBEV neutralizing antibodies consistent with previously undergone TBEV infection. Regarding TBE awareness, half of the blood donors were familiar with TBE, but only 35% were aware of a preventive TBE vaccine. CONCLUSIONS: Our study indicates low prevalence of subclinical TBEV infections among blood donors living in Vestfold and Telemark county and there is a lack of awareness among general public.

Predicting the use of antibiotics after initial symptomatic treatment of an uncomplicated urinary tract infection: analyses performed after a randomised controlled trial.

OBJECTIVE: To predict antibiotic use after initial treatment with ibuprofen using data from a randomised controlled trial comparing ibuprofen to pivmecillinam in the treatment of women with symptoms of an uncomplicated urinary tract infection (UTI). SETTING: 16 sites in a primary care setting in Norway, Sweden and Denmark. PARTICIPANTS: Data from 181 non-pregnant women aged 18-60 presenting with symptoms of uncomplicated UTI, initially treated with ibuprofen. METHODS: Using the least absolute shrinkage and selection operator logistic regression model, we conducted analyses to see if baseline information could help us predict which women could be treated with ibuprofen without risking treatment failure and which women should be recommended antibiotics. RESULTS: Of the 143 women included in the final analysis, 77 (53.8%) recovered without antibiotics and 66 (46.2 %) were subsequently prescribed antibiotics. In the unadjusted binary logistic regression, the number of days with symptoms before inclusion (<3 days) and feeling moderately unwell or worse (≥4 on a scale of 0-6) were significant predictors for subsequent antibiotic use. In the adjusted model, no predictors were significantly associated with subsequent antibiotic use. The area under the curve of the final model was 0.66 (95% CI: 0.57 to 0.74). CONCLUSION: We did not find any baseline information that significantly predicted the use of antibiotic treatment. Identifying women who need antibiotic treatment to manage their uncomplicated UTI is still challenging. Larger data sets are needed to develop models that are more accurate. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01849926).

Microbial risk factors for treatment failure of pivmecillinam in community-acquired urinary tract infections caused by ESBL-producing Escherichia coli.

The aim of this study was to identify microbial risk factors for treatment failure of pivmecillinam in community-acquired urinary tract infections (ca-UTIs) caused by ESBL-producing Escherichia coli. Eighty-nine ESBL-producing E. coli isolated from women suffering from ca-UTIs were included. The susceptibilities to mecillinam were determined using MIC gradient strip. Whole genome sequencing was performed on a MiSeq platform, and genome assembly was performed using SPAdes v3.11.0. Neither mecillinam MICs nor ESBL genotypes were associated with treatment outcome of patients treated with pivmecillinam. Specific STs, however, showed significant differences in treatment outcome. Patients infected with ST131 were more likely to experience treatment failure compared to patients infected with non-ST131 (p 0.02) when adjusted for pivmecillinam dose, mecillinam MIC and severity of infection. Patients infected with ST69 were more often successfully treated compared to patients infected with non-ST69 (p 0.04). Patients infected with blaCTX-M-15 ST131 strains were more likely to experience treatment failure than those infected with non-blaCTX-M-15 ST131 strains (p 0.02). The results suggest that specific STs are associated with the clinical efficacy of pivmecillinam. Further studies with a larger number of strains, including a larger number of mecillinam resistant strains, are needed to confirm these results.

Serological diagnostics of Lyme borreliosis: comparison of assays in twelve clinical laboratories in Northern Europe.

Lyme borreliosis (LB), caused by spirochetes belonging to the Borrelia burgdorferi sensu lato complex, is the most common tick-borne infection in Europe. Laboratory diagnosis of LB is mainly based on the patients' medical history, clinical signs and symptoms in combination with detection of Borrelia-specific antibodies where indirect enzyme-linked-immunosorbent assay (ELISA) is the most widely used technique. The objective of the study was to evaluate and compare the diagnostic accuracy (sensitivities and specificities) of serological tests that are currently in use for diagnosis of LB in clinical laboratories in Northern Europe, by use of a large serum panel. The panel consisted of 195 serum samples from well-characterized and classified patients under investigation for clinically suspected LB (n = 59) including patients with Lyme neuroborreliosis, Lyme arthritis, acrodermatitis chronica atrophicans, erythema migrans or other diseases (n = 112). A total of 201 serum samples from healthy blood donors were also included. The panel (396 serum samples altogether) was sent to 12 clinical laboratories (using five different ELISA methods) as blinded for group affiliation and the laboratories were asked to perform serological analysis according to their routine procedure. The results from the study demonstrated high diagnostic concordance between the laboratories using the same diagnostic assay and lower diagnostic concordance between laboratories using different diagnostic assays. For IgG, the results were in general rather homogenous and showed an average sensitivity of 88% (range 85-91%) compared to IgM which showed lower average sensitivity of 59% (range 50-67%) and more heterogeneous results between assays and laboratories.

