Prospective assessment of the frequency of and risk factors for bleeding events in patients treated with cefazolin.

PURPOSE: Major bleedings have been described with cefazolin. The objective was to determine the frequency of bleeding events in cefazolin-treated patients and to identify risk factors for these complications. METHODS: Monocenter prospective observational study of all consecutive cefazolin-treated patients. Patients benefited from a daily clinical assessment of bleedings and a twice-a-week blood sampling including hemostasis. Bleedings were classified according to the International Society on Thrombosis and Hemostasis classification: major, clinically relevant non-major bleedings (CRNMB) and minor bleedings. RESULTS: From September 2019 to July 2020, 120 patients were included, with a mean age of 59.4 (± 20.7) years; 70% of them (84/120) were men. At least 1 CRNMB or major bleeding were observed in 10% of the patients (12/120). Compared to patients with no or minor bleeding, patients with CRNMB or major bleeding were, upon start of cefazolin, more frequently hospitalized in an intensive care unit (7/12, 58.3%, vs. 12/108, 11.1%, P < 0.001, respectively) and receiving vitamin K antagonists (4/12, 33.3%, vs. 8/108, 7.4%, P = 0.019, respectively). After multivariate analysis, patients receiving vitamin K antagonists the day prior bleeding and/or treated for endocarditis were factors associated with an increased risk of CRNMB or major bleeding (odd ratio 1.36, confidence interval 95%, 1.06-1.76, P = 0.020 and 1.30, 1.06-1.61, P = 0.015, respectively). CONCLUSIONS: Bleeding events associated with cefazolin treatment are frequent. Close clinical monitoring should be performed for patients treated for endocarditis and/or receiving vitamin K antagonists. Hemostasis work-up could be restricted to these patients.

Evaluating the heart valve tissue diffusion of amoxicillin in infective endocarditis: a pilot prospective observational non-comparative study.

OBJECTIVES: Treating patients with infective endocarditis (IE) due to streptococci and enterococci currently involves high-dosage antibiotics. Recent literature suggests a 30%-70% diffusion rate could be extrapolated to human heart valve tissue. The objective of this study was to evaluate the diffusion coefficient of amoxicillin in heart valve tissue of patients operated for IE. METHODS: Adult patients were prospectively included that underwent surgery at the European Hospital Georges Pompidou for IE due to streptococci and enterococci and had previous IV amoxicillin treatment. Plasma (taken 48 h preoperatively) and heart valve tissue amoxicillin concentrations were measured with a validated LC-MS/MS method. The MIC values of amoxicillin were measured for all available isolates. RESULTS: Seventeen patients were included. Eleven (64.7%) patients had native valve IE and six (35.3%) had prosthetic valve IE. Fourteen IE cases (82.4%) were due to streptococci, one (5.9%) was due to enterococci and two (11.8%) were Haemophilus spp, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae group infections. Median (IQR) amoxicillin dose administered was 10.5 (8.0-12.0) g/day corresponding to 138.2 (112.5-160.0) mg/kg/day. The median amoxicillin plasma concentrations pre-surgery and intra-tissular weighted concentrations were 31.9 (25.9-51.9) mg/L and 19.0 (7.9-31.4) µg/g, respectively. Median tissue/plasma concentration ratio was 0.47 (0.24-0.67), with a median amoxicillin plasma/MIC ratio of 487 (179-745), and median amoxicillin tissue/MIC ratio of 42 (14-116). CONCLUSIONS: With a significant diffusion coefficient, amoxicillin dosage in heart valve tissues showed a concentration/MIC ratio well above current recommendations for bactericidal activity. Our study suggests that lower doses can be considered for susceptible bacteria.

Antifungal Drugs TDM: Trends and Update.

