Pharmacokinetics of Voriconazole in Peritoneal Fluid of Critically Ill Patients.

Data on the distribution of voriconazole (VRC) in the human peritoneal cavity are sparse. This prospective study aimed to describe the pharmacokinetics of intravenous VRC in the peritoneal fluid of critically ill patients. A total of 19 patients were included. Individual pharmacokinetic curves, drawn after single (first dose on day 1) and multiple (steady-state) doses, displayed a slower rise and lower fluctuation of VRC concentrations in peritoneal fluid than in plasma. Good but variable penetration of VRC into the peritoneal cavity was observed, and the median (range) peritoneal fluid/plasma ratios of the area under the concentration-time curve (AUC) were 0.54 (0.34 to 0.73) and 0.67 (0.63 to 0.94) for single and multiple doses, respectively. Approximately 81% (13/16) of the VRC steady-state trough concentrations (Cmin,ss) in plasma were within the therapeutic range (1 to 5.5 µg/mL), and the corresponding Cmin,ss (median [range]) in peritoneal fluid was 2.12 (1.39 to 3.72) µg/mL. Based on the recent 3-year (2019 to 2021) surveillance of the antifungal susceptibilities for Candida species isolated from peritoneal fluid in our center, the aforementioned 13 Cmin,ss in peritoneal fluid exceeded the MIC90 of C. albicans, C. glabrata, and C. parapsilosis (0.06, 1.00, and 0.25 µg/mL, respectively), which supported VRC as a reasonable choice for initial empirical therapies against intraabdominal candidiasis caused by these three Candida species, prior to the receipt of susceptibility testing results.

Species distribution and antifungal susceptibility of fungi originating from positive blood cultures in Guangdong, 2019-2021 / 中国热带医学

@#Abstract: Objective　To investigate the species distribution and the antifungal susceptibility of fungi originating from positive blood cultures in Guangdong, so as to provide a basis for the rational use of antifungal drugs in clinical fungal bloodstream infections. Methods All data were collected for retrospective study from monitoring units of the Guangdong Fungal Disease Surveillance Network between 2019-2021, including clinical characteristics, species distribution and antifungal susceptibility. Results A total of 3 589 fungi strains were isolated, most of which were Candida spp. (86.5%, 3 105/3 589). The most common species was Candida albicans (36.6%, 1 315/3 589), followed by Candida tropicalis (17.4%, 1 626/3 589) and Candida parapsilosis (14.5%, 520/3 589). There were 42.1%(1 512/3 589) of strains isolated from ICU. The proportions of Candida albicans strains were 40.0%-50.0% among ICU, general surgery, organ transplantation and emergency department. Candida tropicalis (60.0%, 144/240) was the most common species in hematology department. Both Cryptococcus neoformans (35.4%, 69/195) and Talaromyces marneffei (35.9%,70/195) were common in infection department. All of the Candida isolates were of wild-type (WT) phenotype to amphotericin B. Resistance rates of caspofungin and micafungin for Candida spp. ranged from 0.0% to 4.2%. The resistance rates of Candida tropicalis to fluconazole and voriconazole were 42.3% and 38.9%, which were significantly higher than other common Candida spp. The cryptococcus neoformans strains were totally of WT phenotype to fluconazole and voriconazole. Conclusions Candida albicans is the most common species originating from positive blood cultures in Guangdong Province. Common Candida strains are highly sensitive to echinocandins and amphotericin B. Candida tropicalis has a high resistance rate to triazole drugs.

Population pharmacokinetic model-guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction.

STUDY OBJECTIVES: This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. DESIGN: Prospective pharmacokinetics study. SETTING: The intensive care unit in a tertiary-care medical center. PATIENTS: A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. METHODS: Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS: A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS: For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.

Clinical characteristics and risk factors of Talaromyces marneffei infection in human immunodeficiency virus-negative patients: A retrospective observational study.

