Update from a 12-Year Nationwide Fungemia Surveillance: Increasing Intrinsic and Acquired Resistance Causes Concern.

New data from the years 2012 to 2015 from the Danish National Fungemia Surveillance are reported, and epidemiological trends are investigated in a 12-year perspective (2004 to 2015). During 2012 to 2015, 1,900 of 1,939 (98%) fungal bloodstream isolates were included. The average incidence was 8.4/100,000 inhabitants, and this appears to represent a stabilizing trend after the increase to 10.1/100,000 in 2011. The incidence was higher in males than females (10.0 versus 6.8) and in patients above 50 years, and those changes were mainly driven by an increasing incidence among 80-to-89-year-old males (65.3/100,000 in 2014 to 2015). The proportion of Candida albicans isolates decreased from 2004 to 2015 (64.4% to 42.4%) in parallel with a doubling of the proportion of Candida glabrata isolates (16.5% to 34.6%, P < 0.0001). C. glabrata was more common among females (34.0% versus 30.4% in males). Following an increase in 2004 to 2011, the annual drug use stabilized during the last 2 to 3 years of that time period but remained higher than in other Nordic countries. This was particularly true for the fluconazole and itraconazole use in the primary health care sector, which exceeded the combined national levels of use of these compounds in each of the other Nordic countries. Fluconazole susceptibility decreased (68.5%, 65.2%, and 60.6% in 2004 to 2007, 2008 to 2011, and 2012 to 2015, respectively, P < 0.0001), and echinocandin resistance emerged in Candida (0%, 0.6%, and 1.7%, respectively, P < 0.001). Amphotericin B susceptibility remained high (98.7%). Among 16 (2.7%) echinocandin-resistant C. glabrata isolates (2012 to 2015), 13 harbored FKS mutations and 5 (31%) were multidrug resistant. The epidemiological changes and the increased incidence of intrinsic and acquired resistance emphasize the importance of continued surveillance and of strengthened focus on antifungal stewardship.

Epidemiological changes with potential implication for antifungal prescription recommendations for fungaemia: data from a nationwide fungaemia surveillance programme.

Significant changes in the management of fungaemia have occurred over the last decade with increased use of fluconazole prophylaxis, of empirical treatment and of echinocandins as first-line agents for documented disease. These changes may impact the epidemiology of fungaemia. We present nationwide data for Denmark from 2010 to 2011. A total of 1081 isolates from 1047 episodes were recorded in 995 patients. The numbers of patients, episodes and recovered isolates increased by 13.1%, 14.5% and 14.1%, respectively, from 2010 to 2011. The incidence rate was significantly higher in 2011 (10.05/100 000) than in 2010 (8.82/100 000), but remained constant in the age groups 0-79 years. The incidence rate was highest at the extremes of age and in males. Candida albicans accounted for 52.1% but declined during 2004-11 (p 0.0155). Candida glabrata accounted for 28% and increased during 2004-2011 (p <0.0001). Candida krusei, Candida tropicalis and Candida parapsilosis remained rare (3.3-4.2%). The species distribution changed with increasing age (fewer C. parapsilosis and more C. glabrata) and by study centre. Overall, the susceptibility rates were: amphotericin B 97.3%, anidulafungin 93.8%, fluconazole 66.7%, itraconazole 69.6%, posaconazole 64.2% and voriconazole 85.0%. Acquired echinocandin resistance was molecularly confirmed in three isolates. The use of systemic antifungals doubled over the last decade (2002-2011) (from 717 000 to 1 450 000 defined daily doses/year) of which the vast majority (96.9%) were azoles. The incidence of fungaemia continues to increase in Denmark and is associated with a decreasing proportion being susceptible to fluconazole. Changes in demography, higher incidence in the elderly and higher antifungal consumption can at least in part explain the changes.

[Staphylococcus aureus endocarditis in Denmark 1982-1991. Clinical picture, complications and antibiotic therapy in non-drug addicts]. / Staphylococcus aureus-endocarditis i Danmark 1982-1991. Klinisk billede, komplikationer og antibiotisk behandling hos ikke-narkomaner.