Bacteriology in uncomplicated urinary tract infections in Norwegian general practice from 2001-2015.

BACKGROUND: Uncomplicated urinary tract infections in women are common, and urine samples from these patients are not routinely cultured. Empirical treatment is based on knowledge of resistance patterns for common uropathogens. AIM: To evaluate the bacteriological findings and resistance patterns in urine samples from women with uncomplicated urinary tract infections, and to assess the relationship between antimicrobial use and resistance patterns from 2000-2015 in Norway. METHOD: Bacteriology and resistance patterns were compared in 184 urine cultures from 2001, 406 urine cultures from 2010-2011 and 259 urine cultures from 2013-2015. Antibiotic use data from 2000-2015 were obtained from national databases. RESULTS: Escherichia coli (E. coli) was the main bacterial agent in 80% of the cultures. Staphylococcus saprophyticus (Staph. saprophyticus) represented 6-17%. For E. coli, resistance to mecillinam showed some variation but remained below 9%. There was negligible resistance to nitrofurantoin. Resistance to trimethoprim seemed to stabilise over the last 5 years at around 20%. Amoxicillin resistance had some variations, but remained stable around 30%. There was a steady rise in total consumption of selected antibiotics commonly used to treat urinary tract infections for the period 2000-2015. CONCLUSION: Mecillinam and nitrofurantoin are both excellent first choices for empirical treatment of uncomplicated urinary tract infections. This study suggests that increasing resistance to trimethoprim challenges the rationale for its use as a first-line agent.

Predictors of Symptom Duration and Bacteriuria in Uncomplicated Urinary Tract Infection.

OBJECTIVE: To identify baseline predictors of symptom duration after empirical treatment for uncomplicated urinary tract infection (UTI) and significant bacteriuria in a cohort of women treated for UTI. DESIGN: Prospective single-centre cohort study. SETTING: Outpatient clinic in Norway. PATIENTS: From September 2010 to November 2011, 441 women aged 16-55 years with symptoms of uncomplicated UTI were included. RESULTS: Dipstick findings of leukocyte esterase 1 + (incidence rate ratio (IRR) 1.93, 95% confidence interval (CI) 1.23-3.01, p < 0.01) and microbe resistant to mecillinam treatment (IRR 1.41, 95% CI 1.07-1.89, p = 0.02) predicted longer symptom duration. More pronounced symptoms did not predict longer symptom duration (IRR 1.18, 95% CI 0.94-1.46, p = 0.15) or significant bacteriuria (odds ratio [OR] 1.16, 95% CI 0.72-1.88, p = 0.54). Leukocyte esterase 2 + (OR 2.51, 95% CI 0.92-6.83, p = 0.07) or 3 + (OR 2.40, 95% CI 0.88-6.05, p = 0.09) and nitrite positive urine dipstick test (OR 3.22, 95% CI 1.58-7.01, p = <0.01) were associated with bacteriuria. CONCLUSION: More pronounced symptoms did not correlate with significant bacteriuria or symptom duration after empirical treatment for acute cystitis. One might reconsider the current practice of treating uncomplicated UTI based on symptoms alone. Key Points Treatment strategies for milder infectious diseases must consider ways of reducing antibiotic consumption to decelerate the increase in antibiotic resistance. Our findings suggest that more emphasis should be put on urine dipstick results and bacteriological findings in the clinical setting. One might reconsider the current practice of treating uncomplicated UTIs based on symptoms alone.

Clinical and bacteriological efficacy of pivmecillinam treatment for uncomplicated urinary tract infections caused by ESBL-producing Escherichia coli: a prospective, multicentre, observational cohort study.