PURPOSE: The increasing burden of invasive fungal infections results in growing challenges to antifungal (AF) therapeutic drug monitoring (TDM). This review aims to provide an overview of recent advances in AF TDM. METHODS: We conducted a PubMed search for articles during 2016-2020 using "TDM" or "pharmacokinetics" or "drug-drug-interaction" with "antifungal," consolidated for each AF. Selection was limited to English language articles with human data on drug exposure. RESULTS: More than 1000 articles matched the search terms. We selected 566 publications. The latest findings tend to confirm previous observations in real-life clinical settings. The pharmacokinetic variability related to special populations is not specific but must be considered. AF benefit-to-risk ratio, drug-drug interaction (DDI) profiles, and minimal inhibitory concentrations for pathogens must be known to manage at-risk situations and patients. Itraconazole has replaced ketoconazole in healthy volunteers DDI studies. Physiologically based pharmacokinetic modeling is widely used to assess metabolic azole DDI. AF prophylactic use was studied more for Aspergillus spp. and Mucorales in oncohematology and solid organ transplantation than for Candida (already studied). Emergence of central nervous system infection and severe infections in immunocompetent individuals both merit special attention. TDM is more challenging for azoles than amphotericin B and echinocandins. Fewer TDM requirements exist for fluconazole and isavuconazole (ISZ); however, ISZ is frequently used in clinical situations in which TDM is recommended. Voriconazole remains the most challenging of the AF, with toxicity limiting high-dose treatments. Moreover, alternative treatments (posaconazole tablets, ISZ) are now available. CONCLUSIONS: TDM seems to be crucial for curative and/or long-term maintenance treatment in highly variable patients. TDM poses fewer cost issues than the drugs themselves or subsequent treatment issues. The integration of clinical pharmacology into multidisciplinary management is now increasingly seen as a part of patient care.

Belatacept-based immunosuppression: A calcineurin inhibitor-sparing regimen in heart transplant recipients.

Belatacept (BTC) is indicated for prophylaxis of graft rejection in adults receiving a renal transplant (Tx). This retrospective observational study (three centers) included all heart transplant recipients receiving BTC between January 2014 and October 2018. Forty EBV+ patients mean GFR 35 ± 20 mL/min/m2 were identified, among whom belatacept was initiated during the first 3 months after transplantation in 12 patients, and later in 28 patients. Several patients were multiorgan transplant recipients. Study outcomes were GFR, safety, and changes in immunosuppressive therapy. The main reason for switching to BTC was to preserve renal function, resulting in discontinuation of CNI and changes in immunosuppressive therapy in 76% of cases. At study closeout, 24/40 patients were still on BTC therapy. GFR was improved (+59%, P = .0002*) within 1 month, particularly in the early group. More episodes of rejection were observed among "late" patients (1 death). Sixteen treatment discontinuations were recorded: GFR recovery (n = 4), DSA no longer detectable (n = 1), compliance issues (n = 3), poor venous access (n = 2), multiple infections (n = 1), 1 death (fungal lung infection), and treatment failure (n = 4). Median follow-up was 24 months. Four patients developed de novo DSA (MFI<1500). BTC is an effective alternative immunosuppressive for postoperative transient kidney failure, stabilizing delayed renal function, with acceptable safety profile under careful monitoring.

Is there any Hope for Monitoring Adherence in an Efficient and Feasible Way for Resistant Hypertension Diagnosis and Follow-Up?

PURPOSE OF REVIEW: Non-adherence to antihypertensive treatment is highly prevalent and represents a major factor affecting their effectiveness in hypertensive patients, thus contributing to apparent treatment resistance. It is however often overlooked because the methods to assess non-adherence are mainly subjective, limiting their usefulness in clinical practice. Non-adherence to treatment affects daily patient management, resulting in inappropriate, costly, and potentially harmful treatments and loss of the expected benefits from antihypertensive drugs. RECENT FINDINGS: Specialized centers now use a combination of objective screening tools. Firstly, snapshots of adherence levels can be provided by analytical drug detection in various biological matrixes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and secondly electronic monitoring systems of drug delivery which provide longitudinal data on adherence. Routine utilization of those tools allows the detection of non-adherence in patients with resistant hypertension, thus enabling implementation of appropriate interventions to improve drug adherence and avoid unnecessary treatment intensification. Other complementary techniques, such as digital health feedback system with ingestible sensors, are currently evaluated. In the context of an increasing burden of uncontrolled and apparent treatment-resistant hypertension, detecting non-adherence to antihypertensive therapy is, as acknowledged by the latest guidelines, a top priority to implement in clinical practice but still faces medical conservatism and disbelief.

Low Central Nervous System Posaconazole Concentrations during Cerebral Phaeohyphomycosis.

