Håkan Hanberger

Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme

Increasing use of antibiotics and the spread of resistant pneumococcal clones in the early 1990s alarmed the medical profession and medical authorities in Sweden. Strama (Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance) was therefore started in 1994 to provide surveillance of antibiotic use and resistance, and to implement the rational use of antibiotics and development of new knowledge. Between 1995 and 2004, antibiotic use for outpatients decreased from 15.7 to 12.6 defined daily doses per 1000 inhabitants per day and from 536 to 410 prescriptions per 1000 inhabitants per year. The reduction was most prominent in children aged 5-14 years (52%) and for macrolides (65%). During this period, the number of hospital admissions for acute mastoiditis, rhinosinusitis, and quinsy (peritonsillar abscess) was stable or declining. Although the epidemic spread in southern Sweden of penicillin-resistant Streptococcus pneumoniae was curbed, the national frequency increased from 4% to 6%. Resistance remained low in most other bacterial species during this period. This multidisciplinary, coordinated programme has contributed to the reduction of antibiotic use without measurable negative consequences. However, antibiotic resistance in several bacterial species is slowly increasing, which has led to calls for continued sustained efforts to preserve the effectiveness of available antibiotics.

Pharmacodynamics of daptomycin and vancomycin on Enterococcus faecalis and Staphylococcus aureus demonstrated by studies of initial killing and postantibiotic effect and influence of Ca2+ and albumin on these drugs.

The pharmacodynamics of daptomycin and vancomycin on Enterococcus faecalis ATCC 29212 and Staphylococcus aureus ATCC 25923 were investigated by studying the postantibiotic effect (PAE) and initial killing. The influence of Ca2+ and albumin on these drugs was also evaluated. The PAE was studied by use of bioluminescence assay of bacterial ATP. Daptomycin at clinically achievable concentrations produced a dose-dependent PAE on E. faecalis (0.6 to 6.7 h) and S. aureus (1.0 to 6.3 h). The long PAE of daptomycin was seen simultaneously with a potent dose-dependent initial killing assayed by viable count determination. The initial change in bacterial ATP was not as extensive as the decrease in viability. Vancomycin at corresponding concentrations produced shorter PAEs on E. faecalis (0.5 to 1.0 h) and S. aureus (1.3 to 1.8 h). This coincides with a weak non-dose-dependent initial change in viability and intracellular ATP. The MICs of vancomycin were not influenced by different Ca2+ concentrations or by the addition of albumin to the broth. The MICs of daptomycin for both strains were lowered, and the PAEs were prolonged with increasing concentrations of Ca2+ in the broth. The PAE of daptomycin was Ca2+ dependent to the same extent as the MIC was. In the presence of physiological concentrations of albumin and free Ca2+, the PAEs of daptomycin on both strains were reduced and the MICs were increased in comparison with the results obtained in pure Mueller-Hinton broth with approximately the same free Ca2+ concentration. This decrease in daptomycin activity was considered to be due to the albumin binding of daptomycin. Despite the albumin binding of daptomycin, the PAE produced on E. faecalis and S. aureus in the presence of a physiological free Ca2+ concentration was still over 6 h at clinically achievable concentrations.

Increased mortality associated with meticillin-resistant Staphylococcus aureus (MRSA) infection in the Intensive Care Unit: Results from the EPIC II study

Controversy continues regarding whether the presence of meticillin resistance increases mortality risk in Staphylococcus aureus infections. In this study, we assessed the role of meticillin resistance in survival of patients with S. aureus infection included in the EPIC II point-prevalence study of infection in critically ill patients performed on 8 May 2007. Demographic, physiological, bacteriological and therapeutic data were collected for 13796 adult patients in 1265 participating Intensive Care Units (ICUs) from 75 countries on the study day. ICU and hospital outcomes were recorded. Characteristics of patients with meticillin-sensitive S. aureus (MSSA) and meticillin-resistant S. aureus (MRSA) infections were compared. Co-morbidities, age, Simplified Acute Physiology Score (SAPS) II, site of infection, geographical region and MRSA/MSSA were entered into a multivariate model, and adjusted odds ratios (ORs) [95% confidence interval (CI)] for ICU and hospital mortality rates were calculated. On the study day, 7087 (51%) of the 13796 patients were classified as infected. There were 494 patients with MRSA infections and 505 patients with MSSA infections. There were no significant differences between the two groups in use of mechanical ventilation or haemofiltration/haemodialysis. Cancer and chronic renal failure were more prevalent in MRSA than in MSSA patients. ICU mortality rates were 29.1% and 20.5%, respectively (P<0.01) and corresponding hospital mortality rates were 36.4% and 27.0% (P<0.01). Multivariate analysis of hospital mortality for MRSA infection showed an adjusted OR of 1.46 (95% CI 1.03-2.06) (P=0.03). In ICU patients, MRSA infection is therefore independently associated with an almost 50% higher likelihood of hospital death compared with MSSA infection.

