Helga Erlendsdóttir

Increasing Incidence of Candidemia: Results from a 20-Year Nationwide Study in Iceland

ABSTRACT A nationwide study on candidemia was conducted in Iceland from 1980 to 1999. The annual incidence increased from 1.4 cases/100,000 inhabitants/year between 1980 and 1984 to 4.9 cases/100,000 inhabitants/year between 1995 and 1999 (P < 0.0001). Candidemia episodes at university hospitals increased from 0.15/1,000 admissions to 0.55/1,000 admissions (P < 0.0001). Candida albicans was the predominant species responsible (64.4%). The national import of fluconazole increased approximately fourfold during the second half of the study, but increased resistance to this agent was not observed.

Molecular epidemiology of candidemia: evidence of clusters of smoldering nosocomial infections

BACKGROUND Invasive fungal infections pose a serious threat to hospitalized patients worldwide. In particular, the prevalence of clusters of nosocomial infection among patients with candidemia remains unknown. The aim of this study was to investigate the molecular epidemiology of candidemia in a nationwide setting in Iceland during a 16-year period. METHODS The genotypes of all available fungal bloodstream isolates during 1991-2006 (n = 219) were determined by polymerase chain reaction fingerprinting with use of 4 separate primers. Clusters were defined as isolation of > or =2 strains with genotypes that had > or =90% relatedness in the same hospital within a period of 90 days. RESULTS Candida albicans represented 61.6% of isolates, followed by Candida glabrata (13.7%), Candida tropicalis (9.1%), and Candida parapsilosis (8.7%). Polymerase chain reaction fingerprinting revealed 35 clones of C. albicans, 10 clones of C. glabrata, 7 clones of C. tropicalis, 4 clones of C. parapsilosis, and 5 clones of Candida dubliniensis. Overall, 18.7%-39.9% of all infections were part of nosocomial clusters, most commonly caused by C. albicans, C. parapsilosis, and C. tropicalis. Most clusters involved 2 cases and disproportionately affected patients in adult and neonatal intensive care units (P = .045). The 7-day (16%) and 30-day (32%) case-fatality rates among cluster-associated cases did not differ statistically significantly from those for sporadic nosocomial infections. None of the clusters were identified by the hospital surveillance team. CONCLUSIONS In an unselected patient population, as many as one-third of all cases of candidemia may be attributable to nosocomial clusters. The risk is dependent on hospital wards and patient populations; it is highest in intensive care units. Small clusters are not identified by routine hospital surveillance.

Nationwide Study of Candidemia, Antifungal Use, and Antifungal Drug Resistance in Iceland, 2000 to 2011

ABSTRACT Candidemia is often a life-threatening infection, with highly variable incidence among countries. We conducted a nationwide study of candidemia in Iceland from 2000 to 2011, in order to determine recent trends in incidence rates, fungal species distribution, antifungal susceptibility patterns, and concurrent antifungal consumption. A total of 208 infection episodes in 199 patients were identified. The average incidence during the 12 years was 5.7 cases/100,000 population/year, which was significantly higher than that from 1990 to 1999 (4.3/100,000/year; P = 0.02). A significant reduction in the use of blood cultures was noted in the last 3 years of the study, coinciding with the economic crisis in the country (P < 0.001). Age-specific incidence rates were highest among patients at the extremes of age, 20.7/100,000 for <1 year of age and 18.1/100,000 for >60 years, and varied by gender. Age-specific incidence among males >80 years old was 28.6/100,000/year, and it was 8.3/100,000/year for females in this age group (P = 0.028). The 30-day survival rate among adult patients remained unchanged compared to that from 1990 to 1999 (70.4% versus 69.5%, P = 0.97). Candida albicans was the predominant species (56%), followed by C. glabrata (16%) and C. tropicalis (13%). The species distribution remained stable compared to that from previous decades. Fluconazole use increased 2.4-fold from 2000 to 2011, with no increase in resistance. In summary, the incidence of candidemia in Iceland has continued to increase but may have reached a steady state, and no increase in antifungal drug resistance has been noted. Decreased use of blood cultures toward the end of the study may have influenced detection rates.