Posaconazole diffusion has been documented in various organs, which contrasts with the scarce data available for the human central nervous system (CNS). We analyzed posaconazole concentrations in plasma and multiple CNS specimens taken from a patient who received posaconazole because of cerebral phaeohyphomycosis. Low posaconazole concentrations were obtained in CNS specimens, with sample-to-plasma ratios between 5% and 22%. This case highlights the role of neurosurgery during cerebral phaeohyphomycoses, even those caused by posaconazole-susceptible black fungi.

Posaconazole Tablets in Real-Life Lung Transplantation: Impact on Exposure, Drug-Drug Interactions, and Drug Management in Lung Transplant Patients, Including Those with Cystic Fibrosis.

Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations (C0) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were <0.7 mg/liter for prophylaxis and 1 to 3 mg/liter for cure. The tacrolimus (TRL) and everolimus (ERL) C0 measured during PSZ exposure were also collected. The interaction with proton-pump inhibitors (PPI) was evaluated. We recorded the results for 21 CF patients with LT (CFLT patients), 11 non-CF patients with LT (NCFLT patients), and 27 nontransplant (NT) patients in pneumology departments. The weights of the NCFLT, CFLT, and NT patients were 59.2 ± 8.4, 48.8 ± 8.4, and 63.7 ± 16.6 kg, respectively (P = 0.001* [asterisk means that statistical test is significant]), and the PSZ C0 exposures for these patients were 1.9 ± 1.5, 1.1 ± 0.8, and 2.4 ± 1.8 mg/liter, respectively (P < 0.00001*). More than 60% of the concentrations were in the therapeutic range. In CFLT patients, the administration of one 300-mg PSZ tablet quickly achieved an exposure similar to that achieved with the PSZ oral suspension formulation (OSF) administered 3 or 4 times a day for several months. The TRL C0/dose ratio (C0/D) was 7.4 ± 4.4 mg/liter with PSZ tablets, whereas it was 4.6 ± 0.8 mg/liter with the PSZ oral solution (P = 0.034*). The ERL C0/D was similar with both formulations. PPI had no impact on the PSZ concentration (1.49 ± 1.07 mg/liter without PPI versus 1.33 ± 1.17 mg/liter with PPI; P = 0.4134*). Despite the high levels of exposure, PSZ remained well tolerated (one case of diarrhea and one case of fatigue were reported). PSZ tablet administration allows satisfactory exposure, even in CFLT patients, with a dosage lower than that of the PSZ OSF. This once-a-day formulation was not impacted by PPI, which are extensively used in CF patients.

Clinical outcome of cystic fibrosis patients colonized by Scedosporium species following lung transplantation: A single-center 15-year experience.

BACKGROUND: Fungi of the genus Scedosporium are emerging pathogens responsible for severe infections in lung transplant recipients. These infections are associated with poor prognosis and some centers consider now Scedosporium species colonization as a contraindication to lung transplantation (LT) even though no published evidence demonstrates that Scedosporium species colonization is associated with higher morbidity or mortality after LT. METHODS: Here, we aim to describe characteristics and outcome of cystic fibrosis (CF) lung transplant recipients colonized with Scedosporium species in a single center over a 15-year period. RESULTS: During the study period, 14 patients had scedosporial colonization reported. Only one patient, colonized before transplantation by Lomentospora prolificans, developed scedosporial disease. Among the eight patients colonized before transplantation by Scedosporium apiospermum complex, the median survival was 1.92 year (range 0.21-12.5). All these patients except one became free of fungal colonization after transplantation with antifungal prophylaxis including voriconazole or posaconazole. For the five patients colonized after LT, including two with L. prolificans, the median survival was 1.75 years (range 0.1-13); three of them are still alive. CONCLUSIONS: It appears to us that scedosporial colonization may not be a contraindication for LT in CF patients, as long as S. apiospermum complex is involved and a life-long azole prophylaxis prescribed.

Therapeutic Drug Monitoring of Everolimus: A Consensus Report.