Morphologic conversion of Helicobacter pylori from bacillary to coccoid form

The morphologic conversion ofHelicobacter pylori from bacillary to coccoid form was studied by microscopy, viable count on agar plates, and bioluminescence assay of bacterial ATP. When morphologic conversion from bacillary to coccoid form was detected by microscopy, the viable counts and the bacterial ATP decreased. No viable count was found after nine days of incubation, but bacterial ATP was still present. In these cultures in which only the coccoid form ofHelicobacter pylori was present, there was no accumulation of extracellular ATP, indicating no leaky cells. During the transition phase from the bacillary to the coccoid form ofHelicobacter pylori, the addition of fresh medium increased the intracellular ATP 26-fold. The coccoid form ofHelicobacter pylori had a 1000-fold lower ATP level per cell compared to the bacillary form, which indicates a decreased metabolic activity in the coccoid form. Addition of fresh medium to the coccoid cultures from days 9 and 10 increased the ATP level twofold. However, no conversion from coccoid to bacillary form was found in these cultures during prolonged incubation in fresh broth for four weeks. Such conversion needs to be demonstrated before it is proven that the coccoid form ofHelicobacter pylori is responsible for transmission and relapse of infection.

Surveillance of microbial resistance in European Intensive Care Units: a first report from the Care-ICU programme for improved infection control

PurposeTo report initial results from a European ICU surveillance programme focussing on antibiotic consumption, microbial resistance and infection control.MethodsThirty-five ICUs participated during 2005. Microbial resistance, antibiotic consumption and infection control stewardship measures were entered locally into a web-application. Results were validated locally, aggregated by project leaders and fed back to support local audit and benchmarking.ResultsMedian (range) antibiotic consumption was 1,254 (range 348–4,992) DDD per 1,000 occupied bed days. The proportion of MRSA was median 11.6% (range 0–100), for ESBL phenotype of E. coli and K. pneumoniae 3.9% (0–80) and 14.3% (0–77.8) respectively, and for carbapenem-resistant P. aeruginosa 22.5% (0–100). Screening on admission for alert pathogens was commonly omitted, and there was a lack of single rooms for isolation.ConclusionsThe surveillance programme demonstrated wide variation in antibiotic consumption, microbial resistance and infection control measures. The programme may, by providing rapid access to aggregated results, promote local and regional audit and benchmarking of antibiotic use and infection control practices.

Secular Trends in Nosocomial Bloodstream Infections: Antibiotic-Resistant Bacteria Increase the Total Burden of Infection

BACKGROUND It is unknown whether rising incidence rates of nosocomial bloodstream infections (BSIs) caused by antibiotic-resistant bacteria (ARB) replace antibiotic-susceptible bacteria (ASB), leaving the total BSI rate unaffected. METHODS We investigated temporal trends in annual incidence densities (events per 100 000 patient-days) of nosocomial BSIs caused by methicillin-resistant Staphylococcus aureus (MRSA), ARB other than MRSA, and ASB in 7 ARB-endemic and 7 ARB-nonendemic hospitals between 1998 and 2007. RESULTS 33 130 nosocomial BSIs (14% caused by ARB) yielded 36 679 microorganisms. From 1998 to 2007, the MRSA incidence density increased from 0.2 to 0.7 (annual increase, 22%) in ARB-nonendemic hospitals, and from 3.1 to 11.7 (annual increase, 10%) in ARB-endemic hospitals (P = .2), increasing the incidence density difference between ARB-endemic and ARB-nonendemic hospitals from 2.9 to 11.0. The non-MRSA ARB incidence density increased from 2.8 to 4.1 (annual increase, 5%) in ARB-nonendemic hospitals, and from 1.5 to 17.4 (annual increase, 22%) in ARB-endemic hospitals (P < .001), changing the incidence density difference from -1.3 to 13.3. Trends in ASB incidence densities were similar in both groups (P = .7). With annual increases of 3.8% and 5.4% of all nosocomial BSIs in ARB-nonendemic and ARB-endemic hospitals, respectively (P < .001), the overall incidence density difference of 3.8 increased to 24.4. CONCLUSIONS Increased nosocomial BSI rates due to ARB occur in addition to infections caused by ASB, increasing the total burden of disease. Hospitals with high ARB infection rates in 2005 had an excess burden of BSI of 20.6 per 100 000 patient-days in a 10-year period, mainly caused by infections with ARB.

