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Background: Inpatient quality indicators (IQIs) were previously developed to assess responsible antibiotic use., Aim: Practice testing of these QIs in the hospital setting., Method: This study was performed within a Dutch-Belgian border network of hospitals implementing the Infection Risk Scan (IRIS) point prevalence survey (PPS) as part of the i-4-1-Health project. Twenty out of 51 DRIVE-AB IQIs, including 13 structure and seven process IQIs, were tested. Data on structure IQIs were obtained through a web-based questionnaire sent to the hospital medical microbiologists. PPS data from October to December 2018 were used to calculate performance scores for the process QIs., Findings: Nine hospitals participated. Regarding structure IQIs: the lowest performance scores were observed for recommendations for microbiological investigations in the guidelines and the use of an approval system for restricted antibiotics. In addition, most hospitals reported that some antibiotics were out of stock due to shortages. Regarding process IQIs: 697 systemic antibiotic prescriptions were used to calculate performance scores. The lowest score was observed for documentation of an antibiotic plan in the medical file (58.8%). Performance scores for IQIs on guideline compliance varied between 74.1% and 82.3% for different aspects of the antibiotic regimen (duration, choice, route, timing)., Conclusion: This multicentre practice testing of IQIs identified improvement targets for stewardship efforts for both structure and process aspects of antibiotic care (approval system for restricted antibiotics, documentation of antibiotic plan). These results can guide the design of future PPS studies and a more extensive evaluation of the clinimetric properties of the IQIs., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Vaccines are applied to large populations, but only recently has research into immunologic responses and mechanisms started to increase exponentially. Some live vaccines, such as the tuberculosis vaccine bacillus Calmette-Guérin, protect against other infections nonspecifically by eliciting complex immune responses which are not specific antibody related. These heterologous effects are explained by the concept of trained immunity. This editorial introduces five narrative reviews offering recent insights on innate and adaptive immune memory towards a variety of pathogens., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: To explore inpatients experiences and views with regard to antibiotics in five European hospitals., Methods: Qualitative study where a patient-centred framework was used to explore inpatients' experiences concerning antibiotic treatment. A purposeful sample of inpatients treated with antibiotics in five hospitals participated in interviews (all centres) and focus groups (Switzerland only)., Results: A total of 31 interviews (five in Belgium, ten in Croatia, nine in France, five in the Netherlands and two in Switzerland) and three focus groups (in Switzerland, 11 participants) were performed. The median age of participants was 61 years (range 33-86 years). The following main themes emerged: (a) patients trust doctors to take the best decisions for them even though communication concerning different antibiotic-related aspects is often insufficient, (b) patients feel that doctors do not prioritize communication due to time constraints and do not seem to adapt information based on patients' preferences, (c) patients differ in their wish to be informed but overall want to be informed on the main aspects in an understandable way, (d) patients often find reassurance in sharing information about their antibiotic treatment with close family, (e) professionals should explore patients' preferences to be involved or not in shared decision making for antibiotic treatment., Conclusion: Inpatients often doubt their ability to understand medical information and trust their physicians to take the best decisions for them. Tailored strategies that inform hospitalized patients, acknowledging their concerns and preferences, may be useful to promote patient involvement and to improve communication regarding antibiotic use., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: We aimed to assess patient-related determinants potentially influencing antibiotic use., Methods: Studies published in MEDLINE until 30 September 2015 were searched. We included: qualitative studies describing patients' self-reported determinants of antibiotic use; and quantitative studies on either self-reported or objectively assessed determinants associated with antibiotic use. Whenever possible, reported determinants were categorized as 'barriers' or 'facilitators' of responsible antibiotic use., Results: A total of 87 studies from 33 countries were included. Seventy-five (86.2%) were quantitative and described self-reported (45/75, 60.0%), objectively assessed (20/75, 26.7%) or self-reported and objectively assessed (10/75, 13.3%) patient-related determinants. Twelve (12/87, 13.8%) were qualitative studies or had a qualitative and quantitative component. Eighty-six of the studies (98.8%) concerned the outpatient setting. We identified seven broad categories of determinants having an impact on different aspects of antibiotic use (in descending order of frequency): demographic and socio-economic characteristics, patient-doctor interactions (e.g. counselling), treatment characteristics (e.g. administration frequency), attitudes (e.g. expecting antibiotics), access to treatment (e.g. patients' direct costs), characteristics of the condition for which the antibiotic was prescribed (e.g. duration of symptoms), knowledge (e.g. regarding indications for treatment). Most determinants were classified as 'barriers' to responsible antibiotic use., Conclusion: A large variety of patient-related determinants impact antibiotic use. The most easily 'modifiable' determinants concern patient-doctor interactions, treatment characteristics and knowledge. Data from the inpatient setting and low- and middle-income countries were underrepresented. Further studies should develop and test interventions that take these determinants into account with the ultimate aim of improving responsible use of antibiotics., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Non-tuberculous mycobacteria are a known cause of skin and soft tissue infections. However, only too often it takes inordinately long to arrive at the appropriate diagnosis and start treatment. Actively searching for predilection factors, exposure risks and specific clinical clues may speed up the diagnostic process. Deep tissue biopsy cultures are indispensable to determine the species and strain of mycobacterium, with important consequences for treatment. Less well known as a causative agent of prolonged tenosynovitis is Mycobacterium tuberculosis. We present a case series and performed a literature search concerning mycobacterial tenosynovitis.

