Considerable variation of trough ß-lactam concentrations in older adults hospitalized with infection-a prospective observational study.

In older adults, few studies confirm that adequate concentrations of antibiotics are achieved using current dosage regimens of intravenous ß-lactam antibiotics. Our objective was to investigate trough concentrations of cefotaxime, meropenem, and piperacillin in older adults hospitalized with infection. We included 102 patients above 70 years of age. Total trough antibiotic concentrations were measured and related to suggested target intervals. Information on antibiotic dose, patient characteristics, and 28-day outcomes were collected from medical records and regression models were fitted. Trough concentrations for all three antibiotics exhibited considerable variation. Mean total trough concentrations for cefotaxime, meropenem, and piperacillin were 6.5 mg/L (range 0-44), 3.4 mg/L (range 0-11), and 30.2 mg/L (range 1.2-131), respectively. When a target range of non-species-related breakpoint - 5× non-species-related breakpoint was applied, only 36% of patients had both values within the target range. Regression models revealed that severe sepsis was associated with varying concentration levels and increasing age and diminishing kidney function with high concentration levels. The study was not powered to demonstrate consequences in clinical outcomes. Conclusively, in older adults treated with cefotaxime, meropenem, or piperacillin-tazobactam, trough antibiotic concentrations varied considerably. Better predictors to guide dosing regimens of ß-lactam antibiotics or increased use of therapeutic drug monitoring are potential ways to address such variations.

Repeated nationwide point-prevalence surveys of antimicrobial use in Swedish hospitals: data for actions 2003-2010.

This study sought to analyse antimicrobial pressure, indications for treatment, and compliance with treatment recommendations and to identify possible problem areas where inappropriate use could be improved through interventions by the network of the local Swedish Strategic Programme Against Antibiotic Resistance (Strama) groups. Five point-prevalence surveys were performed in between 49 and 72 participating hospitals from 2003 to 2010. Treatments were recorded for 19 predefined diagnosis groups and whether they were for community-acquired infection, hospital-acquired infection, or prophylaxis. Approximately one-third of inpatients were treated with antimicrobials. Compliance with guidelines for treatment of community-acquired pneumonia with narrow-spectrum penicillin was 17.0% during baseline 2003-2004, and significantly improved to 24.2% in 2010. Corresponding figures for quinolone use in uncomplicated cystitis in women were 28.5% in 2003-2004, and significantly improved, decreasing to 15.3% in 2010. The length of surgical prophylaxis improved significantly when data for a single dose and 1 day were combined, from 56.3% in 2003-2004 to 66.6% in 2010. Improved compliance was possibly the effect of active local feedback, repeated surveys, and increasing awareness of antimicrobial resistance. Strama groups are important for successful local implementation of antimicrobial stewardship programs in Sweden.

Risk factors, outcome and impact of empirical antimicrobial treatment in extended-spectrum ß-lactamase-producing Escherichia coli bacteraemia.

BACKGROUND: To investigate patient characteristics and empirical antimicrobial treatment of extended-spectrum ß-lactamase-producing Escherichia coli (ESBL-EC) bacteraemia, to determine risk factors, outcome and impact of empirical antimicrobial treatment. METHODS: We performed a retrospective case-control study of all patients diagnosed with ESBL-EC from January 2011 to September 2012. The control group consisted of patients with non-ESBL E. coli bacteraemia. The groups were compared with respect to empirical treatment, risk factors and outcome, using univariate and multivariate analysis. RESULTS: The study consisted of 70 consecutive cases of ESBL-producing and 140 controls of non-ESBL-producing E. coli bacteraemia. ESBL-EC prevalence of bloodstream invasive E. coli isolates was 6.1%. The independent risk factor found for ESBL-EC bacteraemia was a prior culture with ESBL production (p < 0.001). A higher frequency of inappropriate empirical antibiotic treatment (p < 0.001) and a trend towards worse outcome was observed in patients infected with ESBL-EC and empirical guidelines were more often not followed (p = 0.013). If the guidelines were followed this was associated with adequate initial antibiotic treatment (p < 0.001). CONCLUSIONS: Patients with ESBL-EC frequently received inappropriate empirical treatment and guidelines were more often not followed. A prior culture of ESBL-producing bacteria was an independent predictor and risk factor for ESBL-EC bacteraemia. Since the prevalence of ESBL-producing E. coli is increasing the importance of adequate guidelines must be emphasized.

