Sutep Jaruratanasirikul

Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis

BACKGROUND Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. METHODS In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. FINDINGS Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). INTERPRETATION Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. FUNDING Astellas Pharma Global Development, Basilea Pharmaceutica International.

Comparison of the Pharmacodynamics of Meropenem in Patients with Ventilator-Associated Pneumonia following Administration by 3-Hour Infusion or Bolus Injection

ABSTRACT The time that concentrations in serum are above the MIC (T>MIC) is the pharmacokinetic/pharmacodynamic parameter correlating with the therapeutic efficacy of β-lactam antibiotics. The aim of this study was to demonstrate the T>MIC of meropenem when administered by a 3-h infusion compared with that when administered by bolus injection. The study was conducted with nine patients with ventilator-associated pneumonia. Each subject received meropenem in three regimens consecutively: (i) bolus injection of 1 g every 8 h for 24 h; (ii) 3-h infusion of 1 g every 8 h for 24 h; and (iii) 3-h infusion of 2 g every 8 h for 24 h. Following bolus injection, the percentages of the T>MICs of 16, 8, 4, and 1 μg/ml were 28.33% ± 11.67%, 45.89% ± 22.90%, 57.00% ± 24.82%, and 74.67% ± 17.94% of an 8-h interval, respectively. For the 3-h infusion of 1 g of meropenem, the percentages of the T>MICs of 16, 8, 4, and 1 μg/ml were 37.78% ± 20.57%, 58.11% ± 24.38%, 72.67% ± 21.97%, and 93.56% ± 6.84% of an 8-h interval, respectively. For the 3-h infusion of 2 g of meropenem, the percentages of the T>MICs of 16, 8, 4, and 1 μg/ml were 57.89% ± 24.26%, 72.89% ± 22.40%, 85.56% ± 16.42%, and 98.56% ± 3.28% of an 8-h interval, respectively. In conclusion, a 3-h infusion resulted in greater T>MICs than those after a bolus injection. For the treatment of infections caused by pathogens with intermediate resistance, a 3-h infusion of 2 g of meropenem every 8 h can provide concentrations in serum above the MIC of 16 μg/ml for almost 60% of an 8-h interval.

Effects of long-term use of HAART on oral health status of HIV-infected subjects

BACKGROUND The aim of this study was to determine the effects of long-term use of highly active antiretroviral therapy (HAART) on oral health status of HIV-infected subjects. METHODS Oral examination and measurement of saliva flow rate of both unstimulated and wax-stimulated whole saliva were performed in HIV-infected subjects with and without HAART, and in non-HIV individuals. The following data were recorded; duration and risk of HIV infection, type and duration of HAART, CD4 cell count, viral load, presence of orofacial pain, oral dryness, oral burning sensation, oral lesions, cervical caries, and periodontal pocket. Multiple logistic regression analysis was performed to determine the effects of long-term use of HAART on oral health status of HIV-infected subjects. RESULTS One hundred and fifty-seven HIV-infected subjects - 99 on HAART (age range 23-57 years, mean 39 years) and 58 not on HAART (age range 20-59 years, mean 34 years) - and 50 non-HIV controls (age range 19-59 years, mean 36 years) were enrolled. The most common HAART regimen was 2 NRTI + 2 NNRTI. HIV-infected subjects without HAART showed greater risks of having orofacial pain, oral dryness, oral lesions, and periodontal pockets than those with short-term HAART (P < 0.01). The subjects with long-term HAART were found to have a greater risk of having oral lesions than those with short-term HAART (P < 0.05). The unstimulated and stimulated salivary flow rates of the subjects with HAART were significantly lower than in those without HAART (P < 0.05). CONCLUSION We conclude that long-term HAART has adverse effects on oral health status of HIV-infected subjects.

Continuous infusion versus intermittent administration of cefepime in patients with Gram-negative bacilli bacteraemia.

