***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Arbekacin ( ABK ) was approved and widely used in Japan for treatment of patients infected with MRSA , and TDM was introduced in clinical practice . The Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring decided to develop a clinical practice guidelines for TDM of ABK for the following reasons . First , although the daily dose of 150e200 mg was approved in Japan , recent PK- PD studies revealed that higher serum concentration is required to achieve better clinical efficacy and several findings concerning the usefulness of higher dosage regimen have obtained recently . Second , although maximal concentrations that obtained immediately after the end of administration ( Cmax ) w as generally adopted , the serum concentration at 1 h after initiation of administration ( peak serum con- centration ( Cpeak ) ) proved to be more suitable as an efficacy indicator of aminoglycosides . Lastly , as ABK is approved only in Japan , no international practice guideline for TDM has not been available in ABK to date . This guideline evaluated the scientific data associated with serum ABK  monitoring and provided rec- ommendations based on the available evidence . Potential limitations of this guideline , however , include the findings that few prospect i ve clinical trials of TDM of ABK are available in the treatment of MRSA infections and that most of the published literature describes observational studies BACKGROUND Voriconazole is a triazole agent with excellent antifungal activity against Aspergillus species . However , despite its potential advantages , the occurrence of unpredictable toxicities might be critical in immunocompromised patients . The aim of this study was to analyze risk factors for voriconazole-related  severe adverse events ( SAEs ) . METHODS This prospect i ve observational study was conducted in Korean patients with hematological malignancies and invasive aspergillosis on intravenous voriconazole therapy between June 2008 and April 2009 . RESULTS Of the 25 patients enrolled , eight ( 32 % ) showed voriconazole-related SAEs , which included hepatotoxicities ( n=5 ) , cardiac tachyarrhythmias ( n=2 ) , and neurotoxicity ( n=1 ) . Sex , age , underlying hematological malignancies , voriconazole dose , the co-administration of a proton pump inhibitor , and CYP2C19 genotype were not found to be related to the occurrence of SAEs . However , trough plasma concentrations of voriconazole  were found to be significantly higher in the patients with an SAE : median 6.32 mg/l ( interquartile range ( IQR ) 2.86 - 9.71 mg/l ) vs. median 2.15 mg/l ( IQR 0.92 - 4.00 mg/l ) ; p=0.011 . Receiver operating characteristic curve analysis identified a cut-off trough concentration for SAEs of 5.83 mg/l ( sensitivity 62.5 % and specificity 94.1 % ) . Furthermore , multivariate analysis showed that a trough concentration of ≥ 5.83mg/l was the only significant independent risk factor of an SAE . CONCLUSIONS 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 Seventy-one allograft recipients receiving voriconazole , in whom complete clinical , microbiologic and pharmacokinetic data were available , were studied to determine the efficacy of voriconazole in preventing fungal infections . The length of voriconazole therapy was 6–956 days ( median 133 ) . The  total number of patient-days on voriconazole was 13 805 ( ∼38 years ) . A total of 10 fungal infections were seen in patients on  voriconazole ( 18 % actuarial probability at 1 year ) : C and ida glabrata ( n=5 ) , C and ida krusei ( n=1 ) , Cunninghamella ( n=1 ) , Rhizopus ( n=2 ) and Mucor ( n=1 ) . Two of the four zygomycosis cases were preceded by short duration s of voriconazole therapy , but prolonged itraconazole prophylaxis . The plasma steady-state trough voriconazole levels around the time the infection occurred were < 0.2 , < 0.2 , 0.33 , 0.55 , 0.63 and 1.78 μg/ml in the six c and idiasis cases . Excluding the four zygomycosis cases , all the six c and idiasis cases were seen among the 43 patients with voriconazole levels of ⩽2 μg/ml and none among the 24 with levels of > 2 μg/ml ( P=0.061 ) . We conclude that voriconazole is effective at preventing aspergillosis . However , breakthrough zygomycosis is seen in a small proportion of patients . The role of therapeutic voriconazole monitoring with dose adjustment to avoid breakthrough infections with fungi that are otherwise susceptible to the drug needs to be explored prospect ively BACKGROUND Blood levels of voriconazole , a first line therapy for invasive aspergillosis , may correlate with adverse events and treatment response . However , no r and omized controlled studies have been conducted to evaluate the clinical utility of routine therapeutic drug monitoring ( TDM ) of voriconazole . This study aim ed to determine whether routine TDM of voriconazole reduces drug adverse events or improves treatment response in invasive fungal infections . METHODS This was a r and omized , assessor-blinded , controlled , single center trial . One hundred ten adult patients were r and omly assigned to TDM or non-TDM groups . In the TDM group , voriconazole dosage was adjusted ( target range , 1.0 - 5.5 mg/L ) according to the serum trough level measured on the fourth day after initiation of voriconazole . The non-TDM group received a fixed , st and ard dosage . Voriconazole-related adverse events were monitored , and treatment response was assessed three months after the initiation of therapy . RESULTS Baseline characteristics including the CYP2C19 genotype were comparable between the two groups . While the incidence of adverse events was not different between the TDM group and the non-TDM group ( both 42 % ; P = .97 ) , the proportion of voriconazole discontinuation due to adverse events was significantly lower in the TDM group than in the non-TDM group ( 4 % vs 17 % ; P = .02 ) . A complete or partial response was observed in 81 % ( 30 of 37 ) of patients in the TDM group compared to 57 % ( 20 of 34 ) in the non-TDM group ( P = .04 ) . CONCLUSIONS Routine TDM of voriconazole may reduce drug discontinuation due to adverse events and improve the treatment response in invasive fungal infections . CLINICAL TRIAL REGISTRATION NCT00890708 ABSTRACT Voriconazole prophylaxis is common following lung transplantation , but the value of therapeutic drug monitoring is unknown . A prospect i ve , observational study of lung transplant recipients ( n = 93 ) receiving voriconazole prophylaxis was performed .  Serum voriconazole troughs ( n = 331 ) were measured by high-pressure liquid chromatography . The median initial and subsequent troughs were 1.91 and 1.46 μg/ml , respectively . The age of the patient directly correlated with initial troughs ( P = 0.005 ) . Patients that were ≥60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs , respectively . In 95 % ( 88/93 ) of patients , ≥2 troughs were measured . In 28 % ( 25/88 ) and 32 % ( 28/88 ) of these patients , all troughs were ≤1.5 μg/ml or > 1.5 μg/ml , respectively . Ten percent ( 10/93 ) and 27 % ( 25/93 ) of the patients developed invasive fungal infection ( tracheobronchitis ) and fungal colonization , respectively . The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 μg/ml ( P = 0.07 ) . Invasive fungal infections or colonization were more likely with troughs of ≤1.5 μg/ml ( P = 0.01 ) and among patients with no trough of > 1.5 μg/ml ( P = 0.007 ) . Other cutoff troughs correlated less strongly with microbiologic outcomes . Troughs correlated directly with aspartate transferase levels ( P = 0.003 ) , but not with other liver enzymes  . Voriconazole was discontinued due to suspected toxicity in 27 % ( 25/93 ) of the patients . The troughs did not differ at the times of suspected drug-induced hepatotoxicity , central nervous system ( CNS ) toxicity , or nausea/vomiting and in the absence of toxicity  . Voriconazole prophylaxis was most effective at troughs of > 1.5 μg/ml . A cutoff for toxicity was not identified , but troughs of > 4 μg/ml were rare . The data support a target range of > 1.5 to 4 μg/ml There are limited data on the relationship between voriconazole levels and clinical outcomes relative to invasive aspergillosis ( IA ) . We therefore analyzed the association between initial voriconazole trough blood levels and clinical responses of IA in patients with hematologic malignancies . All adult patients treated with voriconazole in a tertiary care hospital in Seoul , South Korea , between August 2009 and April 2011 were identified from pharmacy records .  Initial voriconazole trough levels were routinely measured 1 week after therapy and patient responses were classified as success ( complete or partial response ) or failure ( stable response , progression of disease , or death ) at 2 weeks post-therapy . Fifty-two patients , involving 2 ( 4 % ) proven , 29 ( 56 % ) probable , and 21 ( 40 % ) possible IA infections , were included . Of these , 11 ( 21 % ) had initial voriconazole levels of ≤ 2 mg/l and the remaining 41 ( 79 % ) had > 2 mg/l . There were slightly fewer successful responses ( 45 % , 5/11 ) in the patients with initial voriconazole levels ≤ 2 mg/l than in those with voriconazole levels > 2 mg/l ( 51 % , 21/41 ) , but the difference was not statistically significant ( P= 0.73 ) . Neutropenia ( OR 0.1 , P= 0.008 ) and immunosuppression ( OR 0.1 , P= 0.004 ) were independently associated with 2-week successful response after voriconazole therapy . In conclusion , initial voriconazole trough levels may not significantly affect clinical outcomes of IA at 2 weeks after voriconazole therapy in patients with hematologic malignancies . Further studies of prospect i ve design are needed to establish the optimal procedure for voriconazole drug monitoring Background Genetic 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 . Material s and Methods In this prospect i ve 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. Results A 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 ) . Conclusions While 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 
    Output:
    
A trough concentration > 3.0 mg/L is associated with increased hepatotoxicity , particularly for the Asian population , and > 4.0 mg/L is associated with increased neurotoxicity