Continuous Infusions of Meropenem in Ambulatory Care: Clinical Efficacy, Safety and Stability

Objectives: Concerns regarding the clinical impact of meropenem instability in continuous infusion (CI) devices may contribute to inconsistent uptake of this method of administration across outpatient parenteral antimicrobial therapy (OPAT) services. Methods: We retrospectively reviewed the clinical efficacy and safety of CIs of meropenem in two Australian tertiary hospitals and assessed its stability under simulated OPAT conditions including in elastomeric infusion devices containing 1% (2.4 g) or 2% (4.8 g) concentrations at either ‘room temperature’ or ‘cooled’ conditions. Infusate aliquots were assayed at different time-points over 24 hours. Results: Forty-one (82%) of 50 patients had clinical improvement or were cured. Adverse patient outcomes including hemato-, hepato- and nephrotoxicity were infrequent. Cooled infusers with 1% meropenem had a mean 24-hour recovery of 90.3%. Recoveries of 1% and 2% meropenem at room temperature and 2% under cooled conditions were 88%, 83% and 87%, respectively. Patients receiving 1% meropenem are likely to receive >95% of the maximum deliverable dose (MDD) over a 24-hour period whilst patients receiving 2% meropenem should receive 93% and 87% of the MDD under cooled and room temperature conditions, respectively. Conclusions: Meropenem infusers are likely to deliver ~95% MDD and maintain effective plasma concentrations throughout the dosing period. These data reflect our local favourable clinical experience with eropenem CIs

Piperaquine Pharmacokinetic and Pharmacodynamic Profiles in Healthy Volunteers of Papua New Guinea after Administration of Three-Monthly Doses of Dihydroartemisinin–Piperaquine

Mass drug administration (MDA) with monthly dihydroartemisinin-piperaquine (DHA-PQP) appears useful in malaria control and elimination strategies. Determining the relationship between consecutive piperaquine phosphate (PQP) exposure and its impact on QT interval prolongation is a key safety consideration for MDA campaigns

The gene-specific codon counting database: a genome-based catalog of one-, two-, three-, four- and five-codon combinations present in Saccharomyces cerevisiae genes

A codon consists of three nucleotides and functions during translation to dictate the insertion of a specific amino acid in a growing peptide or, in the case of stop codons, to specify the completion of protein synthesis. There are 64 possible single codons and there are 4096 double, 262 144 triple, 16 777 216 quadruple and 1 073 741 824 quintuple codon combinations available for use by specific genes and genomes. In order to evaluate the use of specific single, double, triple, quadruple and quintuple codon combinations in genes and gene networks, we have developed a codon counting tool and employed it to analyze 5780 Saccharomyces cerevisiae genes. We have also developed visualization approaches, including codon painting, combination and bar graphs, and have used them to identify distinct codon usage patterns in specific genes and groups of genes. Using our developed Gene-Specific Codon Counting Database, we have identified extreme codon runs in specific genes. We have also demonstrated that specific codon combinations or usage patterns are over-represented in genes whose corresponding proteins belong to ribosome or translation-associated biological processes. Our resulting database provides a mineable list of multi-codon data and can be used to identify unique sequence runs and codon usage patterns in individual and functionally linked groups of genes

Quality of antimalarial drugs and antibiotics in Papua New Guinea: A survey of the health facility supply chain

Background: Poor-quality life-saving medicines are a major public health threat, particularly in settings with a weak regulatory environment. Insufficient amounts of active pharmaceutical ingredients (API) endanger patient safety and may contribute to the development of drug resistance. In the case of malaria, concerns relate to implications for the efficacy of artemisinin-based combination therapies (ACT). In Papua New Guinea (PNG), Plasmodium falciparum and P. vivax are both endemic and health facilities are the main source of treatment. ACT has been introduced as first-line treatment but other drugs, such as primaquine for the treatment of P. vivax hypnozoites, are widely available. This study investigated the quality of antimalarial drugs and selected antibiotics at all levels of the health facility supply chain in PNG.Methods and Findings: Medicines were obtained from randomly sampled health facilities and selected warehouses and hospitals across PNG and analysed for API content using validated high performance liquid chromatography (HPLC). Of 360 tablet/capsule samples from 60 providers, 9.7% (95% CI 6.9, 13.3) contained less, and 0.6% more, API than pharmacopoeial reference ranges, including 29/37 (78.4%) primaquine, 3/70 (4.3%) amodiaquine, and one sample each of quinine, artemether, sulphadoxine-pyrimethamine and amoxicillin. According to the package label, 86.5% of poor-quality samples originated from India. Poor-quality medicines were found in 48.3% of providers at all levels of the supply chain. Drug quality was unrelated to storage conditions.Conclusions: This study documents the presence of poor-quality medicines, particularly primaquine, throughout PNG. Primaquine is the only available transmission-blocking antimalarial, likely to become important to prevent the spread of artemisinin-resistant P. falciparum and eliminating P. vivax hypnozoites. The availability of poor-quality medicines reflects the lack of adequate quality control and regulatory mechanisms. Measures to stop the availability of poor-quality medicines should include limiting procurement to WHO prequalified products and implementing routine quality testing

