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[STRAMA sticks to the otitis consensus], År 2000 presenterades nya riktlinjer, Otitkonsensus, för handläggning av akut öroninflammation hos barn. Riktlinjerna påtalade att eftersom en stor del av akuta öroninflammationer hos i övrigt friska barn läker ut av sig själv kan man primärt avstå från antibiotika till barn över 2 år utan allmänpåverkan eller perforation. Flera internationella studier visar att besöksfrekvensen för övre luftvägsinfektioner och öroninflammation har minskat under de senaste tio åren. Antibiotikaanvändningen bland svenska barn har halverats på tio år. Några tecken till ökning av allvarliga komplikationer som mastoidit kan man inte se. En nyligen publicerad meta-analys stöder slutsatserna i Otitkonsensus.

The aim of this study was to develop and validate a new in-vitro kinetic model for the combination of two drugs with different half-lives, and to use this model for the study of the pharmacodynamic effects of amphotericin B and voriconazole, alone or in combination, against a strain of Candida albicans. Bolus doses of voriconazole and amphotericin B were administered to a starting inoculum of C. albicans. Antifungal-containing medium was eliminated and replaced by fresh medium using a peristaltic pump, with the flow-rate adjusted to obtain the desired half-life of the drug with the shorter half-life. A computer-controlled dosing pump compensated for the agent with the longer half-life. Voriconazole and amphotericin B half-lives were set to 6 and 24 h, respectively. Pharmacokinetic parameters were close to target values when both single doses and sequential doses were simulated. Voriconazole and amphotericin B administered alone demonstrated fungistatic and fungicidal activity, respectively. Simultaneous administration resulted in fungicidal activity, whereas pre-exposure of C. albicans to voriconazole, followed by amphotericin at 8 and 32 h, resulted in fungistatic activity similar to that observed with voriconazole alone. Using this model, which allowed a combination of antifungal agents with different half-lives, it was possible to demonstrate an antagonistic effect of voriconazole on the fungicidal activity of amphotericin B. The characteristics and clinical relevance of this interaction require further investigation.

Since the prescription of antibiotics in the hospital setting is often empiric, particularly in the critically ill, and therefore fraught with potential error, we analysed the use of antibiotic agents in Swedish intensive care units (ICUs). We examined indications for antibiotic treatment, agents and dosage prescribed among 393 patients admitted to 23 ICUs at 7 tertiary care centres, 11 secondary hospitals and 5 primary hospitals over a 2-week period in November 2000. Antibiotic consumption was higher among ICU patients in tertiary care centres with a median of 84% (range 58-87%) of patients on antibiotics compared to patients in secondary hospitals (67%, range 35-93%) and in primary hospitals (38%, range 24-80%). Altogether 68% of the patients received antibiotics during the ICU stay compared to 65% on admission. Cefuroxime was the most commonly prescribed antibiotic before and during admission (28% and 24% of prescriptions, respectively). A date for decision to continue or discontinue antibiotic therapy was set in 21% (6/29) of patients receiving prophylaxis, in 8% (16/205) receiving empirical treatment and in 3% (3/88) when culture-based therapy was given. No correlation between antibiotic prescription and laboratory parameters such as CRP levels, leukocyte and thrombocyte counts, was found. The treatment was empirical in 64% and prophylactic in 9% of cases. Microbiological data guided prescription more often in severe sepsis (median 50%, range 40-60% of prescriptions) than in other specified forms of infection (median 32%, range 21-50%). The empirically chosen antibiotic was found to be active in vitro against the pathogens found in 55 of 58 patients (95%) with a positive blood culture. This study showed that a high proportion of ICU patients receive antimicrobial agents and, as expected, empirical-based therapy is more common than culture-based therapy. Antibiotics given were usually active in vitro against the pathogen found in blood cultures. We ascribe this

Fluoroquinolones are important antibiotics for treatment of serious infections. Increased usage has, in many countries, resulted in rapid development of resistance towards this class of antibiotics. Moreover, it has been shown that use of fluoroquinolones is associated with selection of multi-resistant bacteria, such as methicillin-resistant S. aureus and vancomycin-resistant enterococci. The risks related to overuse of fluoroquinolones among both humans and animals are reviewed and strict indications for use are suggested.