Clonal Spread of Resistant Pneumococci Despite Diminished Antimicrobial Use

The effects of community-wide interventions to reduce resistance rates are poorly understood. This study evaluated the effect of reduced antimicrobial usage on the spread of penicillin-nonsusceptible pneumococci (PNSP) in four communities in Iceland. The study was performed after interventions to reduce antimicrobial usage and compared to an identical study performed 5 years before. A randomized sample of 953 children was chosen from all 2,900 1- to 6-year-old children living in four well-defined communities. The main outcome measures were nasopharyngeal carriage of PNSP and individual and community use of antimicrobials. Pneumococci were carried by 51.7% of the 743 children enrolled, and 8.1% of the pneumococci were PNSP as opposed to 8.5% in the previous study. The antimicrobial use of participants had been reduced from 1.5 to 1.1 courses/year and the overall use among children <7 years old living in the study areas from 13.6 to 11.1 defined daily dosages/1000 children per day. The prevalence of PNSP increased in the two areas furthest away from the capital area despite reduced consumption. The major risk factors for carriage of PNSP remained the same. Interventions can be effective in reducing antimicrobial use. Pandemic multiresistant clones can also spread fast in small communities with low antimicrobial use, where their appearance may be delayed compared to highly populated urban areas. Clonal spread and herd immunity are important factors to be considered in the evaluation of intervention effects.

Impact of pH and cationic supplementation on in vitro postantibiotic effect.

Most studies on pharmacodynamic variables in vitro, including the postantibiotic effect (PAE), are performed at pH 7.4 in noncationic-supplemented media, a situation which may differ significantly from the true microenvironment in most infected foci. We studied the impact of five different pH levels (pH 5, 6, 7, 7.4, and 8) on the duration of the PAE, the MIC, and bactericidal activity. Acid pH was found to have in general a deleterious effect on the activity of aminoglycosides and ciprofloxacin against Escherichia coli and Pseudomonas aeruginosa, with the MIC being higher, the bactericidal rate being lower, and the PAE being shorter at pH 5 (and to a lesser extent at pH 6) than at more alkaline pH levels. Similar results were observed for imipenem against P. aeruginosa. The PAEs induced by ampicillin against E. coli and dicloxacillin against Staphylococcus aureus were not predictably dependent on the pH, whereas the PAEs induced by ciprofloxacin against S. aureus were longest at either end of the pH spectrum. The bactericidal activity of these agents was, however, pH dependent, being slower at acid pHs. The addition of 50 mg of Ca2+ and 20 mg of Mg2+ per liter of liquid medium at pH 7.4 did not affect the duration of the PAE. Since the pH in abscess cavities may be close to 5, these observations may be of importance for employment of the agents studied in closed or poorly drained infections.

Age specific prevalence of antibodies against Chlamydia pneumoniae in Iceland

Chlamydia pneumoniae is a newly recognized common cause of respiratory tract infections. The aim of this study was to examine its prevalence in Iceland. The study was based on 1020 serum samples from individuals 0-99 years old. The samples were divided into 10-year age groups. IgG and IgM antibodies were determined with microimmunofluorescence assay. An IgG titer > or = 32 and IgM titer > or = 16 were considered positive. The prevalence of positive IgG titer in the study population was 53 +/- 16% (mean +/- SD, age group range 14-66%). Neither seasonal nor gender-based difference in IgG antibody prevalence was demonstrated. It was lowest in the youngest group, 0-9 years old (p < 0.001), but rose linearly to age 70 (p < 0.005). 34 samples were IgM positive on initial testing; most from the older age groups. 12 were rheumatoid factor positive as well. After treatment with caprine antihuman IgG antibodies all became negative. The prevalence of C. pneumoniae infections is high in Iceland according to these results and similar to that in neighbouring countries. The presence of IgM rheumatoid factor may cause false positive tests for pathogen-specific IgM by immune complex binding with pathogen-specific IgG, thereby requiring its removal before testing.

Selection of Resistant Streptococcus pneumoniae during Penicillin Treatment In Vitro and in Three Animal Models

ABSTRACT 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 β-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 strains; and in the mouse peritonitis model, the susceptible strain disappeared and was overgrown by the less-susceptible strains. These findings with the experimental infection models confirm the importance of eradicating all the bacteria taking part in the infectious process in order to avoid selection of resistant clones.