High incidence of septic shock caused by Streptococcus pneumoniae serotype 3--a retrospective epidemiological study.

BACKGROUND: More than 90 immunologically distinct serotypes of Streptococcus pneumoniae exist, and it is not fully elucidated whether the serotype is a risk factor for severity of invasive pneumococcal disease (IPD). Our hypothesis is that serotypes differ in their capacity to cause septic shock. METHODS: We performed a retrospective study in Southern Sweden based upon 513 patients with IPD in the pre-vaccine era 2006-2008. The serotype, co-morbidity, and sepsis severity were determined. Serotypes were compared to serotype 14 as a reference and grouped according to their invasive potential, that is, high (serogroups 1, 5 and 7), intermediate (serogroups 4, 9, 14 and 18) and, finally, low invasive potential (serogroups 3, 6, 8, 15, 19, 23 and 33). RESULTS: Patients with S. pneumoniae serotype 3 had significantly more often septic shock (25%, odds ratio (OR) 6.33 [95% confidence interval (CI) 1.59-25.29]), higher mortality (30%, OR 2.86 [CI 1.02-8.00]), and more often co-morbidities (83%, OR 3.82 [CI 1.39-10.54]) when compared to serotype 14. A significant difference in age and co-morbidities (p ≤ 0.001) was found when patient data were pooled according to the invasive potential of the infecting pneumococci. The median age and percentage of patients with underlying co-morbidities were 72 years and 79%, respectively, for serogroups associated with low invasiveness, 68 years and 61%, respectively, for serogroups with intermediate invasiveness, and, finally, 62 years and 48%, respectively, for serogroups with high invasiveness. No difference in sepsis severity was found between the three groups. CONCLUSIONS: S. pneumoniae serotype 3 more often caused septic shock compared to serotype 14. Our results support the hypothesis that serotypes with high invasiveness mainly cause IPD in younger patients with less co-morbidities. In contrast, serogroups with low and intermediate invasive potential mostly cause IPD in the elderly with defined co-morbidities, and thus can be considered as opportunistic.

Increase of ß-lactam-resistant invasive Haemophilus influenzae in Sweden, 1997 to 2010.

The proportions of Haemophilus influenzae resistant to ampicillin and other ß-lactam antibiotics have been low in Sweden compared to other countries in the Western world. However, a near-doubled proportion of nasopharyngeal Swedish H. influenzae isolates with resistance to ß-lactams has been observed in the last decade. In the present study, the epidemiology and mechanisms of antimicrobial resistance of H. influenzae isolates from blood and cerebrospinal fluid in southern Sweden from 1997 to 2010 (n = 465) were studied. Antimicrobial susceptibility testing was performed using disk diffusion, and isolates with resistance to any tested ß-lactam were further analyzed in detail. We identified a significantly increased (P = 0.03) proportion of ß-lactam-resistant invasive H. influenzae during the study period, which was mainly attributed to a significant recent increase of ß-lactamase-negative ß-lactam-resistant isolates (P = 0.04). Furthermore, invasive ß-lactamase-negative ß-lactam-resistant H. influenzae isolates from 2007 and onwards were found in higher proportions than the corresponding proportions of nasopharyngeal isolates in a national survey. Multiple-locus sequence typing (MLST) of this group of isolates did not completely separate isolates with different resistance phenotypes. However, one cluster of ß-lactamase-negative ampicillin-resistant (BLNAR) isolates was identified, and it included isolates from all geographical areas. A truncated variant of a ß-lactamase gene with a promoter deletion, bla(TEM-1)-PΔ dominated among the ß-lactamase-positive H. influenzae isolates. Our results show that the proportions of ß-lactam-resistant invasive H. influenzae have increased in Sweden in the last decade.

Duration of colonization with extended-spectrum beta-lactamase-producing Escherichia coli in patients with travellers' diarrhoea.