In 2014, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology called a meeting of international experts to provide recommendations to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice. EVR is a potent inhibitor of the mammalian target of rapamycin, approved for the prevention of organ transplant rejection and for the treatment of various types of cancer and tuberous sclerosis complex. EVR fulfills the prerequisites for TDM, having a narrow therapeutic range, high interindividual pharmacokinetic variability, and established drug exposure-response relationships. EVR trough concentrations (C0) demonstrate a good relationship with overall exposure, providing a simple and reliable index for TDM. Whole-blood samples should be used for measurement of EVR C0, and sampling times should be standardized to occur within 1 hour before the next dose, which should be taken at the same time everyday and preferably without food. In transplantation settings, EVR should be generally targeted to a C0 of 3-8 ng/mL when used in combination with other immunosuppressive drugs (calcineurin inhibitors and glucocorticoids); in calcineurin inhibitor-free regimens, the EVR target C0 range should be 6-10 ng/mL. Further studies are required to determine the clinical utility of TDM in nontransplantation settings. The choice of analytical method and differences between methods should be carefully considered when determining EVR concentrations, and when comparing and interpreting clinical trial outcomes. At present, a fully validated liquid chromatography tandem mass spectrometry assay is the preferred method for determination of EVR C0, with a lower limit of quantification close to 1 ng/mL. Use of certified commercially available whole-blood calibrators to avoid calibration bias and participation in external proficiency-testing programs to allow continuous cross-validation and proof of analytical quality are highly recommended. Development of alternative assays to facilitate on-site measurement of EVR C0 is encouraged.

Dried Urine Spot Analysis for assessing cardiovascular drugs exposure applicable in spaceflight conditions.

Cardiovascular pharmacological countermeasures will be required as a preventive measure of cardiovascular deconditioning and early vascular ageing for long term space travelers. Physiological changes during spaceflight could have severe implications on drug pharmacokinetics and pharmacodynamics (PK/PD). However, limitations exist for the implementation of drug studies due to the requirements and constraints of this extreme environment. Therefore, we developed an easy sampling method on dried urine spot (DUS), for the simultaneous quantification of 5 antihypertensive drugs in human urine: irbesartan, valsartan, olmesartan, metoprolol and furosemide analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), considering spaceflight parameters. This assay was validated in terms of linearity, accuracy, and precision with satisfactory results. There were no relevant carry-over, matrix interferences. The targeted drugs were stable in urine collected by DUS until 6 months at +21 °C, +4°C, -20 °C (with or without desiccants) and at 30 °C during 48 h. Irbesartan, valsartan and olmesartan were not stable at 50 °C during 48 h. This method was found to be eligible for space pharmacology studies in terms of practicality, safety, robustness and energy costs. It has been successfully implemented in space tests programs led in 2022.

Pulmonary toxicity of mTOR inhibitors. Comparisons of two populations: Solid organ recipients and cancer patients.

INTRODUCTION: Mammalian target of rapamycin (mTOR) inhibitors-associated pneumonitis (mTOR-IP) has long been described in solid organ recipients (T) patients but more recently in cancer (K) patients. Its overall characteristics have never been compared between these 2 populations. The aim of this study was to compare them in terms of presentation, severity and outcome in T and in K patients. MATERIAL AND METHODS: We carried out a retrospective study in a single French tertiary center. Four databases were used to ensure the exhaustive collection of all mTOR-IP cases between 2001 and 2020. All clinical, biological, radiological, pathological and outcome data were reviewed. RESULTS: Thirty-nine patients with mTOR-IP were diagnosed during this period, 24T and 15K patients. The average dosage of everolimus and sirolimus was 2,65mg (±1,78) and 2,75mg (±0,96) in T patients, respectively, versus 8,75mg (±2,26) for everolimus in K patients. The overall prevalence of mTOR-IP was 6.4% with a median time of occurrence of 7 months [IQR 3-35 months]. mTOR-IP were significantly more frequent (P<0.001) and occurred earlier (P<0.001) in cancer patients. No clinical, functional, radiological, pathological nor outcome differences were otherwise observed between the 2 groups. Average everolimus blood levels at the time of mTOR-IP diagnosis were in the range of recommended therapeutic values. CONCLUSION: Our study shows that mTOR-IP is comparable in terms of presentation in T and in K patients but that it occurs significantly earlier after drug introduction in the latter. This raises questions as to the potential role of the higher doses used in K patients as well as that of co-treatments in the pathogeny of the disease.

