Cost-utility analysis of antiviral use under pandemic influenza using a novel approach - linking pharmacology, epidemiology and heath economics.

Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) - dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients' quality of life. Integrating PK/PD-EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.

The posology of oseltamivir in infants with influenza infection using a population pharmacokinetic approach.

Infants are at increased risk for morbidity and mortality due to influenza. Until recently, few data were available with which to optimize oseltamivir dosing in this high-risk population. Here, data for 133 infants were pooled from two prospective pharmacokinetic/pharmacodynamic safety studies to develop a population pharmacokinetic model. A three-compartment model with allometric scaling of all clearance and volume parameters described the disposition of oseltamivir and its carboxylate metabolite (OC). Weight dependence, OC clearance, and volume of distribution increased linearly with age. Analyses showed no association between OC exposure and viral clearance, the development of resistance (phenotypic/genotypic), normalization of body temperature, or safety endpoints. Pharmacokinetic bridging showed that a 3 mg/kg dose yielded acceptable OC exposure and good tolerability while minimizing the risk of underexposure and resistance/treatment failure. These pharmacological analyses formed the basis of the US Food and Drug Administration's recent approval of oseltamivir treatment for infants with influenza aged as young as 2 weeks.

Pharmacokinetic-pharmacodynamic determinants of oseltamivir efficacy using data from phase 2 inoculation studies.

Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC(50)] = 0.18 nM) or B/Yamagata (IC(50) = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC(0-24)), minimum concentration of OC in plasma (C(min)), and maximum concentration of OC in plasma (C(max)). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC(0-24 )evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC(0-24) threshold (~14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.

Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers.

Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of oseltamivir. This single-center, open-label study explored the pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [C(max)], 2.4 ng/ml [oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean C(max), 115 ng/ml [oseltamivir] and 544 ng/ml [OC]), with corresponding C(max) CSF/plasma ratios of 2.1% (oseltamivir) and 3.5% (OC). Overall exposure to oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.

Linezolid in the treatment of osteomyelitis: results of compassionate use experience.

BACKGROUND: This case series examines osteomyelitis patients enrolled into a prospective, open label, noncomparative, non-randomized compassionate use program. Patients received 600 mg bid iv or po linezolid. PATIENTS AND METHODS: 89 patients were enrolled into the compassionate use program with the diagnosis of osteomyelitis and were evaluated for clinical efficacy, safety and tolerability. Informed consent was obtained from the patients or their guardians and guidelines for human experimentation of the US Department of Health and Human Services and/or those of the investigators' institutions were followed in the conduct of this clinical research. RESULTS: 55 cases of osteomyelitis met the inclusion criteria for clinical assessment. The 55 courses included long bone (53%), diabetic foot (18%), sternal wound (14.5%) and vertebral osteomyelitis (15%). Clinical assessment at longterm follow-up occurred at a median of 195 days after the last dose, and the clinical cure rate in 22 evaluable cases was 81.8% and failure rate 18.2%. The most common clinical adverse drug events (ADEs) were gastrointestinal disturbances. Reduction in hemoglobin/hematocrit and in platelet counts were the most common laboratory ADEs. CONCLUSION: Linezolid iv or po was successful in treating patients with osteomyelitis caused by resistant grampositive organisms or those with intolerance or nonresponsiveness to other potentially effective treatments. Larger comparator controlled studies should be performed to confirm these findings.

Multidisciplinary HIV adherence intervention: a randomized study.

Maintaining greater than 95% adherence to antiretroviral medication is necessary in order to have the greatest therapeutic impact on HIV infection. Furthermore, evidence suggests that adherence rates of between 70% and 89% are significantly associated with viral rebound and the development of drug resistance. Adherence rates at and above the 95% level are difficult for patients to achieve and maintain. Our aim was to determine if an adherence intervention could improve adherence among patients attending an ambulatory care clinic at a large public hospital. The intervention was delivered by a multidisciplinary team of health care professionals and consisted of education coupled with the provision of devices designed to assist patient memory and adherence. A crucial component of the intervention consisted of the identification of patient specific barriers to adherence and the development of strategies to circumvent these problems. Adherence was assessed using patient self-report over the past 4, 7, and 28 days and by calculation of the Morisky score. The study was conducted as a randomised controlled trial using the stepped wedge design with a total of 68 subjects randomised to receive the intervention over a 20-week period. Adherence before and after the intervention formed the analysis. There was a significant decrease in the number of missed doses over the past 4 (1.9 to 1.0, p < 0.001), 7 (3.0 to 1.8, p < 0.001) and 28 (7.4 to 4.2, p < 0.001) days and a decrease in the Morisky score, indicating an improvement in medication taking behaviour (1.3 to 0.5 p < 0.001).