BACKGROUND: Resistant Enterobacteriaceae have become a worldwide epidemic during the last decade and are a great threat to health care worldwide. International travel is a major risk factor for becoming colonized with extended-spectrum beta-lactamase (ESBL)-producing bacteria. Data on the persistence of colonization with ESBL-producing bacteria in the faecal flora are limited. METHODS: A prospective cohort study was performed between October 2007 and October 2010. Fifty-eight patients with faecal carriage of ESBL-producing Escherichia coli from a previous study of patients with travellers' diarrhoea were included. RESULTS: Forty-one of the patients had a complete follow-up. Ten of these patients (24%) carried ESBL-producing E. coli at the first follow-up point (3-8 months), of whom 4 had a new ESBL strain. At the 3-y follow-up, 4 patients carried ESBL (10%), of whom 1 had 2 new ESBL strains. CONCLUSIONS: The long duration of ESBL carriage is worrisome. These carriers may be an important source of the spread of ESBLs in the population and this has implications for the clinical management of patients.

Eradication of nasopharyngeal carriage of penicillin-non-susceptible Streptococcus pneumoniae--is it possible?

BACKGROUND: The South Swedish Pneumococcal Intervention Project (SSPIP) was started in 1995 with the aim of limiting the spread of penicillin-non-susceptible pneumococci (PNSP) in Skåne County, Sweden. As part of the SSPIP, eradication therapy with rifampicin in combination with 1 more antibiotic was considered on a social indication after prolonged carriage of 2-3 months. METHODS: In this retrospective study, 125 medical records were analyzed. Children aged 0-10 y referred for eradication therapy in Malmö and Lund, due to a prolonged nasopharyngeal carriage of PNSP with a penicillin G minimum inhibitory concentration of ≥ 0.5 mg/l, between the y 1997 and 2011 were included. Two consecutive negative cultures, with the second one no shorter than 7 days after treatment completion, were required for the carriage to be considered eradicated. RESULTS: Out of 125 children, 71 received treatment with rifampicin in combination with amoxicillin (n = 44), erythromycin (n = 22), or clindamycin (n = 5) for 7 days. Eradication treatment was successful in 91.5% of the children. Six children (8.5%) had treatment failure with amoxicillin and rifampicin; 3 were found by late follow-up. There was a trend towards a better outcome with erythromycin and clindamycin combinations in comparison to amoxicillin. CONCLUSIONS: Eradication therapy was successful, but a proper follow-up is essential.

Necrotizing myositis and septic shock caused by Haemophilus influenzae type f in a previously healthy man diagnosed with an IgG3 and a mannose-binding lectin deficiency.

An increased incidence of infections by Haemophilus influenzae type f (Hif) has recently been suggested, but such infections have mainly been regarded as opportunistic. We present here a dramatic case of Hif necrotizing myositis and septic shock. A subsequently diagnosed IgG3 and mannose-binding lectin deficiency possibly contributed to the severe outcome.

Duration of methicillin-resistant Staphylococcus aureus colonization after diagnosis: a four-year experience from southern Sweden.

BACKGROUND: The duration of colonization with methicillin-resistant Staphylococcus aureus (MRSA) is not well known and there is debate as to whether a patient colonized with MRSA ever can be defined as 'MRSA-negative'. METHODS: Since 2003 all notified MRSA cases have been systematically followed in Skåne County, southern Sweden. Cultures are taken from the nares, throat, perineum and possible skin lesions. Contact tracing is conducted. The screening program continues as long as cultures are positive and then until 1 y of consecutive negative cultures for MRSA is completed. RESULTS: Of the 578 MRSA cases during 2003-2006, 535 were included in this retrospective study. The median duration of colonization with MRSA was 5.9 months. Having household contacts with MRSA, young age, spa-type t002 and colonization in 2 or more locations, were significantly associated with a longer duration of colonization. Having a clinical infection treated with antibiotics (compared to clinical infection with no antibiotic treatment or asymptomatic carriage) was significantly associated with a shorter carriage time. Eradication treatment was associated with a shorter carriage time. CONCLUSION: These results may have implications for the management of patients with MRSA carriage. The study indicates that MRSA carriage can be defined as 'negative' in a follow-up program and shows the importance of performing contact tracing among household members.

Bacterial aetiology in ventilator-associated pneumonia at a Swedish university hospital.