Postantibiotic effect of beta-lactam antibiotics on Escherichia coli evaluated by bioluminescence assay of bacterial ATP.

The in vitro postantibiotic effects (PAE) of aztreonam, ceftazidime, cefuroxime, imipenem, and piperacillin on Escherichia coli ATCC 25922 were studied by a bioluminescence assay of bacterial ATP. In parallel with the PAE investigation, viability and morphology studies were performed. The strain was exposed for 2 h to different concentrations of beta-lactam antibiotics. The antibiotic activity was eliminated by 10(-4) dilutions, and regrowth of bacteria was monitored hourly by the bioluminescence assay of bacterial ATP. The length of PAE was dose dependent for ceftazidime (0.5 to 2.6 h), cefuroxime (0.4 to 2.6 h), and imipenem (0.3 to 4.5 h). The long PAE for these antibiotics at higher concentrations was associated with a potent initial killing and the presence of spheroplasts. Aztreonam and piperacillin produced a short, non-dose-dependent PAE (0.4 to 0.95 h). Short PAEs (below 1 h) were seen concomitantly with production of filaments, except in the case of imipenem, which only produced spheroplasts. The bioluminescence method was not jeopardized by filament formation, in contrast to the viable count assay which is normally used for PAE investigations. This makes it possible to study PAE for beta-lactam antibiotics on gram-negative bacteria with bioluminescence.

Molecular detection of aggregation substance, enterococcal surface protein, and cytolysin genes and in vitro adhesion to urinary catheters of Enterococcus faecalis and E. faecium of clinical origin

It has been hypothesized that nosocomial enterococci might have virulence factors that enhance their ability to colonise hospitalised patients. The objectives of this study were to investigate the prevalence of genes encoding 3 virulence factors: aggregation substance (asa1), enterococcal surface protein (esp), and 5 genes within the cytolysin operon (cylA, cylB, cylM, cylL(L), cylL(S)) and cytolysin production in 115 enterococcal clinical isolates (21 Enterococcus faecium and 94 E. faecalis). Adhesion to siliconized latex urinary catheters in relation to presence of esp was analysed in a subset of isolates. The isolates were previously characterised by pulsed-field gel electrophoresis (PFGE). esp was the only virulence gene found in E. faecium. It was found in 71% of the 21 E. faecium isolates. asa1, esp, and the cyl operon were found in 79%, 73% and 13% respectively, of the 94 E. faecalis isolates. There was a complete agreement between presence of the cyl operon and phenotypic cytolysin production. Isolates belonging to a cluster of genetically related isolates carried esp and asa1 more often when compared to unique isolates. No difference was found with respect to cyl genes. E. faecalis isolates adhered with higher bacterial densities than E. faecium. E. faecalis isolates within the same PFGE cluster adhered with similar bacterial densities, but there was no association between adhesion and the presence of esp when isolates within the same cluster were compared. In conclusion, E. faecalis isolates with high-level gentamicin resistance (HLGR) belonging to clusters of genetically related isolates widely distributed in Swedish hospitals, were likely to carry both esp and asa1. Adhesion was not affected by esp.

High antibiotic susceptibility among bacterial pathogens in Swedish ICUs Report from a nation-wide surveillance program using TA90 as a novel index of susceptibility

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.

Antibiotic prescription practices, consumption and bacterial resistance in a cross section of Swedish intensive care units

Background: The purpose of this work was to study usage of antibiotics, its possible determinants, and patterns of bacterial resistance in Swedish intensive care units (ICUs).