Emerging Treatment Strategies for Impetigo in Endemic and Nonendemic Settings: A Systematic Review.

PURPOSE: Impetigo affects approximately 162 million children worldwide at any given time. Lack of consensus on the most effective treatment strategy for impetigo and increasing antibiotic resistance continue to drive research into newer and alternative treatment options. We conducted a systematic review to assess the effectiveness of new treatments for impetigo in endemic and nonendemic settings. METHODS: We searched PubMed, MEDLINE, CINAHL, Web of Science, and Embase via Scopus for studies that explored treatments for bullous, nonbullous, primary, and secondary impetigo published between August 1, 2011, and February 29, 2020. We also searched online trial registries and hand-searched the reference lists of the included studies. We used the revised Cochrane risk of bias (version 2.0) tool for randomized trials and the National Heart, Lung, and Blood Institute for nonrandomized uncontrolled studies to assess the risk of bias. FINDINGS: We included 10 studies that involved 6651 participants and reported on 9 treatments in the final analysis. Most clinical trials targeted nonbullous impetigo or did not specify this. The risk of bias varied among the studies. In nonendemic settings, ozenoxacin 1% cream appeared to have the strongest evidence base compared with retapamulin and a new minocycline formulation. In endemic settings, oral co-trimoxazole and benzathine benzylpenicillin G injection were equally effective in the treatment of severe impetigo. Mass drug administration intervention emerged as a promising public health strategy to reduce the prevalence of impetigo in endemic settings. IMPLICATIONS: This review highlights the limited research into new drugs used for the treatment of impetigo in endemic and nonendemic settings. Limited recent evidence supports the use of topical ozenoxacin or retapamulin for impetigo treatment in nonendemic settings, whereas systemic antibiotics and the mass drug administration strategy have evidence for use in endemic settings. Given the troubling increase in resistance to existing treatments, there is a clear need to ensure the judicious use of antibiotics and to develop new treatments and alternative strategies; this is particularly important in endemic settings. PROSPERO identifier: CRD42020173042.

The Effect of Renal Replacement Therapy and Antibiotic Dose on Antibiotic Concentrations in Critically Ill Patients: Data From the Multinational Sampling Antibiotics in Renal Replacement Therapy Study.

BACKGROUND: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. METHODS: We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. RESULTS: We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. CONCLUSIONS: In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

When fear and misinformation go viral: Pharmacists' role in deterring medication misinformation during the 'infodemic' surrounding COVID-19.

The world has faced an unprecedented challenge when coronavirus (COVID-19) emerged as a pandemic. Millions of people have contracted the virus and a significant number of them lost their lives, resulting in a tremendous social and economic shock across the globe. Amid the growing burden of the pandemic, there are parallel emergencies that need to be simultaneously tackled: the proliferation of fake medicines, fake news and medication misinformation surrounding COVID-19. Pharmacists are key health professionals with the required skills and training to contribute to the fight against these emergencies. Primarily, they can be a relevant source of accurate and reliable information to the public or other fellow health professionals thereby reducing the spread of COVID-19 medication misinformation. This can be achieved by providing accurate and reliable information based on recommendations given by relevant health authorities and professional associations to make sure the community understand the importance of the message and thus minimise the detrimental consequences of the pandemic. This commentary aims to summarise the existing literature in relation to the promising treatments currently under trial, the perils of falsified medications and medicine-related information and the role of pharmacists in taking a leading role in combating these parallel global emergencies.

Challenges in Antifungal Therapy in Diabetes Mellitus.

Diabetic patients have an increased propensity to Candida sp. infections due to disease-related immunosuppression and various other physiological alterations. The incidence of candidiasis has increased in number over the years and is linked to significant morbidity and mortality in critically ill and immunosuppressed patients. Treatment of infection in diabetic patients may be complicated due to the various disease-related changes to the pharmacokinetics and pharmacodynamics (PK/PD) of a drug, including antifungal agents. Application of PK/PD principles may be a sensible option to optimise antifungal dosing regimens in this group of patients. Further studies on PK/PD of antifungals in patients with diabetes mellitus are needed as current data is limited or unavailable.

How Do We Combat Bogus Medicines in the Age of the COVID-19 Pandemic?