Background: Antiretroviral agents pose a high risk for drug-drug interactions (DDIs), mainly but not limited to being a substrate, inducer or inhibitor of P450 cytochrome enzymes. In part metabolised by other pathways, integrase inhibitors might show a more favourable profile. The aim of this study was to investigate the prevalence of DDIs in daily clinical practice for patients starting different antiretroviral treatment (ART) regimens., Methods: All patients starting ART in our centre from January 2009 to April 2016 were included. All prescribed co-medications since the start of ART were recorded retrospectively from the medical files and screened for DDIs using the Liverpool HIV drug interaction database. Only DDIs between antiretroviral and non-antiretroviral drugs were considered., Results: We included 145 patients, of which 42% were on an integrase inhibitor-based regimen, mainly dolutegravir and elvitegravir. Of the patients, 78% (n = 113) took co-medication. Potential DDIs were seen in 63% of the patients with co-medication; contraindicated prescriptions were detected in 1%. Protease inhibitor-based ART was a risk factor for DDI (odds ratio (OR) 2.57; 95% confidence interval (CI) 1.06-6.19), in contrast to non-nucleoside reverse transcriptase inhibitor-based ART (OR 0.77; 95% CI 0.32-1.84). Concerning integrase inhibitors, a significantly lower risk was seen with dolutegravir-based treatment (OR 0.35; 95% CI 0.15-0.82), though not for elvitegravir-based ART (OR 2.51; 95% CI 0.66-9.58)., Conclusions: ART regimens pose a dissimilar risk for drug-drug interactions in clinical practice. Regarding the use of integrase inhibitors, a significantly lower risk was seen with dolutegravir-based treatment.

Major abscesses and diabetic foot infections (DFIs) are predominant subtypes of complicated skin and skin structure infections (cSSSIs), and are mainly caused by Staphylococcus aureus and β-hemolytic streptococci. This study evaluates the potential benefit of direct pathogen-specific real-time polymerase chain reaction (PCR) assays in the identification of causative organisms of cSSSIs. One-hundred and fifty major abscess and 128 DFI biopsy samples were collected and microbial DNA was extracted by using the Universal Microbe Detection kit for tissue samples. Pathogen-specific PCRs were developed for S. aureus and its virulence factor Panton-Valentine leukocidin (PVL), Streptococcus pyogenes, S. agalactiae, S. dysgalactiae, and the S. anginosus group. Identification by pathogen-specific PCRs was compared to routine culture and both methods were considered as the gold standard for determination of the sensitivity and specificity of each assay. Direct real-time PCR assays of biopsy samples resulted in a 34 % higher detection of S. aureus, 37 % higher detection of S. pyogenes, 18 % higher detection of S. agalactiae, 4 % higher detection of S. dysgalactiae subspecies equisimilis, and 7 % higher detection of the S. anginosus group, compared to routine bacterial culture. The presence of PVL was mainly confined to S. aureus isolated from major abscess but not DFI biopsy samples. In conclusion, our pathogen-specific real-time PCR assays had a higher yield than culture methods and could be an additional method for the detection of relevant causative pathogens in biopsies.

We surveyed European medical schools regarding teaching of prudent antibiotic prescribing in the undergraduate curriculum. We performed a cross-sectional survey in 13 European countries (Belgium, Croatia, Denmark, France, Germany, Italy, Netherlands, Norway, Serbia, Slovenia, Spain, Switzerland, United Kingdom) in 2013. Proportional sampling was used, resulting in the selection of two to four medical schools per country. A standardized questionnaire based on literature review and validated by a panel of experts was sent to lecturers in infectious diseases, medical microbiology and clinical pharmacology. In-depth interviews were conducted with four lecturers. Thirty-five of 37 medical schools were included in the study. Prudent antibiotic use principles were taught in all but one medical school, but only four of 13 countries had a national programme. Interactive teaching formats were used less frequently than passive formats. The teaching was mandatory for 53% of the courses and started before clinical training in 71%. We observed wide variations in exposure of students to important principles of prudent antibiotic use among countries and within the same country. Some major principles were poorly covered (e.g. reassessment and duration of antibiotic therapy, communication skills). Whereas 77% of the respondents fully agreed that the teaching of these principles should be prioritized, lack of time, mainly due to rigid curriculum policies, was the main reported barrier to implementation. Given the study design, these are probably optimistic results. Teaching of prudent antibiotic prescribing principles should be improved. National and European programmes for development of specific learning outcomes or competencies are urgently needed., (Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Complicated skin and skin structure infections (cSSSIs) are caused by Gram-positive and Gram-negative, aerobic and anaerobic pathogens, with a polymicrobial aetiology being frequent. Recognition of invading pathogens by the immune system results in the production of pro- and anti-inflammatory cytokines, which are extremely important for intercellular communication and control of infection. This study assessed whether genetic variation in genes encoding cytokines influences the susceptibility to cSSSIs. For the association study, 318 patients with cSSSI and 328 healthy controls were genotyped for single nucleotide polymorphisms (SNPs) in cytokine genes IL1A, IL1B, IL1RN, TNF, IL10, IL17A, IL17F and IFNG. For immunological validation, peripheral blood mononuclear cells (PBMCs) from 74 healthy individuals, genotyped for SNPs of interest, were stimulated with Staphylococcus aureus or Escherichia coli and corresponding cytokine levels were determined by enzyme-linked immunosorbent assay (ELISA). Polymorphisms IL6 rs1800797, TNF rs1800629, IL10 rs1800871, IL17A rs8193036 and IFNG rs2069705 influenced susceptibility to cSSSIs. No differences in cytokine responses, stratified for genotype, were detected after PBMC stimulation. No association with cSSSIs was observed for polymorphisms IL1A rs17561 and rs1800587, IL1B rs16944 and rs1143627, IL1RN rs4251961, TNF rs361525, IL10 rs1800896, IL17A rs2275913 and IL17F rs763780. In conclusion, polymorphisms in IL6, TNF, IL10, IL17A and IFNG are associated with susceptibility to cSSSIs.