Objectives: To measure the mutant prevention concentration (MPC) of ciprofloxacin for a set of urinary tract infection (UTI) Escherichia coli isolates with different levels of susceptibility and determine whether MPC can be predicted from MIC. Methods: MPC was defined as the lowest ciprofloxacin concentration that prevented the growth of resistant colonies when 1010 bacteria were spread on solid medium and incubated for 96 h at 37°C. MIC was measured by Etest. Bacteria surviving (persisting) at MPC were isolated and quantified from agar plugs taken after 96 h. The genes hipA and hipB were amplified by PCR from persisters and sequenced. Results: Isolates with MICs above the NCCLS breakpoint for ciprofloxacin resistance (4 mg/L) typically have MPCs greater than 32 mg/L. Isolates with MICs below the breakpoint for ciprofloxacin susceptibility (1 mg/L) have MPCs up to 5 mg/L. MPC/MIC is ∼16 for most susceptible isolates but there are several notable exceptions (MPC/MIC > 100). Resistant colonies arising one dilution step below MPC often had MIC > MPC. In every case tested, a proportion of cells survived (persisted), but did not grow into colonies, at MPC, without any increase in MIC. Conclusions: MPCs were determined for all ciprofloxacin-susceptible isolates. MPC is not accurately predicted from MIC. Colonies selected below MPC frequently have MIC > MPC, suggesting multiple mutations. A small fraction of cells from all strains tested survived for 96 h at MPC, without any associated increase in MIC. These survivors/persisters are not hipAB mutants.

Part of urn:nbn:se:su:diva-8477

Local infection control measures, antibiotic consumption and patient demographics from 1999-2000 together with bacteriological analyses were investigated in 29 ICUs participating in the ICU-STRAMA programme. The median antibiotic consumption per ICU was 1147 (range 605-2143) daily doses per 1000 occupied bed d (DDD1000). Antibiotics to which >90% of isolates of an organism were susceptible were defined as treatment alternatives (TA90). The mean number of TA90 was low (1-2 per organism) for Enterococcus faecium (vancomycin:VAN), coagulase negative staphylococci (VAN), Pseudomonas aeruginosa (ceftazidime:CTZ, netilmicin: NET) and Stenotrophomonas maltophilia (CTZ, trimethoprim-sulfamethoxazole: TSU), but higher (3-7) for Acinetobacter spp. (imipenem:IMI, NET, TSU), Enterococcus faecalis (ampicillin:AMP, IMI, VAN), Serratia spp. (ciprofloxacin:CIP, IMI, NET), Enterobacter spp. (CIP, IMI, NET, TSU), E. coli (cefuroxime:CXM, cefotaxime/ceftazidime:CTX/CTZ, CIP, IMI, NET, piperacillin-tazobactam:PTZ, TSU), Klebsiella spp. (CTX/CTZ CIP, IMI, NET, PTZ, TSU) and Staphylococcus aureus (clindamycin, fusidic acid, NET, oxacillin, rifampicin, VAN). Of S. aureus isolates 2% were MRSA. Facilities for alcohol hand disinfection at each bed were available in 96% of the ICUs. The numbers of TA90 available were apparently higher than in ICUs in southern Europe and the US, despite a relatively high antibiotic consumption. This may be due to a moderate ecological impact of the used agents and the infection control routines in Swedish ICUs.

BACKGROUND: We examined how prolonged antibiotic treatment affected the resistance and mutation frequency of human microflora isolated from intestine (Escherichia coli, enterococci spp.), pharynx (alpha-streptococci) and nostril (coagulase-negative staphylococci, CoNS). METHODS: Samples were collected from patients at the Center of Cystic Fibrosis (n=18) and the haematology ward (n=18) of the University Hospital, Uppsala, Sweden. The individually used amount of antibiotics for 1 year was recorded as the defined daily dose (DDD). Primary health care patients (n=30), with no antibiotic treatment for 1 year before sampling, were used as controls. Three isolates of each bacterium from each patient were examined. Antibiotic susceptibilities were determined by disc diffusion. Mutation frequencies to rifampicin resistance were measured on 30 independent cultures of each bacterial species from each individual by plating on rifampicin agar plates. For alpha-streptococci the mutation frequency to streptomycin resistance was also determined. RESULTS: Isolates from patients with high antibiotic use showed a pronounced shift towards increased resistance and a small but significant increase in the mutation frequency compared with isolates from the controls. For E. coli, enterococci and CoNS the increase in geometric mean mutation frequency in the patient group was 3-, 1.8- and 1.5-fold, respectively (P values 0.0001, 0.016 and 0.012). For alpha-streptococci there was a significant difference in geometric mean mutation frequency between patient and control groups for streptomycin resistance (P=0.024) but not for rifampicin resistance (P=0.74). CONCLUSIONS: High antibiotic use selected for commensals with highly increased resistance and a slight increase in mutation frequency.