The COVID-19 pandemic has brought concurrent challenges. The increased incidence of fake and falsified product distribution is one of these problems with tremendous impact, especially in low- and middle-income countries. Up to a tenth of medicines including antibiotics and antimalarial drugs in the African market are considered falsified. Pandemics make this worse by creating an ecosystem of confusion, distraction, and vulnerability stemming from the pandemic as health systems become more stressed and the workload of individuals increased. These environments create opportunities for substandard and falsified medicines to be more easily introduced into the marketplace by unscrupulous operators. In this work we discuss some of the challenges with fake or falsified product distribution in the context of COVID-19 and proposed strategies to best manage this problem.

Plasma and interstitial fluid population pharmacokinetics of vancomycin in critically ill patients with sepsis.

Vancomycin is a commonly prescribed antibiotic in the intensive care unit. However, there are limited data describing its distribution into the interstitial fluid (ISF) of tissues. The aim of this study was to describe the plasma and tissue ISF population pharmacokinetics of vancomycin in critically ill patients with sepsis. Serial vancomycin blood and ISF samples were collected at pre-specified time intervals in critically ill patients with sepsis. ISF sampling occurred using a subcutaneously inserted microdialysis catheter. Bioanalysis was undertaken using a validated spectrometric assay method. Population pharmacokinetic analysis was performed using Pmetrics®. Seven patients were recruited and pharmacokinetic data were available for six of them. The median (interquartile range) age, weight, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score and measured creatinine clearance (CLCr) were 55 (44-67) years, 85 (81-102) kg, 20 (16-29), 5 (4-8) and 90 (83-98) mL/min, respectively. Vancomycin pharmacokinetics was best described by a three-compartment linear model. Measured CLCr (on vancomycin clearance) and weight (on volume of distribution of the central compartment) were the only patient covariates that improved the model fit. Coefficients of variation for the vancomycin rate constants into and out of the peripheral and tissue ISF compartments were also high, ranging from 47% to 134%. There is significant variability of vancomycin distribution into tissue ISF, which it was not possible to explain with patient characteristics.

Pharmacokinetics of piperacillin in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration.

Background: Piperacillin is a ß-lactam penicillin antibiotic commonly used for the empirical therapy of sepsis and other hospital-acquired infections. However, knowledge regarding the effect of sustained low-efficiency diafiltration (SLED-f), a technique increasingly being used in ICUs, on piperacillin pharmacokinetics (PK) and dosing in critically ill patients is lacking. Objectives: To describe the PK of piperacillin during SLED-f and compare the results with those reported for other forms of renal replacement therapies. Methods: Serial blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f in one session and from an arterial catheter during sampling without SLED-f. Piperacillin concentrations were measured using a validated chromatography method. Non-compartmental PK analysis of the data was performed. Results: The median clearance and area under the concentration-time curve during SLED-f were 6 L/h and 532 mg·h/L, respectively. Fifty-eight percent of piperacillin was cleared by a single SLED-f session (6 h) compared with previous reports of 30%-45% clearance by a 3.5 h intermittent haemodialysis session. Clearance, half-life and area under the concentration-time curve during SLED-f obtained from this study were comparable with those reported in the post-dilution mode of continuous veno-venous haemodiafiltration studies. Conclusions: As it can be challenging to accurately predict when SLED-f will be initiated in the critically ill, a maintenance dose of at least 4 g every 12 h with at least a 2 g replacement dose post-SLED-f would be a practical approach to piperacillin dosing in ICU patients with anuria receiving SLED-f with a duration similar to the current study.

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients.

Our objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n = 6) and morbidly obese (n = 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m2, respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment (Vc) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of >30 kg/m2 A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.

In Vivo Microdialysis To Determine Subcutaneous Interstitial Fluid Penetration and Pharmacokinetics of Fluconazole in Intensive Care Unit Patients with Sepsis.

The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean in vivo fluconazole recovery rates ± standard deviation (SD) for microdialysis were 51.4% ± 16.1% with a mean (±SD) fluconazole ISF penetration ratio of 0.52 ± 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC0-24) was significantly higher than the median ISF AUC0-24 (340.4 versus 141.1 mg · h/liter; P = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78; P = 0.106). Both minimum and the maximum concentrations of drug in serum (Cmax and Cmin) showed a significant correlation with the fluconazole plasma exposure (Cmax, R(2) = 0.86, P < 0.0001; Cmin, R(2) = 0.75, P < 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection.

Influence of sustained low-efficiency diafiltration (SLED-f) on interstitial fluid concentrations of fluconazole in a critically ill patient: Use of microdialysis.