BACKGROUND: To investigate the clinical characteristics and risk factors of human immunodeficiency virus (HIV)-negative patients with Talaromyces marneffei (T. marneffei) infection. METHODS: We retrospectively collected the clinical information of HIV-negative patients with T. marneffei infection from January 1, 2010 to June 30, 2019, and analyzed the related risk factors of poor prognosis. RESULTS: Twenty-five cases aging 22 to 79 years were included. Manifestations of T. marneffei infection included fever, cough, dyspnea, chest pain or distress, lymphadenopathy, ear, nose, and throat (ENT) and/or skin lesions, bone or joint pain, edema and pain in the lower extremities, digestive symptoms, icterus, malaise, and hoarseness. Two cases had no comorbidity, while 23 cases suffered from autoimmune disease, pulmonary disease, cancer, and other chronic diseases. Sixteen cases had a medication history of glucocorticoids, chemotherapy or immunosuppressors. Pulmonary lesions included interstitial infiltration, nodules, atelectasis, cavitary lesions, pleural effusion or hydropneumothorax, bronchiectasis, pulmonary fibrosis, pulmonary edema, and consolidation. The incidence of osteolytic lesions was 20%. Eight patients received antifungal monotherapy, and 11 patients received combined antifungal agents. Fifteen patients survived and ten patients were dead. The Cox regression analysis showed that reduced eosinophil counts, higher levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), myoglobin (Mb), procalcitonin (PCT), and galactomannan were related to poor prognosis (hazard ratio [HR]>1, P<0.05). CONCLUSIONS: Bone destruction is common in HIV-negative patients with T. marneffei infection. Defective cell-mediated immunity, active infection, multiple system, and organ damage can be the risk factors of poor prognosis.

Pneumonia caused by extensive drug-resistant Acinetobacter baumannii among hospitalized patients: genetic relationships, risk factors and mortality.

BACKGROUND: The clonal spread of multiple drug-resistant Acinetobacter baumannii is an emerging problem in China. We analysed the molecular epidemiology of Acinetobacter baumanni isolates at three teaching hospitals and investigated the risk factors, clinical features, and outcomes of hospital-acquired pneumonia caused by extensive drug-resistant Acinetobacter baumannii (XDRAB) infection in Guangzhou, China. METHODS: Fifty-two A. baumannii isolates were collected. Multilocus sequence typing (MLST) was used to assess the genetic relationships among the isolates. The bla OXA-51-like gene was amplified using polymerase chain reaction (PCR) and sequencing. The resistance phenotypes were determined using the disc diffusion method. A retrospective case-control study was performed to determine factors associated with XDRAB pneumonia. RESULTS: Most of the 52 A. baumannii isolates (N = 37, 71.2%) were collected from intensive care units (ICUs). The respiratory system was the most common bodily site from which A. baumannii was recovered (N = 45, 86.5%). Disc diffusion classified the isolates into 17 multidrug-resistant (MDR) and 35 extensively drug-resistant (XDR) strains. MLST grouped the A. baumannii isolates into 5 existing sequence types (STs) and 7 new STs. ST195 and ST208 accounted for 69.2% (36/52) of the isolates. The clonal relationship analysis showed that ST195 and ST208 belonged to clonal complex (CC) 92. According to the sequence-based typing (SBT) of the bla OXA-51-like gene, 51 A. baumannii isolates carried OXA-66 and the rest carried OXA-199. There were no significant differences with respect to the resistance phenotype between the CC92 and non-CC92 strains (P = 0.767). The multivariate analysis showed that the APACHE II score, chronic obstructive pulmonary disease (COPD) and cardiac disease were independent risk factors for XDRAB pneumonia (P < 0.05). The mortality rate of XDRAB pneumonia was high (up to 42.8%), but pneumonia caused by XDRAB was not associated with in-hospital mortality (P = 0.582). CONCLUSIONS: ST195 may be the most common ST in Guangzhou, China, and may serve as a severe epidemic marker. SBT of bla OXA-51-like gene variants may not result in sufficient dissimilarities to type isolates in a small-scale, geographically restricted study of a single region. XDRAB pneumonia was strongly related to systemic illnesses and the APACHE II score but was not associated with in-hospital mortality.