The central S. aureus surveillance in Denmark made it possible to analyze the clinical features of S. aureus endocarditis in a nation-wide population of non-drug addicts. Almost all cases of bacteraemia with S. aureus are reported to the Staphylococcus laboratory, Copenhagen. The medical records were reviewed in cases from 1982 to 1991 in which the diagnosis of endocarditis was reported or suspected. Two hundred and sixty patients fulfilled the diagnostic criteria. In 83 patients the diagnosis of endocarditis was not suspected clinically. The overall mortality rate among those patients whose disease was diagnosed clinically was 46% and significantly associated with late congestive heart failure, age and involvement of the central nervous system. A more frequent use of echocardiography as a screening method seems essential to improve the prognosis of patients with S. aureus endocarditis. Involvement of the CNS constitutes a relative indication for early valve replacement.

Clinical features of Staphylococcus aureus endocarditis: a 10-year experience in Denmark.

BACKGROUND: Both morbidity and mortality resulting from Staphylococcus aureus endocarditis are known to be high, and the incidence of this disease seems to increase. The Statens Serum Institut, Copenhagen, Denmark, made it possible for us to analyze the clinical features of S aureus endocarditis in a nation-wide population of non-drug addicts. METHODS: Almost all Danish cases of bacteremia due to S aureus are reported to the Staphylococcus laboratory, Statens Serum Institut. The medical records were reviewed in cases reported from 1982 to 1991 in which the diagnosis of endocarditis was reported or suspected. RESULTS: A total of 260 patients, 145 males and 115 females, fulfilled the diagnostic criteria. The median age was 67.5 years. In 83 patients, the diagnosis of endocarditis was not suspected clinically. The overall mortality rate among those patients whose disease was diagnosed clinically was 46%. Among the subset of patients who received medical therapy only and appropriate antistaphylococcal treatment, mortality was significantly associated with late congestive heart failure, age, and involvement of the central nervous system. CONCLUSIONS: A raised awareness of the paucity of clinical findings and a more frequent use of echocardiography as a screening method seem essential to improve the prognosis of patients with S aureus endocarditis. Involvement of the central nervous system constitutes a relative indication of early valve replacement.

Neurologic manifestations in Staphylococcus aureus endocarditis: a review of 260 bacteremic cases in nondrug addicts.

PURPOSE: To investigate the neurologic manifestations of infective endocarditis caused by Staphylococcus aureus in a population of nondrug addicts with special emphasis on the clinical presentation, epidemiology, and mortality. PATIENTS AND METHODS: During the period from 1982 to 1991 a total of 8,514 cases of bacteremia with S aureus were reported to the Staphylococcus Laboratory, Copenhagen, Denmark. The medical records of cases of suspected infective endocarditis were retrospectively reviewed and classified according to the new diagnostic criteria for endocarditis proposed by Durack. RESULTS: A total of 260 cases from 63 hospitals fulfilled the diagnostic criteria. Overall, 91 patients (35%) experienced neurologic manifestations. Sixty-one presented with neurologic symptoms, whereas 30 patients developed neurologic complications at various intervals (median: 10 days) after the debut of the disease. The most frequent neurologic manifestation was unilateral hemiparesis, which occurred in 41 patients (45%). Forty-two percent of the females had neurologic manifestations compared to only 30% of the males (P = 0.06). Cases with native mitral valve infection had a significantly higher frequency of neurologic manifestations compared with all other valvular involvement (44% versus 29%, P = 0.02) but the frequency of neurologic complications was only nonsignificantly higher in those patients with native mitral valve infection than in those patients with native aortic valve infection (44% versus 31%, P = 0.10). Only two of the patients with tricuspid valve infection and none of those with congenital heart disorder experienced neurologic manifestations. A neurologic manifestation occurred in 22 (35%) of the 63 episodes in which vegetations were detected on the echocardiograms, compared with 17 (26%) of the 65 episodes without vegetations (P = 0.38). The mortality was 74% in patients with major neurologic manifestations and 56% in patients without neurologic manifestations (P = 0.008). In patients with neurologic complications the mortality was significantly higher among those treated with antibiotics alone as compared with those treated surgically (65 of 81, 80% versus 2 of 10, 20%; P = 0.0003). CONCLUSIONS: In a population of nondrug addicts with infective endocarditis caused by S aureus the following main conclusions can be drawn: neurologic manifestations occur with a higher frequency in patients with native mitral valve infection. The presence of vegetations on echocardiograms is not a risk factor for developing neurologic complications but this conclusion is based on the results of transthoracic echocardiograms performed in only one half of the patients. The majority of the neurologic manifestations occur on presentation or shortly thereafter and the risk of recurrent embolism is low. Mortality is increased in patients with neurologic manifestations. A neurologic event per se may constitute an indication for surgical treatment.