Urine N-acetyl-Ser-Asp-Lys-Pro measurement as a versatile biomarker to assess adherence to angiotensin-converting enzyme inhibitors.

BACKGROUND: Poor adherence to treatment is a major health issue in hypertension. The large number of drugs to be detected limits the implementation of chemical adherence testing by liquid chromatography/mass spectrometry (LC-MS/MS). AcSDKP, a peptide accumulating in the presence of angiotensin-converting-enzyme inhibitor (ACEI) treatment, has been validated as a proven marker of adherence by enzyme-linked immunosorbent assay. Our aim was to validate urine measurements of AcSDKP compared with active metabolites of various ACEI, measured simultaneously by LC-MS/MS. METHOD: We first studied the time-dependent relationships between urinary perindoprilat and AcSDKP in a pharmacokinetic/pharmacodynamic study in healthy volunteers. We then compared the sensitivity and specificity of urinary AcSDKP vs. three ACEI active metabolites (enalaprilat, perindoprilat, ramiprilat) taken as reference to detect nonadherence in spot urine samples from a prospective cohort of hypertensive outpatients. RESULTS: The urinary excretion profiles of AcSDKP and perindoprilat were similar, exhibited a significant correlation, and showed excellent agreement in healthy volunteers. In patients, we found a similar agreement between AcSDKP and the three ACEI metabolites urinary concentrations. The sensitivity and specificity for adherence assessment of urine AcSDKP was 92.2 and 100%, respectively. We observed a difference in the evaluation of good adherence between ACEI metabolites (85.7%) and AcSDKP (79.0%) because of discrepancies in samples where AcSDKP reached undetectability quicker than ACEI metabolites. This characteristic of AcSDKP is of particular interest and could better reflect the true adherence status of patients. CONCLUSION: Overall, spot urine AcSDKP measurement by LC-MS/MS is a reliable marker of the intake of ACEI treatment and could substitute ACEI metabolites detection.

Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients.

PURPOSE: Voriconazole is widely used to treat invasive aspergillosis after lung transplantation. In cystic fibrosis patients, the interindividual variability in drug disposition complicates the optimal voriconazole dosing and increases the risk of toxicity. The objective of this retrospective study was to evaluate the influence of CYP2C19 genotype on voriconazole response in lung transplant patients with cystic fibrosis. METHODS: We retrospectively studied 24 Caucasian cystic fibrosis lung transplant recipients who received voriconazole. We analyzed the influence of CYP2C19 genotype (*2 and *17 alleles) on voriconazole exposure and maintenance dose and side effects. RESULTS: Heterozygous carriers of the CYP2C19*2-deficient allele required lower maintenance doses (440 ± 107 mg/day) compared with wild-type and CYP2C19*17-allele carriers (633 ± 197 mg/day and 600 ± 193 mg/day, respectively, P<0.05). The time to achieve the therapeutic range and the proportion of out-of-range concentrations were significantly higher in the CYP2C19*2 group (31.3% vs. 12.1% and 9.8% of above-range levels in the CYP2C19*1 and CYP2C19*17 groups, respectively) or CYP2C19*17 group (37.9% vs. 15.6% and 13% of below-range levels in the CYP2C19*1 and CYP2C19*2 groups, respectively) (P<0.01). No relationship was found between voriconazole toxicity and CYP2C19 status. CONCLUSIONS: In this frail population, voriconazole exposure is strongly influenced by CYP2C19 genotype, and determining the genotype before voriconazole initiation may help determine the initial dosing regimen that will promptly achieve therapeutic plasma levels without producing out-of-range levels.

[Level of evidence for therapeutic drug monitoring of posaconazole]. / Niveau de preuve du suivi thérapeutique pharmacologique du posaconazole.