Ventilator-associated pneumonia (VAP) is a common complication of respiratory support and is associated with increased mortality, morbidity and costs, and a prolonged stay in the intensive care unit. Scandinavian data on the aetiology in VAP are lacking. We hereby present a retrospective study on the aetiology of VAP diagnosed by protective specimen brush culture at Malmö University Hospital in relation to early- and late-onset VAP, antibiotic treatment and the incidence of drug-resistant bacteria. Patients registered with a diagnosis of VAP between January 2004 and September 2007 were included in the study. Sixty-five of 109 patients diagnosed with VAP met the inclusion criteria, and 103 bacterial isolates were cultured from these patients. The most common findings among the 65 VAP episodes were Enterobacteriaceae (28), Pseudomonas aeruginosa (13), Haemophilus influenzae (12) and Staphylococcus aureus (8). Patients with no antibiotic treatment at the onset of VAP had significantly more H. influenzae (p = 0.035) and Gram-positive pathogenic bacteria (p = 0.019). There was no difference in incidence of P. aeruginosa between early- and late-onset VAP. Resistant bacteria were found in 18% of the patients.

Extended-spectrum beta-lactamase-producing Escherichia coli in patients with travellers' diarrhoea.

The identification of patients carrying extended-spectrum beta-lactamase (ESBL)-producing bacteria is important, since these patients are at risk of receiving inappropriate empirical therapy if they become infected. The purpose of this study was to investigate the occurrence of ESBL-producing bacteria in patients with travellers' diarrhoea. Patients with travellers' diarrhoea (N = 242) having delivered stool samples for the diagnosis of Salmonella, Shigella, Yersinia or Campylobacter, were also examined for ESBL-producing Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis. The overall prevalence of faecal carriage of ESBL-producing bacteria was 24% (58/242). Of the patients who had travelled in Europe, 3% (2/63) were found to be ESBL carriers in comparison to 36% (50/138) of those who had travelled outside Europe. ESBL-producing E. coli was especially common among patients returning from India (11/14), Egypt (19/38; 50%) and Thailand (8/38; 22%). In total, 90% of the genes of the ESBL-positive samples were of CTX-M type. The CTX-M-1 group dominated, followed by the CTX-M-9 group. The repetitive sequence-based PCR fingerprint pattern showed that there was no similarity between the ESBL strains found. Patients who have travelled outside Europe are at high risk of being colonized with ESBL-producing Enterobacteriaceae, and, if infected, are also at risk of receiving inappropriate empirical antibiotic therapy.

Hydrogen peroxide vapour treatment inactivates norovirus but has limited effect on post-treatment viral RNA levels.

BACKGROUND: Hydrogen peroxide vapour is used as a room disinfectant. Its activity against murine norovirus, a surrogate viability marker for human norovirus, indicates that it is also active against human norovirus. AIM: The aim of this study is to assess how this effect on viability is reflected in measurements of RNA by quantitative PCR (qPCR). METHODS: Faeces suspensions of two human norovirus field strains, genogroup I and II and one cultured murine norovirus strain, (genogroup V) were dried on plastic plates, and underwent hydrogen peroxide vapour treatment or were mock treated. The influence of hydrogen peroxide on RNA was measured on genogroups I, II and V by qPCRs and for the cultivable murine norovirus also for viability by cell culture. Virucidal activity on murine norovirus was measured by endpoint titrations as the 50% tissue culture infectious dose, based both on cytopathic effect and on presence of replicating intracellular minus strand RNA. RESULTS: The mean impact on the human norovirus qPCRs was 0.4 log10. The murine norovirus qPCR changed by 1.7 log10 but by an alternative qPCR only by 0.4 log10. These minor changes contrasted the 4.5-5.0 log10 murine norovirus viability reduction after treatment measured by cytopathic effect or intracellular negative-strand RNA. CONCLUSION: Inactivation of murine norovirus viability by hydrogen peroxide vapour was not reflected in qPCR levels. This finding might be extrapolated to the related human norovirus genogroups. We further found that cellular minus strand murine norovirus PCR was an observer-independent marker to study reduction of murine norovirus viability.

Pharmacodynamic studies of vancomycin, metronidazole and fusidic acid against Clostridium difficile.