Acute kidney injury is a common complication in critically ill patients, and hybrid techniques including sustained low-efficiency dialysis/diafiltration (SLED-f) are being increasingly utilised in intensive care units. Most fungal infections occur in the interstitial fluid (ISF) of tissues and successful treatment of a fungal infection relies on the ability of an antifungal agent to achieve adequate concentrations at the site of infection. Tissue distribution of antimicrobials is impaired in critically ill patients owing to a variety of disease-related physiological changes, e.g. sepsis. Fluconazole is a widely used antifungal agent used to treat Candida spp. infections in critically ill patients. The implications for ISF concentrations of enhanced elimination during renal replacement therapy have not yet been reported for fluconazole. The aim of this single-patient case report was to describe the influence of SLED-f on subcutaneous (SC) ISF concentrations of fluconazole and the implications for achieving pharmacokinetic/pharmacodynamic targets. Serial blood and ISF samples were collected at pre- and post-filter ports within the SLED-f circuit and subcutaneously inserted microdialysis probe, respectively. Fluconazole concentrations were measured using a validated chromatography method. The SC ISF-to-plasma partition coefficient of fluconazole in this patient was 0.91, indicating rapid equilibrium. SC ISF fluconazole concentrations consistently decreased after initiating SLED-f. The majority of the fluconazole was eliminated from the SC ISF as a result of redistribution. Considering the extensive tissue re-distribution of fluconazole and observed elimination from tissue compartments, higher doses may be required to treat deep-seated fungal infections.

Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: Data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients Study.

INTRODUCTION: The objective of the study was to describe the pharmacokinetics (PK) of fluconazole, anidulafungin, and caspofungin in critically ill patients and to compare with previously published data. We also sought to determine whether contemporary fluconazole doses achieved PK/pharmacodynamic (PD; PK/PD) targets in this cohort of intensive care unit patients. METHODS: The Defining Antibiotic Levels in Intensive care unit patients (DALI) study was a prospective, multicenter point-prevalence PK study. Sixty-eight intensive care units across Europe participated. Inclusion criteria were met by critically ill patients administered fluconazole (n = 15), anidulafungin (n = 9), and caspofungin (n = 7). Three blood samples (peak, mid-dose, and trough) were collected for PK/PD analysis. PK analysis was performed by using a noncompartmental approach. RESULTS: The mean age, weight, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores of the included patients were 58 years, 84 kg, and 22, respectively. Fluconazole, caspofungin, and anidulafungin showed large interindividual variability in this study. In patients receiving fluconazole, 33% did not attain the PK/PD target, ratio of free drug area under the concentration-time curve from 0 to 24 hours to minimum inhibitory concentration (fAUC(0-24)/MIC) ≥100. The fluconazole dose, described in milligrams per kilogram, was found to be significantly associated with achievement of fAUC(0-24)/MIC ≥100 (P = 0.0003). CONCLUSIONS: Considerable interindividual variability was observed for fluconazole, anidulafungin, and caspofungin. A large proportion of the patients (33%) receiving fluconazole did not attain the PK/PD target, which might be related to inadequate dosing. For anidulafungin and caspofungin, dose optimization also appears necessary to minimize variability.

Pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration.

Fluconazole is a widely used antifungal agent in critically ill patients. It is predominantly (60-80%) excreted unchanged in urine. Sustained low-efficiency diafiltration (SLED-f) is increasingly being utilised in critically ill patients because of its practical advantages over continuous renal replacement therapy. To date, the effect of SLED-f on fluconazole pharmacokinetics and dosing has not been studied. The objective of this study was to describe the pharmacokinetics of fluconazole in critically ill patients with acute kidney injury receiving SLED-f and to compare this with other forms of renal replacement therapy. Serial blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f and from an arterial catheter before and after SLED-f from three patients during one session. Fluconazole concentrations were measured using a validated chromatography method. Median clearance (CL) and 24-h area under the concentration-time curve (AUC0-24) were 2.1L/h and 152 mg·h/L, respectively, whilst receiving SLED-f. Moreover, 72% of fluconazole was cleared by a single SLED-f session (6h) compared with previous reports of 33-38% clearance by a 4-h intermittent haemodialysis session. CL and AUC0-24 were comparable with previous observations in a pre-dilution mode of continuous venovenous haemodiafiltration. The observed rebound concentration of fluconazole post SLED-f was <2%. Although a definitive dosing recommendation is not possible due to the small patient number, it is clear that doses >200mg daily are likely to be required to achieve the PK/PD target for common pathogens because of significant fluconazole clearance by SLED-f.

ß-lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: a structured review.