Penicillin Pharmacodynamics in Four Experimental Pneumococcal Infection Models

ABSTRACT Clinical and animal studies indicate that with optimal dosing, penicillin may still be effective against penicillin-nonsusceptible pneumococci (PNSP). The present study examined whether the same strains of penicillin-susceptible pneumococci (PSP) and PNSP differed in their pharmacodynamic responses to penicillin by using comparable penicillin dosing regimens in four animal models: peritonitis, pneumonia, and thigh infection in mice and tissue cage infection in rabbits. Two multidrug-resistant isolates ofStreptococcus pneumoniae type 6B were used, one for which the penicillin MIC was 0.016 μg/ml and the other for which the penicillin MIC was 1.0 μg/ml. Two additional strains of PNSP were studied in the rabbit. The animals were treated with five different penicillin regimens resulting in different maximum concentrations of drugs in serum (Cmaxs) and times that the concentrations were greater than the MIC (T>MICs). The endpoints were bacterial viability counts after 6 h of treatment in the mice and 24 h of treatment in the rabbits. Similar pharmacodynamic effects were observed in all models. In the mouse models bactericidal activity depended on the T>MIC and to a lesser extent on the Cmax/MIC and the generation time but not on the area under the concentration-time curve (AUC)/MIC. Maximal bactericidal activities were similar for both PSP and PNSP, being the highest in the peritoneum and blood (∼6 log10 CFU/ml), followed by the thigh (∼3 log10 CFU/thigh), and being the lowest in the lung (∼1 log10 CFU/lung). In the rabbit model the maximal effect was ∼6 log10 CFU/ml after 24 h. In the mouse models bactericidal activity became marked whenT>MIC was ≥65% of the experimental time andCmax was ≥15 times the MIC, and in the rabbit model bactericidal activity became marked whenT>MIC was ≥35%, Cmaxwas ≥5 times the MIC, and the AUC at 24 h/MIC exceeded 25. By optimization of the Cmax/MIC ratio andT>MIC, the MIC of penicillin for pneumococci can be used to guide therapy and maximize therapeutic efficacy in nonmeningeal infections caused by PNSP.

The importance of strain variation in virulence of Candida dubliniensis and Candida albicans: results of a blinded histopathological study of invasive candidiasis

The pathogenic yeast Candida dubliniensis is increasingly reported as a cause of systemic fungal infections. We compared the virulence of 9 clinical bloodstream isolates of C. dubliniensis with 3 C. albicans isolates in a murine model of invasive candidiasis. Quantification of organisms and inflammatory changes in kidneys of infected animals were evaluated in a blinded, systematic manner. Average 7-day mortality among animals infected with C. dubliniensis was 21.0% (33/157 animals; range for strains: 0-57.1%); and with C. albicans 23.2%, (23/99 animals; range for strains: 6.7-85.0%) (p 0.65). Greater strain variation was noted within species than between the two species. Both species comprised strains of either high or low virulence, and six of the nine C. dubliniensis strains showed negligible virulence. Colony counts determined on samples from liver and kidneys did not differ between species. According to histopathological analysis, C. dubliniensis produced significantly lower levels of hyphae than C. albicans (p <0.001). Candida albicans caused a greater inflammatory response in kidneys (p <0.001) and was more commonly associated with granulomatous inflammation (p 0.003) and greater mononuclear infiltrate (p <0.001). According to multivariate analysis, increasing tissue burden of both hyphal forms (p 0.032) and yeasts (p 0.016) was independently associated with death, whereas higher levels of mononuclear cells were protective (p <0.001). The results suggest a great overlap between the virulence properties of C. dubliniensis and C. albicans. Both yeast and hyphal forms are independently associated with mortality, suggesting similar virulence for both. The source of the fungal isolates may be a neglected confounding factor in virulence studies in animal models.

Risk factors and outcome in ICU-acquired infections

Background: Nosocomial infections are common in intensive care units (ICU). The objectives of this study were to determine risk factors of ICU‐acquired infections, and potential mortality attributable to such infections.