Objective: The aim was to compare the efficacy and safety of two antibiotic regimens in patients with diabetic foot infections (DFIs)., Methods: Data of a subset of patients enrolled in the RELIEF trial with DFIs requiring surgery and antibiotics were evaluated retrospectively. DFI was diagnosed on the basis of the modified Wagner, University of Texas, and PEDIS classification systems. Patients were randomized to receive either intravenous/oral moxifloxacin (MXF, N = 110) 400 mg q.d. or intravenous piperacillin/tazobactam 4.0/0.5 g t.d.s. followed by oral amoxicillin/clavulanate 875/125 mg b.d. (PIP/TAZ-AMC, N = 96), for 7-21 days until the end of treatment (EOT). The primary endpoint was clinical cure rates in the per-protocol (PP) population at the test-of-cure visit (TOC, 14-28 days after EOT)., Results: There were no significant differences between the demographic characteristics of PP patients in either treatment group. At TOC, MXF and PIP/TAZ-AMC had similar efficacy in both the PP and intent-to-treat (ITT) populations: MXF: 76.4 % versus PIP/TAZ-AMC: 78.1 %; 95 % confidence interval (CI) -14.5 %, 9.0 % in the PP population; MXF: 69.9 % versus PIP/TAZ-AMC: 69.1 %; 95 % CI -12.4 %, 12.1 % in the ITT population. The overall bacteriological success rates were similar in both treatment groups (MXF: 71.7 % versus PIP/TAZ-AMC: 71.8 %; 95 % CI -16.9 %, 10.7 %). A similar proportion of patients (ITT population) experienced any adverse events in both treatment groups (MXF: 30.9 % versus PIP/TAZ-AMC: 31.8 %, respectively). Death occurred in three MXF-treated patients and one PIP/TAZ-AMC-treated patient; these were unrelated to the study drugs., Conclusion: Moxifloxacin has shown favorable safety and efficacy profiles in DFI patients and could be an alternative antibiotic therapy in the management of DFI., Clinical Trial: NCT00402727.

We report a case of viral peritonitis caused by coxsackievirus B1 in a 79-year-old male undergoing continuous ambulatory peritoneal dialysis (CAPD), and review the English language literature. Clinicians should be aware of viral peritonitis in patients on CAPD presenting with a viral syndrome and mononuclear peritoneal dialysis effluent. Currently, viral diagnostic tests are available to confirm the diagnosis and avoid unnecessary treatment with antibiotics., (© 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

Macrophages are known to be involved in pathogen recognition and mediate host immune responses, but, in the clinical setting, their purported central role in opportunistic fungal infections has not been demonstrated to date. Herein, we describe a patient with invasive testicular aspergillosis in whom we found, for the first time, a defect in macrophage function., (© 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.)

Although the epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) varies across Europe, healthcare-associated MRSA infections are common in many countries. Despite several national guidelines, the approach to treatment of MRSA infections varies across the continent, and there are multiple areas of management uncertainty for which there is little clinical evidence to guide practice. A faculty, convened to explore some of these areas, devised a survey that was used to compare the perspectives of infection specialists from across Europe on the management of MRSA infections with those of the faculty specialists. The survey instrument, a web-based questionnaire, was sent to 3840 registered delegates of the 19th European Congress of Clinical Microbiology and Infectious Diseases, held in April 2009. Of the 501 (13%) respondents to the survey, 84% were infection/microbiology specialists and 80% were from Europe. This article reports the survey results from European respondents, and shows a broad range of opinion and practice on a variety of issues pertaining to the management of minor and serious MRSA infections, such as pneumonia, bacteraemia, and skin and soft tissue infections. The issues include changing epidemiology, when and when not to treat, choice of treatment, and duration and route of treatment. The survey identified areas where practice can be improved and where further research is needed, and also identified areas of pan-European consensus of opinion that could be applied to European guidelines for the management of MRSA infection.

The Dutch Working Party on Antibiotic Policy (Stichting Werkgroep AntibioticaBeleid, SWAB) was founded in 1996 as an initiative of the Society for Infectious Diseases, the Dutch Society for Medical Microbiology, and the Dutch Association of Hospital Pharmacists. Its primary goal is to contribute to the containment of antimicrobial resistance and the expanding costs incurred for the use of antibiotics. SWAB is the Intersectoral Coordinating Mechanism (ICM) for the Netherlands, and it is at present the National Antimicrobial Resistance (AMR) Focal Point. It coordinates the national surveillance of antibiotic resistance, in collaboration with the National Institute for Public Health and the Environment(RIVM), coordinates the surveillance of the use of antibiotics,and runs a guideline development programme. Information about consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria is presented annually in NethMap. Over the past decade, outpatient consumption of antibiotics has risen only slightly, but in the hospital setting there was an overall significant increase in antibiotic use, due mainly to the steady reduction in the average length of patient hospital stays. In 2006 we introduced our electronic national antibiotic guide 'SWAB-ID' for the antibiotic treatment and prophylaxis of common infectious diseases in hospitals.