Posaconazole, systemic antifungal marketed in France since 2006, is indicated as second line in curative treatment of invasive fungal infections (IFI) (aspergillosis...) and prophylaxis of IFI in patients receiving chemotherapy or hematopoietic stem cell transplantation. The analysis of the literature indicates a concentration-efficacy relationship, but to date, no study has been able to show a concentration-toxicity correlation due to its favourable safety profile and the difficulty to obtain high concentrations. In curative, maintenance of trough plasma concentrations between 0.5 and 1.5 mg/L seems to be associate with an efficacy. In prophylaxis, a threshold of 0.5 mg/L corresponds to a minimal exposure. However this target is not yet well defined. Saturation of absorption above the 800 mg oral dose limits the adjustment of concentrations. As such, the Therapeutic Drug Monitoring of posaconazole can be recommended.

[Level of evidence for therapeutic drug monitoring of vancomycin]. / Niveau de preuve pour le suivi thérapeutique pharmacologique de la vancomycine.

Vancomycin is an antibiotic for exclusive hospital use administrated in intravenous infusion to treat systemic infections. It is mainly eliminated by kidneys and potentially nephrotoxic. Data available show that Therapeutic Drug Monitoring (TDM) of vancomycin is highly recommended. It aims to ensure efficacy and avoid resistance by maintaining trough plasma concentrations above the MIC. Secondary, vancomycine TDM may be indicated to prevent nephrotoxicity in high risk patients. TDM is often underwent at steady state (48 to 72 h after the treatment initiation) unless in case of renal impairment (24 h). While compared with intermittent administration, continuous infusion did not result in prognosis improvement; however it resulted in lower pharmacokinetic variability and better cost-efficiency. Targeted trough concentrations for intermittent infusion are between 15 and 20 mg/L (up to 25-30 mg/L for GISA). In case of continuous infusion, targets are higher (25 to 40 mg/L).

[Not Available]. / Niveau de preuve pour le suivi thérapeutique pharmacologique de la vancomycine.

Level of Evidence for Therapeutic Drug Monitoring of Vancomycin. Vancomycin is an antibiotic for exclusive hospital use administrated in intravenous infusion to treat systemic infections. It is mainly eliminated by kidneys and potentially nephrotoxic. Data available show that Therapeutic Drug Monitoring (TDM) of vancomycin is highly recommended. It aims to ensure efficacy and avoid resistance by maintaining trough plasma concentrations above the MIC. Secondary, vancomycine TDM may be indicated to prevent nephrotoxicity in high risk patients. TDM is often underwent at steady state (48 to 72 h after the treatment initiation) unless in case of renal impairment (24 h). While compared with intermittent administration, continuous infusion did not result in prognosis improvement; however it resulted in lower pharmacokinetic variability and better cost-efficiency. Targeted trough concentrations for intermittent infusion are between 15 and 20 mg/L (up to 25-30 mg/L for GISA). In case of continuous infusion, targets are higher (25 to 40 mg/L).

[Not Available]. / Niveau de preuve du suivi thérapeutique pharmacologique du posaconazole.

Posaconazole, systemic antifungal marketed in France since 2006, is indicated as second line in curative treatment of invasive fungal infections (IFI) (aspergillosis. . . ) and prophylaxis of IFI in patients receiving chemotherapy or hematopoietic stem cell transplantation. The analysis of the literature indicates a concentration-efficacy relationship, but to date, no study has been able to show a concentration-toxicity correlation due to its favourable safety profile and the difficulty to obtain high concentrations. In curative, maintenance of trough plasma concentrations between 0.5 and 1.5 mg/L seems to be associate with an efficacy. In prophylaxis, a threshold of 0.5 mg/L corresponds to a minimal exposure. However this target is not yet well defined. Saturation of absorption above the 800 mg oral dose limits the adjustment of concentrations. As such, the Therapeutic Drug Monitoring of posaconazole can be recommended.

In Vivo Efficacy of Voriconazole in a Galleria mellonella Model of Invasive Infection Due to Azole-Susceptible or Resistant Aspergillus fumigatus Isolates.

Aspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening infections in humans and animals. Azoles are the first-line treatment for aspergillosis, but in recent years, the emergence of azole resistance in A. fumigatus has changed treatment recommendations. The objective of this study was to evaluate the efficacy of voriconazole (VRZ) in a Galleria mellonella model of invasive infection due to azole-susceptible or azole-resistant A. fumigatus isolates. We also sought to describe the pharmacokinetics of VRZ in the G. mellonella model. G. mellonella larvae were infected with conidial suspensions of azole-susceptible and azole-resistant isolates of A. fumigatus. Mortality curves were used to calculate the lethal dose. Assessment of the efficacy of VRZ or amphotericin B (AMB) treatment was based on mortality in the lethal model and histopathologic lesions. The pharmacokinetics of VRZ were determined in larval hemolymph. Invasive fungal infection was obtained after conidial inoculation. A dose-dependent reduction in mortality was observed after antifungal treatment with AMB and VRZ. VRZ was more effective at treating larvae inoculated with azole-susceptible A. fumigatus isolates than larvae inoculated with azole-resistant isolates. The concentration of VRZ was maximal at the beginning of treatment and gradually decreased in the hemolymph to reach a Cmin (24 h) between 0.11 and 11.30 mg/L, depending on the dose. In conclusion, G. mellonella is a suitable model for testing the efficacy of antifungal agents against A. fumigatus.

Influence of the clindamycin administration route on the magnitude of clindamycin-rifampicin interaction: a prospective pharmacokinetic study.

OBJECTIVES: An important clindamycin-rifampicin pharmacokinetic (PK) interaction has been reported, but the potential influence of the clindamycin administration route on that interaction is unknown. This prospective, observational, comparative PK study was undertaken to characterize and analyse the impact of the route, comparing the rifampicin enzyme-inductor effects on clindamycin clearance (CLclin) for oral versus intravenous (IV) administration. METHODS: Patients with bone-and-joint infections (BJIs) were treated with clindamycin monotherapy (n = 20) or clindamycin-rifampicin combination therapy (n = 19). Patients received continuous IV clindamycin infusion for 2-6 weeks, followed by an oral regimen. Liquid chromatography-mass spectrometry was used to measure plasma clindamycin concentrations at the end of IV and after 2 weeks of oral treatment. The ratios of the mean CLclin for the combination and monotherapy groups were calculated for IV (Riv) and oral (Rpo) routes, with the final ratio, Rf = Rpo/Riv, representing the fold change of the rifampicin-inducing effect from the IV to the oral route. RESULTS: Comparing monotherapy with combination-therapy groups, the former's median steady-state concentration was two-fold higher after IV administration (8.49 versus 3.82 mg/L, p < 0.001) and its median AUC0-8h was 12 times higher after oral intake (37.7 versus 3.1 mg.h/L, p < 0.001). Riv, Rpo and Rf were 2.68, 18.8 and 7.0 respectively. CONCLUSION: The magnitude of this interaction was markedly increased by oral intake, questioning the use of oral treatment for difficult-to-treat infections like BJIs. Nevertheless, the clindamycin-rifampicin combination seems possible provided that clindamycin is administered by continuous IV infusion.

Pharmacological considerations for azole antifungal drug management in cystic fibrosis lung transplant patients.

This paper aims to present our experience in the pharmacological approach of the management of azole antifungal drugs in cystic fibrosis lung transplant patients. Cystic fibrosis (CF) lung transplantation is associated with multi-factorial care management, because of immunosuppressive requirements, risk of infections, frequency of gastro-oesophageal reflux disease, hepatic alterations and CF pharmacokinetics (PK) specificities that result in important PK variability. CF is associated with frequent colonization of the airways by filamentous fungi, especially by Aspergillus species. Today the antifungal therapeutic arsenal offers several possibilities for long-term oral therapy including azole drugs (itraconazole, voriconazole and posaconazole). Therefore, nephrotoxic amphotericin B should be avoided. The liver is important in the pharmacological profile of azole drugs, due to metabolic elimination, hepatotoxicity and PK drug-drug interaction (DDI) involving CYP3A4 metabolic inhibition. Targets for such DDI are numerous, but immunosuppressive drugs are of major concern, justifying combined therapeutic drug monitoring (TDM) of both azoles (inhibitors) and immunosuppressants (targets) on an individualized patient basis to adjust the coprescription quantitatively. The risk of long under-dosed periods, frequently addressed in this population, could justify, on a PK basis, the need for combination with an exclusive parenteral antifungal while waiting for azole relevant drug level. High PK variability, the risk of low exposure, therapeutic issues and DDI management in this complex underlying disease justify close monitoring with systematic combined TDM of azole and immunosuppressants, in case of coprescription.