The objective of this study was to compare the pharmacokinetics of cefepime administered by continuous infusion and intermittent injection regimens. A prospective, randomized, cross‐over study of ten patients with Gram‐negative bacilli bacteraemia was conducted. All patients were randomized to receive cefepime either as a 4‐g continuous infusion over 24 h for 48 h or a 2‐g bolus administered intermittently intravenously every 12 h for 48 h. After 48 h the patients received the alternative dose regimen. Cefepime pharmacokinetic studies were carried out during hours 36–48 after the start of both regimens. All of the pathogens isolated from the blood in 7 patients had a minimum inhibitory concentration (MIC) < 1 μg mL−1. In both regimens, the serum cefepime concentrations at all time points were higher than the MIC for the pathogens isolated from this study. For the continuous infusion arm, the highest steady‐state concentration was 49.80±18.40 μg mL−1 and the lowest steady‐state concentration was 41.42±16.48 μg mL−1. The steady‐state concentrations were greater than 4 times the MIC of 8 μg mL−1. For the intermittent injection regimen, the mean trough concentration was 4.74±3.99 μg mL−1. The mean serum cefepime concentration was above 8 μg mL−1 for 81.66% of the dosing interval. Therefore, we conclude that either continuous infusion or intermittent injection can be used as an effective mode of cefepime administration to achieve bactericidal activity.

Pharmacodynamics of meropenem in critically ill patients with febrile neutropenia and bacteraemia.

The bactericidal activity of β-lactams is determined by the time that concentrations in tissue and serum are above the minimum inhibitory concentration (T>MIC) for the pathogen. The aim of this study was to compare the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for meropenem between administration by bolus injection and a 3-h infusion. The study was a randomised, three-way, cross-over design in eight febrile neutropenic patients with bacteraemia. Each subject received meropenem in three regimens consecutively: (i) a bolus injection of 1g every 8 h (q8h) for 24 h; (ii) a 3-h infusion of 1 g q8h for 24 h; and (iii) a 3-h infusion of 2 g q8h for 24h. For pathogens with an MIC of 4 μg/mL, the PTA of achieving 40% T>MIC following administration of meropenem by a bolus injection of 1g q8h, a 3-h infusion of 1 g q8h and a 3-h infusion of 2g q8h was 75.7%, 99.24% and 99.96%, respectively. Only the 3-h infusion of 2 g q8h achieved a PTA >99% for 40% T>MIC for a MIC of 8μg/mL. By referral to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) MIC distributions, the three regimens of meropenem were predicted to achieve a CFR≥90% against Escherichia coli and Klebsiella spp. In conclusion, a 3-h infusion of 2 g of meropenem q8h resulted in the highest PTA rates. The three regimens of meropenem had high probabilities of achieving optimal impact against E. coli and Klebsiella spp.

Pharmacodynamics modeling to optimize dosage regimens of sulbactam.

ABSTRACT The aim of this study was to reveal population pharmacokinetics and assess the efficacies of various dosage regimens of sulbactam in terms of the probability of target attainment with this agent over a range of MICs. Monte Carlo simulations were performed to determine the probability of attaining specific pharmacodynamic targets. The results indicated that a regimen consisting of a 4-h infusion of 3 g of sulbactam every 8 h would be an alternative treatment option for less-susceptible pathogens.

Comparison of the pharmacodynamics of imipenem in patients with ventilator-associated pneumonia following administration by 2 or 0.5 h infusion

OBJECTIVES The aim of this study was to compare the t > MICs of imipenem between administration by a 2 h infusion with a 0.5 h infusion. METHODS The study was a randomized three-way crossover in nine patients with ventilator-associated pneumonia. Each subject received imipenem in three regimens consecutively: (i) a 0.5 h infusion of 0.5 g every 6 h for 24 h; (ii) a 2 h infusion of 0.5 g every 6 h for 24 h; and (iii) a 2 h infusion of 1 g every 6 h for 24 h. RESULTS Following the 0.5 h infusion of 0.5 g of imipenem, the percentages of the t > 4 x MICs of 4, 2 and 1 mg/L were 20.32 +/- 9.32%, 44.11 +/- 16.40% and 64.67 +/- 20.56% of a 6 h interval, respectively. For the 2 h infusion of 0.5 g of imipenem, the percentages of the t > 4 x MICs of 4, 2 and 1 mg/L were 17.71 +/- 19.27%, 53.75 +/- 19.30% and 76.54 +/- 17.36% of a 6 h interval, respectively. For the 2 h infusion of 1 g of imipenem, the percentages of the t > 4 x MICs of 4, 2 and 1 mg/L were 60.26 +/- 23.96%, 77.78 +/- 20.11% and 93.35 +/- 8.26% of a 6 h interval, respectively. CONCLUSIONS The 2 h infusions of imipenem resulted in greater t > MICs than the 0.5 h infusion. For infections caused by pathogens with high MICs, a 2 h infusion of 1 g of imipenem every 6 h can provide plasma concentrations above the MIC of 4 mg/L for 60% of a 6 h interval.