This article estimates the magnitude and quality of antibiotic prescribing in Indonesian hospitals and aims to identify demographic, socio-economic, disease-related and healthcare-related determinants of use. An audit on antibiotic use of patients hospitalized for 5 days or more was conducted in two teaching hospitals (A and B) in Java. Data were collected by review of records on the day of discharge. The method was validated through concurrent data collection in Hospital A. Multivariate logistic regression analysis was performed to determine variables to explain antibiotic prescribing. Prescriptions were assessed by three reviewers using standardized criteria. A high proportion (84%) of 999 patients (499 in Hospital A and 500 in Hospital B) received an antibiotic. Prescriptions could be categorized as therapeutic (53%) or prophylactic (15%), but for 32% the indication was unclear. Aminopenicillins accounted for 54%, and cephalosporins (mostly third generation) for 17%. The average level of antibiotic use amounted to 39 DDD/100 patient-days. Validation revealed that 30% of the volume could be underestimated due to incompleteness of the records. Predictors of antibiotic use were diagnosis of infection, stay in surgical or paediatric departments, low-cost nursing care, and urban residence. Only 21% of prescriptions were considered to be definitely appropriate; 15% were inappropriate regarding choice, dosage or duration, and 42% of prescriptions, many for surgical prophylaxis and fever without diagnosis of infection, were deemed to be unnecessary. Agreement among assessors was low (kappa coefficients 0.13-0.14). Despite methodological limitations, recommendations could be made to address the need for improving diagnosis, treatment and drug delivery processes in this setting.

In the Netherlands, brucellosis is uncommon. Diagnosis is difficult and frequently delayed. We present three patients with back pain and/or arthralgia caused by brucellosis. We emphasise the importance of considering brucellosis in patients returning from a stay in a rural area of an endemic country, who present with osteoarticular symptoms and signs of chronic inflammation. Clues to the diagnosis come from a thorough medical history.

A man from Surinam presented at the Department of Internal Medicine with a perforated septum and progressive collapse of the nose. This condition had existed for 22 years, though earlier analysis had not revealed the cause. Microscopic analysis showed a granulomatous inflammatory reaction, with cultures revealing of Leishmania. The diagnosis was mucocutaneous leishmaniasis and PCR indicated Leishmania braziliensis complex. The patient was treated for mucocutaneous leishmaniasis by a 28-day course of intravenous sodium-stibogluconate therapy. Initially, treatment was stopped briefly due to neurotoxicity, but was recommenced and successfully completed. After treatment the infection parameters returned to normal and the patient was referred for reconstructive nasal surgery. Due to a low parasitic load mucocutaneous leishmaniasis can be difficult to detect, especially in chronic cases. However, the use of molecular techniques has improved both the sensitivity and specificity of detection. The ability to distinguish between different species and sub-species is of prognostic and therapeutic relevance.

The 'Stichting Werkgroep Antibioticabeleid' (Dutch Working Party on Antibiotic Policy) has developed an electronic national antibiotic guide for the antibiotic treatment and prophylaxis of common infectious diseases in hospitals. This guide also contains information on the most important characteristics of antimicrobial drugs. Advice on antibiotic treatment is based on existing national evidence-based guidelines, where available. Where no guideline is available, the advice is based on an inventory of the antibiotic policies of the 12 Dutch centres with an infectious disease or medical microbiology training programme. The national antibiotic guide can be accessed through the SWAB website (www.swab.nl) and can also be downloaded on PDA/PocketPC, free of charge. Every hospital antibiotic formulary committee in the Netherlands will be offered the opportunity to edit The national version for local use.

A growing number of organisations have become involved in the development of guidelines for infectious diseases (ID). The degree of acceptation of guidelines varies from one country to another. Some of these national differences are determining the practices of prescribing antibiotics, and infection control both in hospitals and in the community. This review provides updated information on ID guideline programmes, in particular on the topic of antimicrobial therapy. It is aimed at clinicians, both in their role as care providers and as designers of local antibiotic guidelines (antibiotic booklets). Definitions are given and the process of development is discussed. International and national ID guideline programmes in the English language are presented. Many URLs provide access to the different websites where most guidelines can be downloaded free of charge.

Background: Drug pharmacokinetics may be altered during liver transplantation. Cefotaxime (CTX), used as perioperative prophylaxis, demonstrates time-dependent killing and therefore continuous infusion might have pharmacodynamic advantages., Objectives: To determine the pharmacokinetics of CTX and desacetylcefotaxime (DCTX) in serum, bile and urine during continuous and intermittent infusion when performing liver transplantation., Methods: Fifteen patients undergoing liver transplantation were studied after continuous infusion (CI) (4000 mg iv per 24 h following a loading dose of 1000 mg) and intermittent bolus infusion (BI) (1000 mg iv four times daily). Samples were collected during the first 48 h after liver transplantation. Concentrations of CTX and DCTX were determined by HPLC., Results: During surgery, the mean concentration in serum after CI was 18 mg/L. The lowest serum concentration was 5 mg/L in the CI group and levels were undetectable in the BI group. Target serum concentrations of > or =4 mg/L were reached for 100% of the dosing interval during CI and approximately 60% during BI. Post-operatively, the mean concentration in serum after CI was 26 mg/L. The lowest serum concentration was 8 mg/L in the CI group and levels were undetectable after BI. The peroperative pharmacokinetics of CTX in this patient group were deranged and variable, mainly caused by an increased volume of distribution and decreased hepatic clearance. Metabolism was hampered, but DCTX area under the curve (AUC)/CTX AUC ratios varying between 0.7-0.9 were reached peroperatively. Post-operatively, DCTX AUC/CTX AUC ratios were higher (1.1-1.4). Unchanged CTX in bile was approximately 0.1% of the administered dose, leading to concentrations >4 mg/L throughout the dosing interval for both regimens., Conclusion: Although an intermittent bolus infusion of CTX 1000 mg produces t > target concentration for 60% of the dosing interval during liver transplantation, serum concentrations may be insufficient during the reperfusion phase. Continuous infusion overcomes this. Post-operatively, CTX clearance is impaired by decreased metabolic clearance and there is substantial accumulation of DCTX. In bile, sufficient concentrations of CTX and its active metabolite are reached with both regimens.