Pharmacokinetic (PK) and pharmacodynamic (PD) properties for the selection of resistant pneumococci were studied by using three strains of the same serotype (6B) for mixed-culture infection in time-kill experiments in vitro and in three different animal models, the mouse peritonitis, the mouse thigh, and the rabbit tissue cage models. Treatment regimens with penicillin were designed to give a wide range of T>MICs, the amounts of time for which the drug concentrations in serum were above the MIC. The mixed culture of the three pneumococcal strains, 107 CFU of strain A (MIC of penicillin, 0.016 µg/ml; erythromycin resistant)/ml, 106 CFU of strain B (MIC of penicillin, 0.25 µg/ml)/ml, and 105 CFU of strain C (MIC of penicillin, 4 µg/ml)/ml, was used in the two mouse models, and a mixture of 105 CFU of strain A/ml, 104 CFU of strain B/ml, and 103 CFU of strain C/ml was used in the rabbit tissue cage model. During the different treatment regimens, the differences in numbers of CFU between treated and control animals were calculated to measure the efficacies of the regimens. Selective media with erythromycin or different penicillin concentrations were used to quantify the strains separately. The efficacies of penicillin in vitro were similar when individual strains or mixed cultures were studied. The eradication of the bacteria, independent of the susceptibility of the strain or strains or the presence of the strains in a mixture or on their own, followed the well-known PK and PD rules for treatment with ß-lactams: a maximum efficacy was seen when the T>MIC was >40 to 50% of the observation time and the ratio of the maximum concentration of the drug in serum to the MIC was >10. It was possible in all three models to select for the less-susceptible strains by using insufficient treatments. In the rabbit tissue cage model, a regrowth of pneumococci was observed; in the mouse thigh model, the ratio between the different strains changed in favor of the less-susceptible strain

Ampicillin-resistant enterococci (ARE) have recently emerged as clinical pathogens in Sweden. Between 1991 and 1995 the incidence of ARE among enterococcal isolates at Uppsala University Hospital increased from 0.5% to 8.1%. Shedding of ARE from infected cases and risk factors for infection with ARE were studied during a period of 7 months for 38 ARE cases and 38 controls with ampicillin-susceptible enterococci. ARE cases had longer mean duration of hospitalization than controls (29 d vs. 15 d; p = 0.002). In univariate analysis other risk factors for infection with ARE were found to be prior therapy with > 2 antimicrobials (odds ratio [OR] 3.3; 95% confidence interval [CI] 1.2-9.5), > 4 weeks of antimicrobial therapy (OR 6.9; CI 1.8-28.3) and cephalosporin therapy (OR 9.1; CI 2.6-33.7). Fourteen of 26 skin carriers of ARE were found to be shedding ARE to the environment, compared to 2 of 12 non-skin carriers (p = 0.03). Pulsed-field gel electrophoresis suggested multifocal origin of the majority of the infecting ARE strains. Non-recognized fecal colonization and silent spread of ARE among many patients and over a prolonged time period is suggested to be the main explanation for the increase of ARE infections in our hospital. Infection control measures focusing on protecting patients at high risk for ARE infections and further efforts to optimize antimicrobial use are proposed.

Rates of colonization with enterococci with acquired resistance to vancomycin (vancomycin-resistant enterococci [VRE]) and ampicillin (ampicillin-resistant enterococci [ARE]) were determined by using fecal samples from 670 nonhospitalized individuals and 841 patients in 27 major hospitals. Of the hospitalized patients, 181 (21.5%) were carriers of ARE and 9 (1.1%) were carriers of VRE. In univariate analyses, length of hospital stay (odds ratio [OR], 4.6; 95% confidence interval [CI], 2.5 to 8.9) and antimicrobial therapy (OR, 4.7; 95% CI, 3.3 to 6.7) were associated with ARE colonization, as were prior treatment with penicillins (OR, 3.1; 95% CI, 1.8 to 5. 5), cephalosporins (OR, 2.9; 95% CI, 1.7 to 5.0), or quinolones (OR, 2.7; 95% CI, 1.5 to 4.7). In logistic regression analysis, antimicrobial therapy for at least 5 days was independently associated with ARE carriage (adjusted OR, 3.8; 95% CI, 2.6 to 5.4). Over 90% of the ARE isolates were fluoroquinolone resistant, whereas 14% of the ampicillin-susceptible Enterococcus faecium isolates were fluoroquinolone resistant. ARE carriage rates correlated with the use of fluoroquinolones (P = 0.04) but not with the use of ampicillin (P = 0.68) or cephalosporins (P = 0.40). All nine VRE isolates were E. faecium vanB and were found in one hospital. Seven of these isolates were related according to their types as determined by pulsed-field gel electrophoresis. Among the nonhospitalized individuals, the ARE carriage rate was lower (6%; P < 0.05), and only one person, who had recently returned from Africa, harbored VRE (E. faecium vanA). The absence of VRE colonization in nonhospitalized individuals reflects an epidemiological situation in Sweden radically different from that in countries in continental Europe where glycopeptides have been widely used for nonmedical purposes.