Population Pharmacokinetics and Monte Carlo Dosing Simulations of Meropenem during the Early Phase of Severe Sepsis and Septic Shock in Critically Ill Patients in Intensive Care Units

ABSTRACT Pathophysiological changes during the early phase of severe sepsis and septic shock in critically ill patients, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors influencing therapeutic success. The aims of this study were (i) to reveal the population PK parameters and (ii) to assess the probability of target attainment (PTA) for meropenem. The PK studies were carried out following administration of 1 g of meropenem every 8 h during the first 24 h of severe sepsis and septic shock in nine patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the free plasma drug concentration remains above the MIC (fT>MIC) and 80% fT>MIC. The volume of distribution (V) and total clearance (CL) of meropenem in these patients were 23.7 liters and 7.82 liters/h, respectively. For pathogens with MICs of 4 μg/ml, the PTAs of 40% fT>MIC following administration of meropenem as a 1-h infusion of 1 g every 8 h and a 4-h infusion of 0.5 g every 8 h were 92.52% and 90.29%, respectively. For pathogens with MICs of 2 μg/ml in immunocompromised hosts, the PTAs of 80% fT>MIC following administration of 1-h and 4-h infusions of 2 g of meropenem every 8 h were 84.32% and 94.72%, respectively. These findings indicated that the V of meropenem was greater and the CL of meropenem was lower than the values obtained in a previous study with healthy subjects. The maximum recommended dose, i.e., 2 g of meropenem every 8 h, may be required for treatment of life-threatening infections in this patient population.

Pharmacodynamics of doripenem in critically ill patients with ventilator-associated Gram-negative bacilli pneumonia

Several pathophysiological changes in critically ill patients are important in determining the therapeutic success of β-lactam antibiotics. The aim of this study was to assess the population pharmacokinetics and probabilities of target attainment (PTAs) of doripenem in patients with ventilator-associated pneumonia, comparing administration by 1-h and 4-h infusion. Patients were randomised into two groups: Group I received a 1-h infusion of 0.5 g every 8 h (q8h) for seven doses; and Group II received a 4-h infusion of 0.5 g q8h for seven doses. A Monte Carlo simulation was performed to determine the PTAs. PTAs of achieving 40% T(>MIC) [exposure time during which the free drug concentration remains above the minimum inhibitory concentration (MIC)] and 75% T(>MIC) are required for effective bactericidal activity of this agent in immunocompetent and immunocompromised hosts, respectively. Values of volume of distribution and total clearance of doripenem in these patients were 17.26±1.83 L and 24.89±1.63 L/h, respectively. For pathogens with a MIC of 1 μg/mL, the PTAs of achieving 40% T(>MIC) following administration of doripenem by a 1-h and 4-h infusion of 0.5 g q8h were 92.95% and 98.32%, respectively. For pathogens with a MIC of 2 μg/mL in immunocompromised hosts, the PTAs of achieving 80% T(>MIC) following administration of doripenem by 1-h and 4-h infusion of 2 g q8h were 56.57% and 91.21%, respectively. In conclusion, these findings indicated that higher than recommended doses in this patient population, particularly neutropenic patients, would be necessary to optimise the pharmacokinetics of doripenem.

Effect of indinavir on the pharmacokinetics of rifampicin in HIV-infected patients*

Indinavir, an antiretroviral agent, has an influence on the pharmacokinetics of other drugs by acting as an inhibitor of cytochrome P450‐mediated drug metabolism. The incidence of tuberculosis has increased dramatically in the past decade because of an epidemic of HIV infection. Rifampicin is still one of the most valuable drugs for the standard treatment of tuberculosis. The objective of this study was to investigate the effects of indinavir on the pharmacokinetics of rifampicin in man. Our study was conducted in eleven HIV‐infected patients. All patients received a 600‐mg single dose of oral rifampicin on day 1 and 15‐ and 800‐mg oral indinavir three times a day from day 2 to day 15. Rifampicin pharmacokinetic studies were carried out on day 1 and day 15. The results showed that rifampicin concentrations were higher when it was administered with indinavir than when it was administered alone. With concomitant indinavir medication, the mean AUC0–24 of rifampicin was increased by 73%. Therefore, we conclude that indinavir has an inhibitory effect on the metabolism of rifampicin.