Objective: To compare three different chromogenic agars and MacConkey agar for the detection of aerobic Gram-negative bacteria in the normal intestinal microflora and to assess the accuracy of the chromogenic agars for the direct identification of Escherichia coli., Methods: A total of 164 Gram-negative clinical isolates (E. coli, Proteus, Klebsiella, Enterobacter, Morganella and Pseudomonas species) and 30 stool specimens were inoculated in parallel on four media: Chromagar E. coli/Coliform, Chromogenic urinary tract infection UTI medium, CHROMagar Orientation and MacConkey agar. All colonies that differed by color and/or morphology were selected for further identification by VITEK 1 and/or API 20E from each medium., Results: On E. coli/Coliform agar five out of 32 (16%) E. coli strains failed to produce the color as described by the manufacturer. No remarkable discrepancies were found for the other clinical isolates. There was no significant difference in detection rate (DR) of aerobic Gram-negative bacteria in stool specimens between the different chromogenic agars and MacConkey agar. The overall DR was about 84%, and varied from 100% for monomicrobial specimens to 33% for polymicrobial specimens. The positive predictive values (PPV) for the direct identification of E. coli on Chromagar E. coli/Coliform, Chromogenic UTI medium and CHROMagar Orientation were 1.00, 0.93 and 0.93, respectively. The negative predictive values (NPV) were 0.53, 0.68 and 0.69, respectively., Conclusion: Chromogenic UTI medium and CHROMagar Orientation are the preferred media because of the higher NPV. The high PPV of these agars allows accurate and rapid identification of E. coli.

Objective: To study the adherence to local hospital guidelines for antimicrobial prophylaxis in surgery, and explore reasons for non-adherence., Methods: A prospective, multicentre audit of elective procedures, without prior suspicion of infection, was carried out in 13 Dutch hospitals. By reviewing medical, anaesthetic and nursing records, and medication charts, the prescription of antibiotics was compared with the local hospital guideline on antibiotic choice, duration of prophylaxis, dose, dosing interval and timing of the first dose., Results: Between January 2000 and January 2001, 1763 procedures were studied. Antibiotic choice, duration, dose, dosing interval and timing of the first dose were concordant with the hospital guideline in 92%, 82%, 89%, 43% and 50%, respectively. Overall adherence to all aspects of the guideline, however, was achieved in only 28%. The most important barriers to local guideline adherence were lack of awareness due to ineffective distribution of the most recent version of the guidelines, lack of agreement by surgeons with the local hospital guidelines, and environmental factors, such as organizational constraints in the surgical suite and in the ward., Conclusion: This study shows that, although adherence to separate aspects of local hospital guidelines for surgical prophylaxis in the Netherlands is favourable, overall adherence to all parameters is hard to achieve. Adherence to guidelines on dosing interval and timing needs improvement, in particular. To increase the quality of antimicrobial prophylaxis in surgery, effort should be put into developing guidelines acceptable to surgeons, in adequately distributing the guidelines and to facilitating logistics. Audits of surgical prophylaxis may help hospitals identify barriers to guideline adherence.

Background: As aminoglycosides show concentration-dependent killing, once-daily aminoglycoside (ODA) regimens have been instituted. Data on experience with ODA regimens in critically ill patients are limited., Objectives: 1) To evaluate the ODA-program in critically ill patients; 2) to describe the pharmacokinetics of aminoglycosides (gentamicin and tobramycin); and 3) to assess the incidence of nephrotoxicity associated with an ODA regimen in this specific of group patients., Design: A prospective, descriptive study., Setting: Eighteen-bed surgical and 12-bed medical intensive care unit in a referral centre., Patients: Eighty-nine critically ill patients with a suspected or confirmed infection for which gentamicin or tobramycin was indicated and a creatinine clearance > 30 ml/min were monitored. One hundred and nine pharmacokinetic profiles were gathered., Interventions: A first dose of 7 mg/kg/24 h of gentamicin or tobramycin was given to every patient independent of renal function. Subsequent doses were chosen on the basis of the pharmacokinetic results of the first dose., Measurements: Serum samples were collected 1 h and 6 h after start of the aminoglycoside infusion. All samples were assayed by using immunofluorescence. Pharmacokinetic parameters were estimated using a one-compartment model., Results: The volume of distribution of aminoglycosides was significantly higher in critical ill patients with septic shock than in those without. Consequently, the maximum concentration reached was significantly lower in patients with septic shock. In P. aeruginosa infections the mean (SD) estimated Cmax/MIC ratio was 10.3 (3.3). In n = 17 (49%) of the patients treated > 24 h ( n = 35), a dose adjustment or lengthening of interval was necessary. The recommended dosing interval based on the Hartford Hospital nomogram and one-serum concentration at 6 h was correct in only 62% of all cases. Signs of renal impairment occurred in n = 12 (14%) of the patients; in all survivors renal function recovered completely and no haemofiltration was needed., Conclusions: An ODA-regimen of 7 mg/kg produced Cmax/MIC ratios > 10 in the majority of critically ill patients in our population. Septic shock and renal dysfunction caused an aberrant pharmacokinetic profile of aminoglycosides in these patients. Therefore, individual therapeutic drug monitoring is warranted. Signs of renal impairment were common in the presence of shock, but appeared to be reversible.