BACKGROUND: Pharmacodynamic studies of antibiotics have attracted great interest in recent years. However, studies on the pharmacodynamics of different antibiotics against Clostridium difficile are scarce. METHODS: The postantibiotic effects (PAE) and the postantibiotic sub-minimum inhibitory concentration (MIC) effects (PA SME) of vancomycin, metronidazole and fusidic acid were investigated by viable counts against three different strains of C. difficile. The killing rate and extent of the three antibiotics against the same strains were also studied by adding 2, 4, 8, 16 and 32x MIC of the three antibiotics, respectively. RESULTS: Metronidazole exerted a very rapid bactericidal effect at concentrations of 8x MIC and above against all three strains investigated. Vancomycin gave overall less kill in comparison to metronidazole and was bacteriostatic against two of the three strains. Fusidic acid exerted a concentration-dependent killing against two of the strains. Vancomycin exerted short PAEs and PA SMEs against all three strains. Significantly longer PAEs and PA SMEs were noted for fusidic acid. Metronidazole gave similar short PAEs like vancomycin but longer PA SMEs were noted against two of the investigated strains. CONCLUSION: Metronidazole exerted the most prominent bactericidal effect greater than fusidic acid and greater than vancomycin. Fusidic acid gave overall the longest PAEs and PA SMEs greater than metronidazole and greater than vancomycin.

Assessment of early combination effects of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii in dynamic time-kill experiments.

BACKGROUND: In view of the paucity of clinical evidence, in vitro studies are needed to find antibiotic combinations effective against multidrug-resistant Gram-negative bacteria. Interpretation of in vitro effects is usually based on bacterial growth after 24 h in time-kill and checkerboard experiments. However, the clinical relevance of the effects observed in vitro is not established. In this study we explored alternative output parameters to assess the activities of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii. METHODS: Four strains each of P. aeruginosa and A. baumannii were exposed to colistin and meropenem, alone and in combination, in 8 h dynamic time-kill experiments. Initial (1 h), maximum and 8 h bacterial reductions and the area under the bacterial time-kill curve were evaluated. Checkerboards, interpreted based on fractional inhibitory concentration indices after 24 h, were performed for comparison. RESULTS: In the time-kill experiments, the combination resulted in enhanced 1 h, maximum and 8 h bacterial reductions against 2, 3 and 5 of 8 strains, respectively, as compared to the single drugs. A statistically significant reduction in the area under the time-kill curve was observed for three strains. In contrast, the checkerboards did not identify synergy for any of the strains. CONCLUSIONS: Combination effects were frequently found with colistin and meropenem against P. aeruginosa and A. baumannii in time-kill experiments but were not detected with the checkerboard method. We propose that the early dynamics of bacterial killing and growth, which may be of great clinical importance, should be considered in future in vitro combination studies.

Hydrogen Peroxide Vapor Decontamination in a Patient Room Using Feline Calicivirus and Murine Norovirus as Surrogate Markers for Human Norovirus.

OBJECTIVE: To determine whether hydrogen peroxide vapor (HPV) could be used to decontaminate caliciviruses from surfaces in a patient room. DESIGN: Feline calicivirus (FCV) and murine norovirus (MNV) were used as surrogate viability markers to mimic the noncultivable human norovirus. Cell culture supernatants of FCV and MNV were dried in triplicate 35-mm wells of 6-well plastic plates. These plates were placed in various positions in a nonoccupied patient room that was subsequently exposed to HPV. Control plates were positioned in a similar room but were never exposed to HPV. METHODS: Virucidal activity was measured in cell culture by reduction in 50% tissue culture infective dose titer for FCV and by both 50% tissue culture infective dose titer and plaque reduction for MNV. RESULTS: Neither viable FCV nor viable MNV could be detected in the test room after HPV treatment. At least 3.65 log reduction for FCV and at least 3.67 log reduction for MNV were found by 50% tissue culture infective dose. With plaque assay, measurable reduction for MNV was at least 2.85 log units. CONCLUSIONS: The successful inactivation of both surrogate viruses indicates that HPV could be a useful tool for surface decontamination of a patient room contaminated by norovirus. Hence nosocomial spread to subsequent patients can be avoided.

An Audit-Based, Infectious Disease Specialist-Guided Antimicrobial Stewardship Program Profoundly Reduced Antibiotic Use Without Negatively Affecting Patient Outcomes.