Randomized trial of an adherence programme for clients with HIV.

Our aim was to determine if a comprehensive adherence package improved self reported adherence to antiretroviral therapy. The adherence package included an education programme, individualized planning of regimens, and the opportunity for a patient to choose from a number of adherence aids and reminder devices. A randomized step wedge design was used. Forty-three individuals were randomized to begin the intervention over a five-month period. There was a substantial fall in the number of missed doses reported for the last four days (0.76 to 0.38, P =0.03) and last seven days (1.5 to 0.74, P =0.005) but not for the last 28 days (2.5 to 2.5, P =0.63). There was no statistical difference in the viral load or CD4 lymphocyte count in the period before or after the intervention. The Morisky score during the pre and post intervention periods was significantly different (P =0.006), 2.9 (SD 0.9) and 3.3 (SD 0.8) respectively. This adherence package improved self reported adherence during the last four and seven days.

Safety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia.

BACKGROUND: Linezolid is a recently approved oxazalidinone with extended activity against Gram-positive bacteria. We evaluated the results of linezolid therapy in neutropenic cancer patients with Gram-positive bacterial infections from a compassionate-use program. PATIENTS AND METHODS: This was a prospective, multicenter, open-label, non-comparative, non-randomized compassionate-use treatment program in patients with serious Gram-positive infections. To qualify for enrollment patients were required to have an infection resistant to available antimicrobial agents, or in whom available agents had failed or to which they were intolerant. Patients with absolute neutrophil counts (ANC) <500 cells/mm(3) or <1000 cells/mm(3) and expected to decrease to <500 cells/mm(3), and who received linezolid 600 mg twice daily were included. Plasma samples for population pharmacokinetic analysis were collected. Clinical and microbiological assessments of outcomes were made at the end of therapy and at short-term follow-up. RESULTS: Of the patients in the compassionate-use trial, 103 were neutropenic. The mean [standard deviation (SD)] age was 50.1 (17.5) years, 47% were female, and 47.6% had a baseline ANC

Symptomatic hyperbilirubinemia with indinavir/ritonavir-containing regimen.

OBJECTIVE: To report a case of symptomatic hyperbilirubinemia resulting from the addition of ritonavir to an indinavir-containing antiretroviral regimen. CASE SUMMARY: A 27-year-old white woman developed symptomatic hyperbilirubinemia and anemia while receiving an indinavir/ritonavir-containing antiretroviral (ARV) regimen that required disruption of therapy. Extensive laboratory examinations were performed including determination of indinavir and ritonavir concentrations. The findings were attributed to two independent processes, an unconjugated hyperbilirubinemia due to indinavir and anemia due to zidovudine. DISCUSSION: Indinavir-induced hyperbilirubinemia is generally regarded as an adverse event with no clinical relevance that does not cause significant liver toxicity and does not necessitate discontinuing indinavir. It manifests primarily as an increase in unconjugated bilirubin and is reported to be dose related. We believe that the severe hyperbilirubinemia in this patient was a result of high indinavir concentrations that occurred due to metabolic inhibition caused by ritonavir. The anemia in this case was consistent with erythrocyte maturation arrest due to zidovudine rather than hemolysis. CONCLUSIONS: Combination ARV therapy is the current standard of care for treating patients infected with HIV. It is important for providers to consider that, despite much improved pharmacokinetic profiles associated with pharmacokinetically enhanced protease inhibitor regimens, there may be undesirable effects that may differ in frequency or severity than when drugs are used individually.

Initial concentration-time profile of gentamicin determines efficacy against Enterobacter cloacae ATCC 13047.

In vitro studies were designed to investigate the influence of peak drug concentration (Cmax), the area under the concentration-time curve (AUC), and, consequently, the trough concentration on the bactericidal effects of gentamicin against Enterobacter cloacae (MIC, 0.5 mg/liter) by simulating bolus versus infusion administration and bolus dosing with altered drug clearance. Bacteria in the lag phase were exposed to gentamicin concentration-time profiles modelling either bolus or infusion dosing (AUC constant, Cmax changing) with 30-min postdose peak concentrations (Cpeak30) of 4, 6, 8, and 10 mg/liter or bolus dosing with normal and double drug clearance (Cmax constant, AUC changing) corresponding to normal clearance profiles with Cpeak30 of 6 and 8 mg/liter. Exposure to gentamicin caused early bactericidal effects apparent by 2 h, followed by variable bacteriostatic and recovery phases. Exposure to bolus profiles resulted in greater bactericidal activity than the corresponding infusion profile up to a Cpeak30 of 8 mg/liter. At a Cpeak30 of 10 mg/liter, there were no differences in bactericidal effect. Double clearance profiles had a reduced bactericidal effect at 6 mg/liter compared to the corresponding normal clearance profile, but no differences in bactericidal effect were observed for 8-mg/liter double and normal clearance profiles. These results suggest that the initial exposure (i.e., 0 to 30 min) is a more important determinant for bacterial killing than the AUC or trough concentration for this bacterium. Subject to confirmation of these findings with other gram-negative bacteria, to optimize aminoglycoside efficacy the initial exposure (Cmax) should be maximized by giving higher doses or bolus administration at intervals which may not produce detectable trough concentrations. Clinical trials with a broad range of patients, especially those with higher clearance, would confirm these in vitro observations and define optimal dosing recommendations.