Objective: To assess adherence to antiretroviral therapy (ART) in Dutch and non-Dutch HIV-infected patients., Design: Observational, cross-sectional study., Methods: Consecutive HIV-infected patients taking ART and visiting the internal medicine outpatients' clinic at the Rotterdam Dijkzigt University Hospital between 1 February until 30 April 2001 were interviewed by a multilingual interviewer using a standard questionnaire. Classification of adherence was based on the interview data. Multivariate analysis was used to determine independent predictors of adherence. Nationality was defined as 'Dutch' if the person was born in the Netherlands, and otherwise as 'non-Dutch'., Results: The 203 patients included in this study comprised 131 men and 69 women with an average age of 42 years. There were no data available on treatment adherence for 3 of the patients. Of the 81 Dutch patients, 60 (74%) adhered to the treatment compared with 68 (57%) of the 119 non-Dutch patients. However, after correction for sex, risk group, race and duration of treatment, there was no difference in treatment adherence between these two groups (OR: 0.6; 95% CI: 0.2-1.9). Failure to adhere to treatment was seen most frequently in the 109 heterosexually infected patients (OR: 2.6; 0.98-6.7), the 22 intravenous drug users (OR: 3.3; 1.04-10.1), as well as in the group of Negroid patients (OR: 3.5; 1.1-11.3) and Latin-American patients (OR: 8.5; 1.7-42.7).

Ceftazidime demonstrates time-dependent killing, which is maximal at 4 x or 5 x MIC for the organism, consequently continuous infusion (CI) has been proposed to ensure adequate ceftazidime concentrations for the entire course of therapy. Severe intra-abdominal infections (IAIs) require surgical or percutaneous drainage for management, and ceftazidime is frequently prescribed. Cardiovascular or metabolic changes and renal or liver dysfunction may alter drug pharmacokinetics during severe IAIs, and no data exist on concentrations of ceftazidime reached in the peritoneal fluid. The objectives here were to determine the pharmacokinetics of ceftazidime during continuous and intermittent administration in patients with severe IAIs, and to measure the concentrations of ceftazidime in the peritoneal exudate. Eighteen surgical patients with severe IAI and a creatinine clearance of >30 mL/min were studied. A non-randomized pilot study of six patients treated with CI alone was followed by a prospective, randomized comparative study of 12 patients. Pilot study patients received ceftazidime 1 g iv followed by a 4.5 g CI over 24 h. Randomized patients received either ceftazidime continuously as above or 1.5 g tds. Samples for pharmacokinetic analyses were collected on days 2 and 4. Ceftazidime concentrations were determined by high-performance liquid chromatography. CI resulted in a mean serum concentration >40 mg/L and a T> 4 x MIC for most pathogens encountered in severe IAIs for >90% of the course of therapy in both serum and peritoneal exudate. Eight-hourly administration resulted in T> 4 x MIC for most pathogens encountered in severe IAIs for >90% of the dosing interval, but in peritoneal exudate for only 44% of the dosing interval. During CI, AUCs in the peritoneal exudate were c. 60% of the concomitant serum AUCs. In critically ill surgical patients with severe IAIs, CI of ceftazidime resulted in more favourable concentrations in serum and peritoneal exudate than 8-hourly bolus infusion.

A 23-year-old Turkish woman was admitted with an infection of the left thumb. The clinical picture was typical for cutaneous anthrax. Microbiological tests confirmed the diagnosis 'infection by Bacillus anthracis'. She recovered when treated with penicillin, although later tests revealed that the bacteria were resistant to this antibiotic. The patient became infected in Belgium as a result of wounding herself on the teeth of an illegally slaughtered sheep, which had possibly become infected in the pasture. Recognising the characteristic clinical picture of cutaneous anthrax is essential for prompt treatment and a favourable prognosis.

Objective: To determine the probable site of the nephron and the plasma indinavir (IDV) concentration at which intrarenal IDV crystallization occurs., Design: We performed in vitro crystallization experiments in IDV solutions simulating conditions found in the nephron., Methods: To determine intrarenal IDV concentrations at which conditions in the nephron allow crystallization, several concentrations of IDV basic solutions (0-800 mM) were titrated from pH 4.0 to higher pH values until crystals formed within 1 minute. Based on the combination of pH and ionic strength at which crystals formed, we determined the site of the nephron at which this combination was first attained. Based on the capacity for concentration at that site, we were able to measure the corresponding plasma IDV concentration., Results: Under conditions normally found at the proximal tubule (i.e., pH 6.7 and ionic strength of 200 mM), IDV crystallized at 200 mg/L. Under conditions applying to the loop of Henle, pH 7.4 and ionic strength of 200 mM, IDV crystallized at 125 mg/L, which would correspond to a plasma IDV concentration of 8 mg/L., Conclusions: IDV crystallization is most likely in the loop of Henle and may already start at plasma IDV concentrations as low as 8 mg/L. Increasing hydration does not reduce the risk of IDV crystallization in the loop of Henle but instead prevents IDV crystallization and aggregation in the lower urinary tract. It remains to be confirmed whether prevention of high IDV plasma concentrations will reduce the risk of IDV crystallization in the loop of Henle.

The pharmacodynamic and pharmacokinetic properties of trovafloxacin were studied in a standardized murine model of established subcutaneous abscesses. Daily dosing regimens of 37.5 to 300 mg/kg every 8 h (q8h) or every 24 h (q24h) were started 3 days after inoculation with mixtures containing either Bacteroides fragilis-Escherichia coli-autoclaved cecal contents (ACC) or B. fragilis-vancomycin-resistant Enterococcus faecium (VREF)-ACC. Treatment was continued for 3 or 5 days. The efficacy of treatment was determined by the decrease in abscess bacterial counts and abscess weights, as well as by the reduction in inflammation (biodistribution of (99m)Tc-HYNIC immunoglobulin G) compared to saline-treated controls. Trovafloxacin showed a significant dose-response effect on the bacterial counts, weight, and inflammation of B. fragilis-E. coli abscesses after 3 and/or 5 days of treatment. A maximum 3.4 and 3.1 log(10) reduction in CFU/abscess in the respective B. fragilis and E. coli bacterial counts was attained after 5 days of treatment with daily doses of 300 mg/kg. The peak serum concentration was more predictive for effect than the area under the concentration-time curve. The C(max) was the pharmacodynamic index most predictive for success, and the efficacy of the q24h regimens was significantly better than the q8h regimens. The antibiotic was ineffective against the VREF in mixed infection with B. fragilis, while the killing of the anaerobe in the same combination was significantly less than in the E. coli combination (P < 0.05). We conclude that this is a useful model for studying the activity of antimicrobials for the treatment of small (<1-cm), undrainable, mixed-infection abscesses. In addition, we have shown for the first time that a decrease in bacterial numbers also leads to a reduction in both abscess weight and inflammation.