Objectives: To compare the clinical and bacteriological outcomes of pivmecillinam treatment for community-acquired urinary tract infections (UTIs) caused by ESBL-producing Escherichia coli versus non-ESBL-producing E. coli in an outpatient setting. Methods: A prospective, multicentre, observational cohort study of women aged ≥16 years, with pivmecillinam-treated community-acquired UTIs caused by E. coli with or without ESBL production, recruited from primary care, was conducted in the period from April 2013 to August 2016. Eighty-eight women (mean age 49.4 years) with community-acquired UTIs caused by ESBL-producing E. coli were compared with a control group of 74 women (mean age 50.1 years). Trial registration: Regional Committees for Medical and Health Research Ethics (REC) in Norway, ID 2011/2214, and ClinicalTrials.gov, ID NCT01531023. Results: The median time until symptom resolution after treatment initiation was 5 days for the ESBL cases and 3 days for the non-ESBL controls (P < 0.01). The proportion of women warranting a second antibiotic prescription in the follow-up period was higher for the ESBL cases [30/88 (34.1%) versus 10/72 (13.9%), P < 0.01]. Persistent bacteriuria was non-significantly more common among ESBL cases than in the control group [15/81 (18.5%) versus 6/67 (9.0%), P = 0.10]. A pivmecillinam dosage of 200 mg given three times daily for ≤5 days was associated with treatment failure (OR 4.77, 95% CI 1.40-19.44, P = 0.03) for the ESBL E. coli group. For the subgroup treated with 400 mg of pivmecillinam given three times daily there was no significantly increased OR for treatment failure between ESBL cases and the control group irrespective of treatment duration. Conclusions: Pivmecillinam given at 400 mg three times daily gave comparable clinical and bacteriological cure rates in women with community-acquired E. coli UTIs irrespective of ESBL production.

Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women-A double-blind, randomized non-inferiority trial.

BACKGROUND: Although uncomplicated urinary tract infections (UTIs) are often self-limiting, most patients will be prescribed antibiotic treatment. We assessed whether treatment with ibuprofen was non-inferior to pivmecillinam in achieving symptomatic resolution by day 4, with a non-inferiority margin of 10%. METHODS AND FINDINGS: This was a randomized, controlled, double-blind non-inferiority trial. We recruited patients from 16 sites in a general practice setting in Norway, Sweden, and Denmark. Non-pregnant women aged 18-60 years presenting with symptoms of uncomplicated UTI were screened for eligibility from 11 April 2013 to 22 April 2016. Patients with informed consent were randomized (1:1 ratio) to treatment with either 600 mg ibuprofen or 200 mg pivmecillinam 3 times a day for 3 days. The patient, treating physician, and study personnel were blinded to treatment allocation. The primary outcome was the proportion of patients who felt cured by day 4, as assessed from a patient diary. Secondary outcomes included the proportion of patients in need of secondary treatment with antibiotics and cases of pyelonephritis. A total of 383 women were randomly assigned to treatment with either ibuprofen (n = 194, 181 analyzed) or pivmecillinam (n = 189, 178 analyzed). By day 4, 38.7% of the patients in the ibuprofen group felt cured versus 73.6% in the pivmecillinam group. The adjusted risk difference with 90% confidence interval was 35% (27% to 43%) in favor of pivmecillinam, which crossed the prespecified non-inferiority margin. Secondary endpoints were generally in favor of pivmecillinam. After 4 weeks' follow-up, 53% of patients in the ibuprofen group recovered without antibiotic treatment. Seven cases of pyelonephritis occurred, all in the ibuprofen group, giving a number needed to harm of 26 (95% CI 13 to 103). Five of these patients were hospitalized and classified as having serious adverse events; 2 recovered as outpatients. A limitation of the study was the extensive list of exclusion criteria, eliminating almost half of the patients screened. We did not register symptoms in the screening process; hence, we do not know the symptom burden for those who declined to participate. This might make our results less generalizable. CONCLUSIONS: Ibuprofen was inferior to pivmecillinam for treating uncomplicated UTIs. More than half of the women in the ibuprofen group recovered without antibiotics. However, pyelonephritis occurred in 7 out of 181 women using ibuprofen. Until we can identify those women who will develop complications, we cannot recommend ibuprofen alone as initial treatment to women with uncomplicated UTIs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01849926 EU Clinical Trials Register (EU-CTR), EudraCT Number 2012-002776-14.

Species Level Description of the Human Ileal Bacterial Microbiota.