Bradycardia and hypothermia complicating azithromycin treatment

© Am J Case Rep, 2017. Objective: Unusual or unexpected effect of treatment Background: Azithromycin is a macrolide antibiotic widely used to treat respiratory, urogenital, and other infections. Gastrointestinal upset, headache, and dizziness are common adverse effects, and prolongation of the rate-corrected electrocardiographic QT interval and malignant arrhythmias have been reported. There are rare reports of bradycardia and hypothermia but not in the same patient. Case Report: A 4-year-old boy given intravenous azithromycin as part of treatment for febrile neutropenia complicating leukemia chemotherapy developed hypothermia (rectal temperature 35.2°C) and bradycardia (65 beats/minute) after the second dose, which resolved over several days post-treatment, consistent with persistence of high tissue azithromycin concentrations relative to those in plasma. A sigmoid E max pharmacokinetic/pharmacodynamic model suggested a maximal azithromycin-associated reduction in heart rate of 23 beats/minute. Monitoring for these potential adverse effects should facilitate appropriate supportive care in similar cases. Conclusions: Recommended azithromycin doses can cause at least moderate bradycardia and hypothermia in vulnerable pediatric patients, adverse effects that should prompt appropriate monitoring and which may take many days to resolve

Stability of benzylpenicillin for continuous intravenous infusions: An isotonic formulation for therapeutic use and a low-dose formulation for clinical trial

Introduction: The objectives of this study were to develop a stability-indicating high performance liquid chromatography (HPLC) assay for benzylpenicillin (BPC) in pharmaceutical fluids, and to investigate the stability of (i) isotonic citrate-buffered BPC solutions at the clinically relevant concentration of 30 mg/mL, and (ii) low concentration citrate-buffered BPC intravenous infusions (5–30 μg/mL). Methods: The stability of isotonic BPC solutions containing 3.4 or 7.2 mg/mL sodium citrate was compared against contemporary hypertonic solutions. The HPLC assay was shown to be stability-indicating following acidic, alkali, oxidative and elevated temperature stress testing. Results: After 7 d storage at 4 °C and 24 h at 35 °C, the concentrations of isotonic BPC 30 mg/mL solutions containing 3.4 and 7.2 mg/mL sodium citrate were 96% and 95% respectively, compared to day 0. After 3 d at 4 °C and 24 h at room temperature (22 °C), the concentrations of isotonic BPC solutions with 3.4 and 7.2 mg/mL sodium citrate were 99% and 96% respectively, compared to day 0. These data were comparable to the hypertonic solutions and meet pharmacopeial stability requirements. Low concentration BPC infusions showed 0.5% and 2.5% degradation after 24 h storage at 22 °C and 35 °C, respectively. Conclusions: The isotonic BPC 30 mg/mL formulation is simple to prepare and may offer clinical benefits in settings where hypertonic solutions are problematic. This study provides assurance that high- and low-dose isotonic BPC infusions are stable at room temperature and our findings may be applicable to in vitro studies of BPC

Simultaneous determination of primaquine and carboxyprimaquine in plasma using solid phase extraction and LC-MS assay

Sensitive bioanalytical methods are required for pharmacokinetic studies in children, due to the small volume and modest number of samples that can be obtained. We sought to develop a LC–MS assay for primaquine and its active metabolite, carboxyprimaquine, following simultaneous, solid phase extraction of both analytes from human plasma. The analysis was conducted on a single-quad LC–MS system (Shimadzu Model 2020) in ESI+ mode, with quantitation by selected ion monitoring. Primaquine, carboxyprimaquine and 8-aminoquinoline (internal standard) were separated using a mobile phase of 80:20 methanol:water with 0.1% (v/v) formic acid and a Luna C18 HPLC column, at ambient temperature. Solid phase extraction of the analytes from plasma (0.5 mL) was achieved with Oasis® HLB cartridges. The retention times for primaquine, 8-aminoquinoline and carboxyprimaquine were 3.3, 5.7 and 8.5 min, respectively. The calibration curve range (2–1500 μg/L) was appropriate for the limits of quantification and detection for primaquine (2 μg/L and 1 μg/L, respectively) and carboxyprimaquine (2.5 μg/L and 1 μg/L) and the anticipated plasma concentrations of the analytes. Intra- and inter-day precision for both primaquine and carboxyprimaquine was 85% and sensitivity of 1–2 μg/L

Population pharmacokinetic modeling of tramadol and its O-desmethyl metabolite in plasma and breast milk

Purpose: The aim of this investigation was to demonstrate that nonlinear mixed-effects population pharmacokinetic (PK) modeling can be used to evaluate data from studies of drug transport/excretion into human milk and hence to estimate infant exposure. Methods: A sparse dataset from a previously published study of the use of oral tramadol for post-cesarean pain management in 75 lactating women was used. Milk and plasma samples were collected during days 2–4 of lactation, and tramadol and O-desmethyltramadol (ODT) concentration measurements in these samples were available. Absolute infant dose was obtained from the concentration measurements and estimated milk volume ingested, and expressed in micrograms per kilogram per day. Relative infant dose was calculated as a percentage of the absolute infant dose divided by the maternal dose (μg/kg/day). Nonlinear mixed-effects modeling was used to fit a population PK model to the data. Results: The disposition of tramadol and ODT in plasma and the transition of these substances into milk were characterized by a five-compartment population PK mixture model with first-order absorption. The polymorphic ODT formation clearance in the plasma compartment was able to be characterized in both CYP2D6-poor and -extensive metabolizers. Milk creamatocrit was a significant covariate in ODT transfer between the plasma and milk compartments. The estimated relative infant doses in extensive and poor metabolizers, respectively, were 2.16±0.57 and 2.60±0.57% for tramadol, and 0.93 ± .20 and 0.47±0.10% for ODT. Conclusions: This study demonstrates that a population PK approach with sparse sampling of analytes in milk and plasma can yield quality information about the transfer process and that it also can be used to estimate the extent of infant exposure to maternal drugs via milk