Objectives: (1) To determine the pharmacokinetics of sequential intravenous and enteral fluconazole in the serum of surgical intensive care unit (ICU) patients with deep mycoses. (2) To determine the concentrations of fluconazole reached at the site of infection. (3) To determine if enteral administration of fluconazole, which has an important pharmaco-economic advantage, is justified in this specific patient group., Design: Descriptive, sequential study as a part of a therapeutic drug monitoring programme., Setting: Eighteen-bed surgical ICU in a referral centre., Patients: Fourteen critically ill surgical patients with recent gastro-intestinal (GI) surgery and deep mycosis caused by a fluconazole-susceptible fungus and a calculated creatinine clearance of more than 40 ml/min., Interventions: Fluconazole dosage regimen: 400 mg i. v. every 24 h with an extra dose of 400 mg i.v. after 12 h on day 1. If the clinical condition allowed enteral administration on day 4, the content of two capsules of 200 mg was given via the feeding tube with concomitant enteral feeds., Measurements and Main Results: Serum, exudate from the site of infection and urine samples collected at assumed steady state ( after > or = 5 doses). Fluconazole concentrations were determined by high-performance liquid chromatography (HPLC). The mean area under the concentration curve (AUC0-24 h) in serum after enteral administration did not significantly differ from the AUC0-24 h during intravenous treatment. The elimination half-life was longer compared to healthy volunteers. The mean (95% CI) estimated bioavailability was 124 (90-158)%. The mean (95% CI) area under the concentration time curves (AUCs) achieved in the exudate from the site of infection were 67 (55-79)% of the AUCs reached in serum for both regimens., Conclusions: In critically ill patients with recent GI surgery and/or peritonitis the bioavailability of enteral fluconazole was adequate. The concentrations of fluconazole reached in exudate were lower than those in serum for both regimens, but adequate to treat most cases of deep mycoses in this specific patient group.

Antimicrobial use is the major determinant in the development of resistance. Many parameters of importance for optimal quality of antimicrobial therapy have already been defined. Maximal efficacy of the treatment should be combined with minimal toxicity at the lowest cost. Quality of antimicrobial drug use is dependent on knowledge of many aspects of infectious diseases. Considering efficacy, many of our indications for antimicrobial use need critical evaluation. Irrational use should be discouraged. Avoidance of the development of resistance is a quality parameter that will need increasing attention. This paper reviews the well-established factors that may influence the appropriateness of pharmacotherapy with antimicrobial drugs. It cites recent evidence supporting principles of prudent prescribing and gives an overview of audits that have addressed these parameters. Measures relating to resistance are discussed.

There is worldwide concern about the development of antimicrobial resistance [1]. Selective pressure by antimicrobial drugs is by far the most important driving force for the development of resistance. Antimicrobial drugs are among the most commonly prescribed drugs in hospitals. In developed countries, some 30% of the hospitalized patients will be treated with these drugs. It is generally accepted that antimicrobial prescribing is often suboptimal, even in a country like the Netherlands, where both antibiotic consumption and microbial resistance rates are low [2,3]. The major problem with inappropriate prescribing is because of insufficient education in infectious diseases and antimicrobial therapy. Often, the prescription of these drugs with little toxicity is unjustified because of insecurity about the diagnosis of the clinician; 'drugs of fear' [4]. In our surveys, some 15% of the antibiotic prescriptions in surgical and internal medicine wards were considered unjustified [5,6]. Many prescribers are not yet fully aware that their justified or unjustified prescription adds to the resistance problem. In this paper, aspects of the quality of antimicrobial prescribing in the hospital setting will be discussed.

To determine the efficacy of trovafloxacin as a possible treatment for intra-abdominal abscesses, we have developed an anaerobic time-kill technique using different inocula to study the in vitro killing of Bacteroides fragilis in pure culture or in mixed culture with either Escherichia coli or a vancomycin-resistant strain of Enterococcus faecium (VREF). With inocula of 5 x 10(5) CFU/ml and trovafloxacin concentrations of /=6.1 (log(10) CFU/ml) was attained with all pure and mixed cultures within 24 h. With inocula of 10(8) CFU/ml, a similar E(max) and a similar concentration to produce 50% of E(max) (EC(50)) for B. fragilis were found in both pure cultures and mixed cultures with E. coli. However, to produce a similar killing of B. fragilis in the mixed cultures with VREF, a 14-fold increase in the concentration of trovafloxacin was required. A vancomycin-susceptible strain of E. faecium and a trovafloxacin-resistant strain of E. coli were also found to confer a similar "protective" effect on B. fragilis against the activity of trovafloxacin. Using inocula of 10(9) CFU/ml, the activity of trovafloxacin was retained for E. coli and B. fragilis and was negligible against VREF. We conclude that this is a useful technique to study the anaerobic killing of mixed cultures in vitro and may be of value in predicting the killing of mixed infections in vivo. The importance of using mixed cultures and not pure cultures is clearly shown by the difference in the killing of B. fragilis in the mixed cultures tested. Trovafloxacin will probably be ineffective in the treatment of infections involving large numbers of enterococci. However, due to its ability to retain activity against large cultures of B. fragilis and E. coli, trovafloxacin could be beneficial in the treatment of intra-abdominal abscesses.

