This study shows that therapeutic drug monitoring is indicated in patients with a voriconazole-related SAE and that dose adjustment is required if the trough concentration of voriconazole exceeds 5.83 mg/l.
BackgroundGenetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19 influence voriconazole pharmacokinetics. However, the impact of CYP2C19 genetic polymorphisms on the therapeutic efficacy and toxicity of voriconazole therapy are not well established.Materials and MethodsIn this prospective observational study, we analyzed all consecutive adult patients with hematologic diseases who were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype and routine therapeutic drug monitoring of voriconazole were performed. The target range for voriconazole trough levels was 1-5.5 mg/L.ResultsA total of 104 consecutive patients were enrolled, including 39 homozygous extensive metabolizers (EMs, 38%), 50 heterozygous extensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2 mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followed by HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantly among the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazole-related adverse events did not differ significantly among the 3 groups (P = 0.399, P = 0.412, P = 0.317, and P = 0.518, respectively).ConclusionsWhile none of the initial voriconazole trough levels in PMs was outside the target range, subtherapeutic initial trough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either the clinical outcomes of IA or toxicity of voriconazole, further large-scale multicenter studies using clinical data from homogeneous populations are required.
To define the risk factors and clinical outcomes of community-onset bacteremia caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBLEC), we analyzed 50 consecutive cases of community-onset bacteremia caused by ESBLEC at a secondary hospital in South Korea from 2005 to 2010. Risk factors were assessed by conducting a case-double control study in which cases were compared with (1) control patients with community-onset bacteremia due to non-ESBLEC, and (2) those with community-onset bacteremia not caused by E. coli. Clinical outcome was assessed among patients with community-onset E. coli bacteremia. Community-onset bacteremia due to ESBLEC accounted for 6.7% of all community-onset E. coli bacteremia. In addition, an increasing proportion of ESBLEC among patients without any healthcare risk factors was observed. Comparison with both control groups revealed that the recent use of antibiotics (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.5-12.3) was an independent risk factor for ESBL acquisition. Factors influencing the 30-day mortality were a high Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR, 1.5; 95% CI, 1.1-2.0) and severe sepsis or septic shock (OR, 26.6; 95% CI, 1.5-470.7) and malignancy (OR, 11.9; 95% CI, 1.1-134.8). Increased mortality was not statistically associated either with ESBL production or with inappropriate empirical therapy. ESBLEC has emerged as a significant cause of community-onset bacteremia in this hospital, suggesting that ESBLEC are widely disseminated in the South Korean community.
Escherichia coli and Klebsiella pneumoniae are main pathogens in neutropenic fever even if the proportion of Gram-positive cocci is increasing. Extended-spectrum β-lactamases (ESBL)-producing organisms are an emerging problem in nosocomial infection. Nevertheless, until now, information about risk factors for the acquisition and clinical outcomes of bacteremia due to ESBL-producing organisms is limited in neutropenic patients. From medical records collected between January 2007 and December 2008, we identified a total of 101 consecutive patients who developed bacteremia due to E. coli (n = 87) or K. pneumoniae (n = 14). Twenty-six (26 %) cases of bacteremia were caused by ESBL-producing organisms. A hospital stay of >2 weeks during the 3 months preceding bacteremia [adjusted odds ratio (OR), 5.887; 95 % confidence interval (CI), 1.572-22.041] and the use of broad-spectrum cephalosporins in the 4 weeks prior to bacteremia (adjusted OR, 6.186; 95 % CI, 1.616-23.683) were significantly related to the acquisition of ESBL. Twenty-four (92 %) of the ESBL-producing organisms were susceptible to either piperacillin-tazobactam or amikacin. Aminoglycosides (amikacin or isepamicin) were the main appropriate antimicrobial agents used against the ESBL-producing isolates during the initial empirical treatment (16/22, 73 %). However, the 30-day mortality rates for ESBL bacteremia and non-ESBL bacteremia were not significantly different (15 vs 5 %; p = 0.199). As alternatives to carbapenem, piperacillin-tazobactam plus amikacin or isepamicin combinations may be effective empirical therapeutic options for patients with neutropenic fever who are at high risk of developing bacteremia with ESBL-producing pathogens.
Background The prevalence of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has been increased not only in the hospital but also in the community worldwide. This study was aimed to characterize ESBL- producing E. coli isolates and to investigate the molecular epidemiology of community isolates in comparison with hospital isolates at a single center in Korea. Methods A total of 142 ESBL-producing E. coli isolates were collected at Daejeon St Mary’s Hospital in Korea from January 2008 to September 2009. The ESBLs were characterized by PCR sequencing using specific primers. The genetic relatedness was determined by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Results Of 142 isolates, 139 were positive for CTX-M type ESBLs; CTX-M-14 (n = 69, 49.6 %), CTX-M-15 (n = 53, 38.1 %) and both CTX-M-14 and -15 (n = 17, 12.2 %). CTX-M-14 and CTX-M-15 were detected in both community and hospital isolates whereas isolates producing both CTX-M14 and-15 were mainly identified in the hospital. CTX-M producing E. coli isolates were genetically heterogeneous, revealing 75 distinct PFGE types. By MLST, 21 distinctive STs including 5 major STs (ST131, ST405, ST38, ST10, and ST648) were identified. Major STs were distributed in both community and hospital isolates, and ST131 was the predominant clone regardless of the locations of acquisition. No specific major STs were confined to a single type of ESBLs. However, ST131 clones were significantly associated with CTX-M-15 and the majority of them were multidrug-resistant. Distinctively, we identified a hospital epidemic caused by the dissemination of an epidemic strain, ST131-PFGE type 10, characterized by multidrug resistance and co-producing both CTX-Ms with OXA-1 or TEM-1b. Conclusions The epidemiology of ESBL-producing E. coli is a complex and evolving phenomenon attributed to the horizontal transfer of genetic elements and clonal spread of major clones, predominantly ST131. The multidrug resistant ST131 clone producing CTX-M-15 has emerged as a major clone in both the community and hospital, suggesting the widespread of this epidemic clone in Korea.
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