[An analysis of resistance of nosocomial infection pathogens isolated from 13 teaching hospitals in 2011].

OBJECTIVE: To investigate the pathogen profile of nosocomial infection in China, and to survey the susceptibility rates of these pathogens to the clinical common antibiotics. METHODS: The non-repetitive nosocomial pathogens isolated from bloodstream infection (BSI), hospital acquired pneumonia (HAP) and intra-abdominal infection (IAI) and the case data were collected from 13 teaching hospitals in different areas of China and sent to a central laboratory for re-identification and susceptibility testing. The levels of minimal inhibitory concentration (MIC) of the common antibiotics were determined by agar dilution method. The data were analyzed by WHONET 5.6 software. RESULTS: A total of 2103 clinical isolates were collected from January to December 2011, of which gram positive cocci and gram negative organisms accounted for 23.2% and 76.8% respectively. The top three pathogens of BSI were E. coli (31.0%, 243/784), K. pneumoniae (14.8%, 116/784) and S. aureus (10.6%, 83/784). The top three pathogens of HAP were A. baumannii (24.2%, 158/652), P. aeruginosa (23.0%, 150/652) and K. pneumoniae (16.4%, 107/652). The top three pathogens of IAI were E. coli (34.3%, 229/667), E. faecium (13.3%, 89/667) and K. pneumoniae (9.6%, 64/667). Methicillin-resistant S. aureus (MRSA) and coagulase negative Staphylococcus (MRCNS) accounted for 64.4% and 78.1% respectively. The susceptibility rates of Staphylococcus species to tigecycline, vancomycin, teicoplanin and linezolid were all 100%. The prevalence of MRSA in HAP was significantly higher than that in BSI or IAI. The susceptibility rates of Enterococcus species to tigecycline, teicoplanin and linezolid were all 100%. The prevalence of extended-spectrum ß-lactamases (ESBL) was 64.3% in E. coli and 38.3% in K. pneumonia. Against Enterobacteriaceae, the most active agents were as following in order: tigecycline (92.3% - 100%) [except P.mirabilis], meropenem (87.5% - 100%), imipenem (87.5% - 100%) [except M. morganii], amikacin (87.5% - 100%), polymyxin B (75% - 100%) [except S. marcescens, P. mirabilis and M morganii], cefepime (67.8% - 100%), cefoperazone-sulbactam (66.6% - 100%), piperacillin-tazobactam (61.5% - 100%). Carbapenem-resistance Enterobacteriaceae strains emerged. The susceptibility rates of P. aeruginosa to imipenem and meropenem were 66.2% and 72.2%, respectively. The susceptibility rates of A. baumannii to imipenem and meropenem were 27.7% and 25.9%, respectively. The most active agents against A. baumannii were polymyxin B (100%), followed by tigecycline (79.8%) and minocycline (50.4%). The susceptibility rates of P.aeruginosa to antibiotics in BSI were higher than those in HAP and IAI. Susceptibility rates of S. maltophilia to trimethoprim-sulfamethoxazole, minocycline and levofloxacin were about 90% or above. Susceptibility rates of B. cepacia to trimethoprim-sulfamethoxazole, ceftazidime and meropenem were all 100%. Several P.aeruginosa and A. baumannii strains were resistant to all tested antibiotics except polymyxin B. CONCLUSIONS: The pathogen profile is different in different types of infection. The prevalence of multi-drug resistant A. baumannii is high, which is still a key problem of nosocomial infection. Tigecycline remains relatively high activity against gram-positive cocci and gram-negative bacteria (except P. aeruginosa and P. mirabilis) in vitro.