The Stichting Werkgroep Antibioticabeleid (SWAB, Foundation Antibiotics Policy Team) has issued guidelines for perioperative antibiotic prophylaxis in Dutch hospitals. Antibiotic prophylaxis is generally recommended for surgical procedures with relatively high postoperative infection rates and those in which consequences of infection are really serious. Studies have revealed that prophylaxis given within two hours before incision is most effective. Short-term, preferably single-dose prophylaxis, is as effective as multiple-dose prophylaxis in most procedures. For reasons of cost effectiveness and prevention of induction of resistance, single-dose prophylaxis is recommended. The antimicrobial agent of choice for perioperative prophylaxis should not be widely used as a therapeutic agent, should be selectively active against micro-organisms most frequently isolated from surgical site infections, and should have a plasma-half-life that makes single-dosing possible for most operations. Therefore cefazoline is an agent that is widely used for perioperative prophylaxis.

Major reasons to conduct antibiotic policies are to improve the quality of patient care, to limit the emergence of resistance, and to contain costs. Many studies have addressed overconsumption and misuse of antibiotics. Studies have shown a correlation between antibiotic use in hospitals and the development of microbial resistance. Recommendations for the content and management of future antibiotic policy strategies in hospitals include educational programmes, consultation by infectious diseases physicians, restriction of the formulary, timely narrowing of empirical broad spectrum therapy ('streamlining'), and automatic stop orders. A recent study in a Dutch university hospital revealed overconsumption of antibiotics for prophylaxis in surgery and undertreatment with antibiotics in internal medicine departments. Intervention resulted in better compliance with guidelines, reduction of the consumption of antibiotics in surgical prophylaxis, and cost containment. However optimation of antimicrobial therapy also sometimes resulted in an increase of antimicrobial drug consumption.

Objective: To assess the relationship between indinavir-associated urological complaints and indinavir plasma concentrations., Design: Case series, comparing indinavir plasma concentrations in cases with average concentrations in a control group., Methods: Patients taking 800 mg indinavir three times a day (tid), who presented with overt urological complaints (renal colic, flank pain or haematuria) were selected for the study. Plasma indinavir concentrations were measured by means of a standardized high performance liquid chromatography (HPLC) method. Plasma samples taken at 1.5-8 h after the last indinavir ingestion were included for evaluation. Results were compared with the full pharmacokinetic curves of indinavir plasma concentrations from a control group of 14 patients taking 800 mg indinavir tid without urological complaints, and were expressed as concentration ratios. A ratio of 1 indicated a plasma concentration equalling the average concentration in the control population at the same point in time after the ingestion of indinavir., Results: Seventeen patients (five women) were enrolled and the indinavir concentrations of 15 patients could be evaluated. Fourteen (93%) patients had a concentration above the mean of the controls, 12 (80%) patients had a concentration above the upper 95% confidence limit, and one (7%) patient had a concentration below the lower 95% confidence limit. The mean indinavir concentration in patients with urological complaints (ratio range 0.55-11.49) was significantly higher than the average concentration and the upper 95% confidence limit of the control group (P < 0.05). The results could not be explained by differences in weight, sex or drug interactions. Two patients had chronic active hepatitis B infection. In six patients with indinavir concentrations above the upper 95% limit, indinavir was reduced to 600 mg tid. Upon repeat measurement after the dose adjustment, their indinavir plasma concentrations fell within the 95% confidence interval around the mean of the control population. All six patients remained asymptomatic and had viral loads of less than 500 copies per ml after a follow-up of 5-16 months., Conclusions: Urological complications occurring during indinavir treatment were associated with elevated indinavir plasma concentrations in 80% of patients in this study. Indinavir plasma concentrations should be monitored upon presentation of urological complaints, on the basis of which dose reductions may be applied if brief interruption and increased hydration are ineffective.

Surgical site infections (SSI) remain a major source of postoperative morbidity. The preventive effect of antimicrobial drugs on postoperative infections is without debate. The common basis of accepted indications for prophylaxis is available evidence of effect. Valid reasons to administer antimicrobial prophylaxis include a significant reduction of SSI or reducing the risk of SSI in procedures where the consequences of infection are serious or even disastrous. The antimicrobial drug must be effective against pathogens associated with infection after a given procedure. The first generation cephalosporin, cefazolin, has been considered one of the prophylactic drugs of choice in many authoritative guidelines. The optimal timing of intravenous antimicrobial prophylaxis in surgery is considered to be about 30 minutes before incision, i.e. at induction of anaesthesia. A single dose of antimicrobial drugs before the operation is sufficient prophylaxis for most surgical procedures. The development of bacterial resistance is associated with antimicrobial use, and therefore prophylactic antibiotics should be used as little as possible; in addition, the spectrum of activity of drugs used should be as narrow as possible. Although the principles of antimicrobial prophylaxis in surgery have been clearly established, many reports continue to describe inappropriate drug use. Overconsumption in terms of invalid indications or use of drugs with too broad a spectrum of activity should be eliminated by adhering to accepted guidelines. Practical suggestions are given to optimise timing, such as simple reminders on the daily operating programme, the display of prophylaxis regimens according to type of surgery in table format in the operating room and having the anaesthetist note the complete drug regimen on the patient's anaesthesia record. Such measures will help to optimise antibiotic prophylaxis and restrict if to the operating room where it belongs.