Early, fatal disseminated intravascular coagulation in a patient with 60 per cent burns.

A 23-year-old, previously fit and healthy young man was admitted to the West Midlands Regional Burns Unit at the Birmingham Accident Hospital, with 60 per cent body surface area burns and smoke inhalation. On arrival, he was briskly tachycardiac, hypotensive and disorientated. He was admitted to the intensive care unit, intubated and started on intermittent positive pressure ventilation. Despite prompt commencement of resuscitation and the infusion of enormous volumes of colloids, the patient remained oliguric. He soon developed severe haemorrhage from his gastrointestinal, urinary and respiratory tracts. He required several units of blood, but was persistently hypotensive. His condition deteriorated rapidly despite intensive supportive measures. He developed metabolic acidosis, refractory hypotension and died anuric, 20 h later. The post-mortem examination showed the presence of disseminated intravascular coagulation and adult respiratory distress syndrome.

Teaching plastic surgery to medical students.

A plastic surgery syllabus for third-year medical students is described. It is intended for a teaching programme in which plastic surgery is integrated into the surgical teaching on the same basis as the other surgical specialties. The syllabus was designed to concentrate on aspects of plastic surgery relevant to the needs of undergraduates. An audit of the teaching showed that the students were readily interested and considered the teaching to be relevant to their examinations and to their future as doctors. A survey of all plastic surgery centres in the British Isles showed that similar teaching was being undertaken in 11 centres out of 51.

The differentiation and proliferation of newly formed epidermis on wounds treated with cultured epithelial allografts.

Fifteen patients, eight with burn or scald wounds and seven with split-thickness donor sites, were treated with cultured epithelial allografts. Skin was obtained from HIV-negative donors undergoing circumcision and sheets of epithelium were cultured using the 3T3 feeder method. Multiple post-operative biopsies were performed at various time intervals and stained with a panel of monoclonal antibodies against cytokeratins, involucrin, transferrin receptor and epidermal growth factor receptor. Fresh cultured epithelial sheets, normal skin, standard treated donor sites and burns treated with autografts were also studied. Cytokeratin-10 expression was not observed at treated sites until 4 weeks post-grafting, when normal suprabasal levels were observed. Cytokeratins 13 and 16, usually observed in highly proliferative states such as psoriasis, were observed in epithelial-treated sites for up to 6 months. Other proliferation markers such as Ki67 and transferrin receptor were only expressed 2-3 weeks post-operatively. Involucrin, a marker of keratinocyte terminal differentiation, was expressed throughout newly formed epidermis until 15 weeks, when the normal pattern of granular expression was observed. These results indicate that although the cultured 'allograft' does not survive, it may modulate the proliferation and differentiation of spontaneously regenerating epithelium.

Survival assessment of cultured epidermal allografts applied onto partial-thickness burn wounds.

Cultured epidermal allografts (C.E.A.) were applied to 6 partial thickness burns. Biopsies were obtained at intervals between 8-100 days after grafting. In the second week clinical re-epithelialisation of the allografted sites was confirmed histologically. Blood group- and sex-mismatch studies showed that the allografted cells were not present between 8-100 days post-grafting, suggesting that the newly formed epithelium was of host origin.

Extensor tendon repair: an animal model which allows immediate post-operative mobilisation.

In adult rabbits, an experimentally transected digital extensor tendon was repaired. The technique employed a tongue, created from the proximal tendon, folded over to bridge the transection and reattached distally. Animals were allowed immediate post-operative mobilisation. Tendon material, 14-120 days post-operatively, was examined ultrastructurally in control and experimental animals from four different zones within the repaired tendon. The operation was well tolerated and adhesion free. Associated with the repair, two types of collagen fibril populations were observed. Firstly, in areas where tendon tissue had been removed, there was a population of fibrils with a narrow range of diameters. Secondly, in areas where tendon tissue was subjected to an increased level of stress per unit cross-sectional area, a population of fibrils with a range of diameters similar to that of controls but with a marked increase in the percentage of small diameter fibrils. The relevance of these observations to human tendon repair is discussed.