The small bowel is responsible for most of the body's nutritional uptake and for the development of intestinal and systemic tolerance towards microbes. Nevertheless, the human small bowel microbiota has remained poorly characterized, mainly owing to sampling difficulties. Sample collection directly from the distal ileum was performed during radical cystectomy with urinary diversion. Material from the ileal mucosa were analysed using massive parallel sequencing of the 16S rRNA gene. Samples from 27 Caucasian patients were included. In total 280 unique Operational Taxonomic Units were identified, whereof 229 could be assigned to a species or a species group. The most frequently detected bacteria belonged to the genera Streptococcus, Granulicatella, Actinomyces, Solobacterium, Rothia, Gemella and TM7(G-1). Among these, the most abundant species were typically streptococci within the mitis and sanguinis groups, Streptococcus salivarius, Rothia mucilaginosa and Actinomyces from the A. meyeri/odontolyticus group. The amounts of Proteobacteria and strict anaerobes were low. The microbiota of the distal part of the human ileum is oral-like and strikingly different from the colonic microbiota. Although our patient population is elderly and hospitalized with a high prevalence of chronic conditions, our results provide new and valuable insights into a lesser explored part of the human intestinal ecosystem.

Chlamydia testing in practice - requisitioners and patients. / Klamydiatesting i praksis ­ rekvirenter og pasienter.

BACKGROUND: Optimising the diagnostic work-up and treatment of genital chlamydia infection requires knowledge of the sampling patterns of those who order chlamydia tests. We wished to determine which groups of doctors collect specimens for chlamydia testing, and to examine the sex and age distribution of patients tested, and the proportion of positive tests, from general practitioners, gynaecologists in private practice, and youth health services. MATERIAL AND METHOD: The study includes 43 465 specimens analysed for genital infection with Chlamydia trachomatis at Vestfold Hospital Trust over the period 1 January 2007 to 31 December 2011. Data from the laboratory information system were used to classify the test requisitioners. RESULTS: General practitioners requisitioned 60 % of all chlamydia tests and 63 % of all positive tests. Youth health services requisitioned 13 % of all tests and 22 % of positive tests; gynaecologists in private practice, 12 % of all tests and 5 % of positive tests. Overall, 26 % of specimens were from women over the age of 30 with 2.2 % testing positive, and 82 % of these specimens were submitted by general practitioners or gynaecologists in private practice. Twenty-three per cent of specimens were from men, and 78 % of these were collected in general practice. INTERPRETATION: Knowledge of who requisitions chlamydia testing and of whom is important for planning and improving chlamydia diagnosis, treatment and contact tracing. In this study from Norway, we found that doctors in general practice play a key role in diagnosing and treating chlamydia. The testing of women over the age of 30 by general practitioners and gynaecologists in private practice probably leads to unnecessary use of resources and should be reduced.

Blood donor Borrelia burgdorferi sensu lato seroprevalence and history of tick bites at a northern limit of the vector distribution.

In order to study the antibody seroprevalence of the causal agent of Lyme borreliosis, Borrelia burgdorferi sensu lato (s.l.), and the history of tick bites at a geographical distribution limit of Ixodes ricinus, we compared healthy blood donors in geographically extreme regions: the borreliosis-endemic Vestfold County (59°N) and the region of northern Norway. Blood samples were screened using IgG/VlsE ELISA, and positive/borderline samples were confirmed using C6 ELISA and immunoblot assays. Also, donors completed a questionnaire consisting of several items including the places they have lived, and whether they owned any pets. The seroprevalence was 0.48% (5/1048) in northern Norway and 9.25% (48/519) in Vestfold County. Seven donors (of 1048) had experienced a single tick bite in the southern part of Nordland County (65°N) in northern Norway. This first study on B. burgdorferi s.l. antibody seroprevalence and tick bites on humans and pets in northern Norway showed that the seroprevalence of B. burgdorferi s.l. infection and the risk of tick bite in northern Norway are insignificant; the fact that only five positive IgG samples were detected underscores the very low background seroprevalence. These results suggest that so far I. ricinus has not expanded north of the previously established geographical distribution limit.

Incidence and antibiotic treatment of erythema migrans in Norway 2005-2009.