A study of 47 bacteremic Staphylococcus aureus endocarditis cases: 23 with native valves treated surgically and 24 with prosthetic valves.

A retrospective review of medical records from the Staphylococcus Laboratory, Copenhagen, 1982-1991, was carried out at the Department of Clinical Microbiology, Statens Serum Institut, 1994-1995, to investigate the clinical features and outcome of two subgroups of bacteremic Staphylococcus aureus endocarditis cases in non-drug addicts: patients with prosthetic valve endocarditis (PVE) and patients with native valve endocarditis treated surgically. Twenty-four cases of PVE were included. Six cases were early (within 60 days of valve implantation) and 18 were late. The overall in-hospital mortality was 42%. Surgical treatment resulted in a non-significantly lower mortality as compared with medical treatment alone (0% vs 50%, p = 0.19). Medical treatment of aortic and mitral valve endocarditis resulted in similar mortality rates (44% and 50%, respectively). Twenty-three cases of native valve infective endocarditis had the valve replaced surgically. The in-hospital mortality was 22%, which was significantly lower as compared with medical therapy (69%, p < 0.0001). The treatment changed significantly during the study period: 6 of 112 patients (5%) were treated surgically in the first half of the period (1982-1986) compared to 17 of 124 patients (14%) in the second half (1987-1991, p = 0.049). Severe congestive heart failure was the main indication for cardiac surgery in 21 patients. In conclusion, a shift towards a more aggressive surgical approach has taken place in the 10-year period. This development should be strengthened in the future as surgical intervention may improve survival in patients with infective endocarditis caused by S. aureus whether the infected valve is prosthetic or native.

Dicloxacillin and flucloxacillin: pharmacokinetics, protein binding and serum bactericidal titers in healthy subjects after oral administration.

The pharmacokinetics of dicloxacillin and flucloxacillin were studied in 12 healthy volunteers after oral administration. The participants received a single dose of either dicloxacillin (0.5 g, 0.75 g or 1.0 g) or flucloxacillin (0.75 g) in a cross-over fashion. Antibiotic concentrations were determined in serum and urine by bioassay and followed for 8 and 24 h, respectively. The three dicloxacillin dosages showed no significant differences for the serum elimination half-lives (t1/2 beta, median: 72 min). Comparing 0.75 g flucloxacillin with the same dose of dicloxacillin, no significant differences between the values of Cmax, t1/2 beta and AUC were found. Protein binding as determined by ultrafiltration in pooled serum was 94.7-96.2% for flucloxacillin and 96.4-97.2% for dicloxacillin. The serum bactericidal titers were similar for the two drugs. In conclusion, dicloxacillin and flucloxacillin showed similar pharmacokinetic behavior after 0.75 g doses in human volunteers.

No difference in enterotoxin production among Staphylococcus aureus strains isolated from blood compared with strains isolated from healthy carriers.

The production of enterotoxin A, B, C and D by 196 Staphylococcus aureus strains isolated from blood cultures and 95 strains from nasal carriers was investigated. Half of the bacteraemia strains were from patients who died with or because of their infection, the other half from patients who survived. The nasal strains were selected to match the bacteraemia strains regarding phage types. Overall, 30.6% of the bacteraemia strains and 40.0% of the nasal strains produced enterotoxins; enterotoxins B and C were the toxins produced most frequently in both groups. A similar incidence and pattern of enterotoxin production was found among the bacteraemia strains of S. aureus regardless of acquisition of the infection, the portal of entry, presence or absence of endocarditis and outcome of the infection. Thus, the concept that the enterotoxins play an important role in staphylococcal infections, apart from the diseases caused by the toxins per se such as food poisoning and toxic shock syndrome, cannot be substantiated by the results of the present study.

Antibiotic usage in an intensive care unit in a Danish university hospital.