1. Infections and related sepsis are two of the most prevalent issues in the care of critically ill patients, with mortality as high as 70%. Appropriate antibiotic selection, as well as adequate dosing, is important to improve the clinical outcome for these patients. 2. ß-Lactams are the most common antibiotic class used in critically ill sepsis patients because of their broad spectrum of activity and high tolerability. ß-Lactams exhibit time-dependent antibacterial activity. Therefore, concentrations need to be maintained above the minimum inhibitory concentration (MIC) of pathogenic bacteria. ß-Lactams are hydrophilic antibiotics with small distribution volumes similar to extracellular water and are predominantly excreted through the renal system. 3. Critically ill patients experience a myriad of physiological changes that result in changes in the pharmacokinetics (PK) of hydrophilic drugs such as ß-lactams. A different approach to dosing with ß-lactams may increase the likelihood of positive outcomes considering the pharmacodynamics (PD) of ß-lactams, as well as the changes in PK in critically ill patients. 4. The present review describes the strategies for dose optimization of ß-lactams in critically ill patients in line with the PK and PD of these drugs.

Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review.

The prevalence of invasive fungal infections (IFIs) caused by Candida spp. is increasing in critically ill patients. Recent development of new antifungal agents has significantly contributed to the successful treatment of IFIs. However, the pharmacokinetics of antifungal agents can be altered in a number of disease states, including critical illness. Therefore, doses established in healthy volunteers and other patient groups may not be appropriate for the critically ill. Moreover, inadequate dosing may contribute to treatment failure and the emergence of resistance. This systematic review provides a critical analysis of the pharmacokinetics of antifungal agents in the critically ill and their relevance to dosing requirements in clinical practice. Based on the limited data available, dosing of some antifungal agents may have to be adjusted in critically ill patients with conserved renal function as well as in those requiring renal replacement therapy. Further research to confirm the appropriateness of current dosing strategies to attain the appropriate pharmacodynamic targets is recommended.

Pharmacokinetic evaluation of fluconazole in critically ill patients.

INTRODUCTION: Invasive candidiasis has emerged over the last few decades as an increasingly important nosocomial problem for the critically ill, affecting around 2% of intensive care unit patients. Although poor outcomes associated with invasive candidiasis among critically ill patients may relate to severe underlying disease processes and delayed institution of antifungal therapy, inadequate dosing of antifungal agents may also contribute. AREAS COVERED: This drug evaluation provides a critical appraisal of the published literature pertaining to the pharmacokinetics of fluconazole in critically ill, obese or severely burned patients, including those receiving acute renal replacement therapy. The pharmacodynamics of fluconazole is also covered, as well as the likely clinical implications for optimal dosing and the toxicity of fluconazole. Last, variations in fluconazole susceptibility patterns of Candida spp. are also discussed. EXPERT OPINION: Recently, there has been an increased but geographically variable prevalence of non-albicans Candida spp., causing invasive candidiasis and an overall trend towards reduced fluconazole susceptibility. The pathophysiological changes of critical illness, coupled with a lack of dose finding studies, support the use of local susceptibility patterns to guide fluconazole dosing until such time as pharmacokinetic-pharmacodynamic information to guide optimal fluconazole dosing strategies and pharmacodynamic targets becomes available.

Role of apoptosis in mediating salicylic acid-induced teratogenesis in vitro.

Salicylic acid (SAL) is among the most commonly used drugs worldwide and is known to cause congenital malformations and fetal death in animals. In this study, the effect of SAL on major organogenesis period and the role of apoptosis in mediating congenital malformations have been carried out. In the present study, post-implantation rat embryos of day 11 were cultured for 24 h with various concentrations of SAL, i.e. 10, 100, and 1000 microg/ml cultures, respectively. The growth and developmental of each embryo was evaluated and compared with control ones for the presence of any malformations. The SAL decreased all growth and developmental parameters in a concentration-dependent manner, when compared with control. However, exposure to SAL at 10 microg/ml culture did not show any significant effect on embryonic growth and development. Parallel to this, flow cytometric analysis (cell cycle and annexin V binding) and DNA fragmentation assay were carried out followed by quantitation by 3'-OH labeling of cultured rat embryos to evaluate the role of apoptosis in bringing about SAL-induced teratogenesis. All results were found to be dose-dependent and an increase in apoptosis in embryonic tissues may be related to the increased risk of congenital malformations. The data suggested that apoptosis might be involved in mediating teratogenesis of SAL in vitro.