Background. Antimicrobial stewardship programs are increasingly implemented in hospital care. They aim to simultaneously optimize outcomes for individual patients with infections and reduce financial and health-associated costs of overuse of antibiotics. Few studies have examined the effects of antimicrobial stewardship programs in settings with low proportions of antimicrobial resistance, such as in Sweden. Methods. An antimicrobial stewardship program was introduced during 5 months of 2013 in a department of internal medicine in southern Sweden. The intervention consisted of audits twice weekly on all patients given antibiotic treatment. The intervention period was compared with a historical control consisting of patients treated with antibiotics in the same wards in 2012. Studied outcome variables included 28-day mortality and readmission, length of hospital stay, and use of antibiotics. Results. A reduction of 27% in total antibiotic use (2387 days of any antibiotic) was observed in the intervention period compared with the control period. The reduction was due to fewer patients started on antibiotics as well as to significantly shorter durations of antibiotic courses (P < .001). An earlier switch to oral therapy and a specific reduction in use of third-generation cephalosporins and fluoroquinolones was also evident. Mortality, total readmissions, and lengths of stay in hospital were unchanged compared with the control period, whereas readmissions due to a nonresolved infection were fewer during the intervention of 2013. Conclusions. This study demonstrates that an infectious disease specialist-guided antimicrobial stewardship program can profoundly reduce antibiotic use in a low-resistance setting with no negative effect on patient outcome.

Prevalence of penicillin-non-susceptible Streptococcus pneumoniae in children in day-care centres subjected to an intervention to prevent dispersion.

BACKGROUND: The aim of this study was to evaluate the day-care interventions implemented in southern Sweden to restrict the dispersion of penicillin-non-susceptible pneumococci with a minimum inhibitory concentration of penicillin G of at least 0.5 mg/l (PNSP0.5). METHODS: A retrospective epidemiological study was performed and data from 109 day-care centre interventions from 2000 to 2010 were analysed, including screening results from 7157 individuals. RESULTS: It was found that 42% of the children were carriers of pneumococci and 5% of the screened children were PNSP0.5 carriers. Very few personnel were PNSP0.5 carriers and they were carriers for only a short time. Significantly more contact cases with the same serogroup as the index case were found in the first screening and in the same department as the index case, but a substantial number of contact cases were found in adjacent departments. CONCLUSIONS: Screening of personnel is not worth the effort. Based on our results, procedures to restrict dispersion of PNSP0.5 in day-care centres could be improved. To find the majority of contact cases with PNSP0.5 an early screening including adjacent departments seems to be the best approach.

Activity of three disinfectants and acidified nitrite against Clostridium difficile spores.

OBJECTIVE: To identify environmentally safe, rapidly acting agents for killing spores of Clostridium difficile in the hospital environment. DESIGN: Three classic disinfectants (2% glutaraldehyde, 1.6% peracetyl ions, and 70% isopropanol) and acidified nitrite were compared for activity against C. difficile spores. Four strains of C. difficile belonging to different serogroups were tested using a dilution-neutralization method according to preliminary European Standard prEN 14347. For peracetyl ions and acidified nitrite, the subjective cleaning effect and the sporicidal activity was also tested in the presence of organic load. RESULTS: Peracetyl ions were highly sporicidal and yielded a minimum 4 log10 reduction of germinating spores already at short exposure times, independent of organic load conditions. Isopropanol 70% showed low or no inactivation at all exposure times, whereas glutaraldehyde and acidified nitrite each resulted in an increasing inactivation factor (IF) over time, from an IF greater than 1.4 at 5 minutes of exposure time to greater than 4.1 at 30 minutes. Soiling conditions did not influence the effect of acidified nitrite. There was no difference in the IF among the 4 strains tested for any of the investigated agents. Acidified nitrite demonstrated a good subjective cleaning effect and peracetyl ions demonstrated a satisfactory effect. CONCLUSIONS: Cidal activity was shown against C. difficile spores by glutaraldehyde, peracetyl ions, and acidified nitrite. As acidified nitrite and peracetyl ions are considered to be environmentally safe chemicals, these agents seem well suited for the disinfection of C. difficile spores in the hospital environment.