The first stage of Lyme borreliosis (LB) is mainly the typical skin lesion, erythema migrans (EM), which is estimated to comprise 80-90% of all LB cases. However, the reporting of, and the actual incidence of LB varies throughout Europe. Studies from Sweden and Holland have found EM incidences varying from 53 to 464 EM/100,000 inhabitants/year. Under-reporting of LB is common and a coefficient of three to reach a realistic estimate is suggested. In Norway, it is mandatory to report only the second and third LB stages to the National Institute of Public Health. To find the Norwegian incidence of EM, we extracted data from the electronic medical records of regular general practitioners and out-of-hours services in the four counties with the highest rates of registered LB in the 5 years from 2005 to 2009. We found an EM incidence of 448 EM/100,000 inhabitants/year in these counties, which yields a national incidence of 148 EM/100,000 inhabitants/year. Our findings show that solitary EMs comprised almost 96% of the total LB incidence in Norway. Older females have the highest rates of EM. Phenoxymethylpenicillin is the most commonly used drug to treat EM in Norway, which complies with the national guidelines for antibiotic use. Antibody tests are performed in 15% of cases. Less than 1% of patients are referred to secondary care. The study also shows a high number of patients seeking care for tick bites without signs of infection and there is an overuse of antibiotics in these patients.

Prevalence of M. genitalium and U. urealyticum in urine tested for C. trachomatis.

BACKGROUND: Mycoplasma genitalium and Ureaplasma urealyticum cause sexually transmitted infections. While M. genitalium is an established aetiological agent, U. urealyticum is still controversial as a pathogen. Testing for these microbes is not yet widely available in Norway, and knowledge of their prevalence is limited. In this study we have investigated the prevalence of M. genitalium and U. urealyticum in a heterogeneous population from Vestfold and Telemark. MATERIAL AND METHOD: Urine samples (n = 4,665) received by the laboratory for testing for Chlamydia trachomatis in the period from February 2011 to January 2012 were subsequently tested for M. genitalium and U. urealyticum. Samples were analysed using an in-house PCR protocol. RESULTS: The prevalence of C. trachomatis, M. genitalium and U. urealyticum was 11.9%, 3.6% and 17.9% respectively. M. genitalium was found most frequently in women aged 20-24 years (5.1%), while the proportion of samples positive for U. urealyticum was greatest in persons aged 15-24 years (22.8%). INTERPRETATION: M. genitalium was highly prevalent in urine samples submitted for C. trachomatis testing. M. genitalium testing was requested for only a minority of the samples analysed, suggesting limited knowledge of this microbe. U. urealyticum was the most predominant microbe in the study, which may indicate that it is largely non-pathogenic.

High Mortality from Blood Stream Infection in Addis Ababa, Ethiopia, Is Due to Antimicrobial Resistance.

BACKGROUND: Managing blood stream infection in Africa is hampered by lack of bacteriological support needed for antimicrobial stewardship, and background data needed for empirical treatment. A combined pro- and retrospective approach was used to overcome thresholds in clinical research in Africa. METHODS: Outcome and characteristics including age, HIV infection, pancytopenia and bacteriological results were studied in 292 adult patients with two or more SIRS criteria using univariate and confirming multivariate logistic regression models. Expected randomly distributed resistance covariation was compared with observed co-resistance among gram-negative enteric bacteria in 92 paediatric blood culture isolates that had been harvested in the same hospital during the same period of time. RESULTS: Mortality was fivefold increased among patients with positive blood culture results [50.0% vs. 9.8%; OR 11.24 (4.38-25.88), p < 0.0001], and for this group of patients mortality was significantly associated with antimicrobial resistance [OR 23.28 (3.3-164.4), p = 0.002]. All 11 patients with Enterobacteriaceae resistant to 3rd. generation cephalosporins died. Eighty-nine patients had pancytopenia grade 3-4. Among patients with negative blood culture results, mortality was significantly associated with pancytopenia [OR 3.12 (1.32-7.39), p = 0.01]. HIV positivity was not associated with increased mortality. Antimicrobial resistance that concerned gram-negative enteric bacteria, regardless of species, was characterized by co-resistance between third generation cephalosporins, gentamicin, chloramphenicol, and co-trimoxazole. CONCLUSION: Mortality was strongly associated with growth of bacteria resistant to empirical treatment, and these patients were dead or dying when bacteriological reports arrived. Because of co-resistance, alternative efficient antibiotics would not have been available in Ethiopia for 8/11 Enterobacteriaceae-infected patients with isolates resistant to third generation cephalosporins. Strong and significant resistance covariation between 3rd. generation cephalosporins, chloramphenicol, gentamicin, and co-trimoxazole was identified. Pronounced pancytopenia was common and associated with increased mortality. HIV positive patients had no excess mortality.