We report a study of antimicrobial use in patients admitted to the Intensive Care Unit (ICU) in a Danish university hospital during the course of 1 year. Of 615 patients admitted, 434 (71%) received antibiotics, 220 (36%) for infections and 222 (36%) for prophylaxis. Therapy for suspected infection accounted for 67% of the total consumption of antibiotics and prophylaxis for 33%. Ampicillin was the drug most frequently used; 43% of the patients treated for infection received this drug. One hundred and thirty-one patients (60%) were treated for suspected lower respiratory tract infection. Relevant microbiological specimens were obtained from 120 (92%) of these patients and a possible pathogen was isolated in 92 patients (77%, 92/120). Staphylococcus aureus and Streptococcus pneumoniae were each isolated in almost a quarter of the patients, and Enterobacteriaceae in 53%. However, many of the pathogens isolated were of no clinical relevance and merely reflected a state of colonization. Most treatments were given during the first few days following admission. Of 220 patients receiving antibiotics for an infection, 87% were treated on day 1, but only 34% (14 of 41) on day 11. The frequent use of laboratory investigations combined with good communication between clinicians and microbiologists probably resulted in rapid cessation of unnecessary therapy. Fifty-two per cent of the antibiotics given for prophylaxis were administered later than the first postoperative day. This study emphasizes the need for consultation between surgeons and clinical microbiologists to supervise postoperative antibiotic use.

The effect of antistaphylococcal agents used alone and in combinations on the survival of Staphylococcus aureus ingested by human polymorphonuclear leukocytes.

The intracellular activity of a number of drugs used alone and in combinations against Staphylococcus aureus was investigated using an experimental design which imitates the clinical situation and differs from other published methods. Staphylococci were phagocytosed by human polymorphonuclear leukocytes and, after differential centrifugation and washing, the granulocytes were incubated in 90% pooled human serum with clinically relevant drug concentrations. When exposed to antibiotics, more than 40-50% of the bacteria were located intracellularly. Fusidic acid (100 mg/l), erythromycin (20 mg/l), and clindamycin (20 mg/l) all had a bacteriostatic effect during the first 6 h of incubation, whereas rifampicin (1 and 5 mg/l), vancomycin (5 and 20 mg/l), and ciprofloxacin (2 mg/l) all acted bactericidally with decreases in viable counts between 1.3-1.9 log10. The greatest bactericidal effect was achieved with tobramycin (10 mg/l), which produced more than a 4 log10 decrease in viable counts at 6 h. Combinations of fusidic acid with other antibiotics all resulted in killing kinetics different from those achieved with the drugs used individually. The bactericidal effect of ciprofloxacin and dicloxacillin during the first 6 h was abolished when these drugs were combined with fusidic acid. However, at 24 h no significant difference was found between the effect of dicloxacillin alone versus the combination dicloxacillin and fusidic acid. The combination of fusidic acid and rifampicin resulted in a killing identical to that achieved with rifampicin used alone during the first 6 h, but at 24 h the killing by the combination was significantly greater. The bactericidal effect of the combination dicloxacillin (20 mg/l) and tobramycin (10 mg/l) equalled that obtained with tobramycin (10 mg/l) used alone. Rifampicin (5 mg/l) antagonized the bactericidal effect of ciprofloxacin (2 mg/l) during the first 6 h of incubation but at 24 h the combination acted synergistically. The results obtained are partly in agreement and partly in conflict with previous results.

In-vitro activity of ciprofloxacin combined with either fusidic acid or rifampicin against Staphylococcus aureus.

Killing kinetic experiments were performed with ciprofloxacin, fusidic acid and rifampicin alone and with ciprofloxacin combined with either fusidic acid or rifampicin against ten strains of Staphylococcus aureus. The strains were all clinical isolates and two strains were methicillin-resistant. The antibiotic concentrations tested were in the range obtainable in the serum with recommended doses. The early bactericidal effect of ciprofloxacin alone was substantially greater than that of fusidic acid or rifampicin; thus the extent of killing after 6 h exposure to these antibiotics was 3.4 log10, 0.8 log10 and 0.6 log10, respectively. Fusidic acid as well as rifampicin antagonized the bactericidal activity of ciprofloxacin. Each combination killed 2 log10 cfu less than ciprofloxacin alone. For each combination the mean decrease in the number of organisms was comparable to that achieved with fusidic acid or rifampicin used alone.