Topical Semisolid Drug Product Critical Quality Attributes with Relevance to Cutaneous Bioavailability and Pharmacokinetics: Part I-Bioequivalence of Acyclovir Topical Creams.

PURPOSE: To develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT). METHODS: Product attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system. RESULTS: A toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams. CONCLUSIONS: This research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies.

Physicochemical compatibility of caffeine citrate and caffeine base injections with parenteral medications used in neonatal intensive care settings.

PURPOSE: To investigate the physicochemical compatibility of caffeine citrate and caffeine base injections with 43 secondary intravenous (IV) drugs used in Neonatal Intensive Care Unit (NICU) settings. METHODS: Caffeine citrate (20 mg/mL or 10 mg/mL) or caffeine base injection (10 mg/mL) were mixed in a volume ratio of 1:1 with the secondary drug solution to simulate Y-site co-administration procedures in NICUs. Physical compatibility was evaluated based on visual observation for 2 h, against a black and white background and under polarised light, for changes in colour, precipitation, haze and evolution of gas. Chemical compatibility was determined from caffeine concentration measurements, using a validated high-performance liquid chromatography assay. RESULTS: Six of the 43 secondary drugs tested (aciclovir, amphotericin (liposomal), furosemide, hydrocortisone, ibuprofen and ibuprofen lysine) were physically incompatible with caffeine citrate undiluted injection (20 mg/mL), at their high-end, clinically relevant concentrations for NICU settings. However, when tested at lower concentrations, hydrocortisone (1 mg/mL) was physicochemically compatible, whereas furosemide (0.2 mg/mL) was physically incompatible with caffeine citrate. The six drugs which showed physical incompatibility with caffeine citrate 20 mg/mL injection were also physically incompatible with caffeine citrate 10 mg/mL solution. All 43 secondary drugs tested were physicochemically compatible with caffeine base injection. CONCLUSIONS: Most secondary test drugs, except aciclovir, amphotericin (liposomal), furosemide, hydrocortisone, ibuprofen and ibuprofen lysine, were physicochemically compatible with caffeine citrate injection. Caffeine base injection was physicochemically compatible with all 43 test drugs tested.

Acyclovir dosing in herpes encephalitis: A scoping review.

BACKGROUND: Herpes encephalitis, a rare yet potentially fatal viral infection, is treated exclusively with acyclovir, the sole antiviral medication used for this condition. Acyclovir recommended dose is 10 mg/kg/dose intravenous every 8 hours; however, it is unclear what body weight should be utilized in obese patients. Using the ideal body weight may result in subtherapeutic ineffective concentrations, while utilizing the actual body weight might result in acyclovir induced adverse effects, either nephrotoxicity or neurotoxicity or both. OBJECTIVE: The objective of this scoping review is to explore existing evidence regarding acyclovir dosing for obese patients afflicted with herpes encephalitis. METHODS: MEDLINE, EMBASE, Scopus, Web of Science, and CINAHL databases were searched on 26 May 2023, with no language restrictions. Two independent reviewers utilized the Covidence software to carry out the screening and selection of the articles. A total of 22 articles were included in the current review. RESULTS: The prevalence of acyclovir-associated nephrotoxicity ranged from 13% to 21%, while the prevalence of neurotoxicity was not clearly defined. However, there is lack of evidence regarding what may arise from subtherapeutic concentrations. An approach has been suggested to help clinicians to give the most appropriate acyclovir dose to herpes encephalitis patients. Patients with normal kidney function could receive the normal doses based on actual weight if normal weight and based on adjusted body weight if obese. On the other hand, if the patients are experiencing augmented renal clearance, they could receive up to the maximum recommended doses. CONCLUSION: Overall, there is a lack of consistency on which body weight to use to calculate acyclovir dose in obese patients. So it is recommended that further studies compare the concentration of intravenous acyclovir between obese and nonobese patients and relating the resultant concentration with patient outcomes.

Varicella-zoster virus myelitis as a cause of acute functional decline. / Varicella-zoster-virus-myelitt som årsak til akutt funksjonssvikt.

Background: Acute functional decline is a common reason for hospital admission for older people, often caused by an acute deterioration of an underlying chronic illness. However, occasionally a rare condition is detected. Case presentation: A woman in her eighties was admitted to hospital with acute functional decline. Hyponatraemia, urinary tract infection and pulmonary embolism were initially diagnosed. She developed increasing difficulties in using her legs, and assessment led to the diagnosis of varicella- zoster virus myelitis, which was treated with intravenous acyclovir. After a brief stay in the rehabilitation unit, the patient's condition acutely deteriorated, leading to readmission with neurovascular septic embolism and microvascular haemorrhage in the brain. Anticoagulation was terminated. After 52 days she was discharged to a nursing home for further rehabilitation. Interpretation: Our article presents a case of acute functional decline caused by a rare condition. Collaboration between the geriatric, neurological and infectious disease departments was needed. When treated rapidly with targeted therapy, the prognosis for myelitis is often good.

Intralesional Acyclovir: A Potential Therapeutic Option for Cutaneous Warts.

BACKGROUND: The treatment of warts is challenging and the development of an antiviral drug that can eradicate the human papilloma virus (HPV) is difficult. The viral origin of warts suggests that acyclovir, an antiviral drug with a proven efficacy in DNA viruses, may be a potential therapeutic option. AIM: To evaluate the efficacy and safety of intralesional acyclovir in the treatment of cutaneous warts. METHODS: Thirty-one patients with cutaneous warts were allocated into 2 groups. Group A (19 patients) had intralesional acyclovir (70 mg/ml) injected into the warts, while group B (12 patients) received intralesional saline as control. The treatment was repeated at 2 week intervals until complete clearance or for a maximum of 5 sessions. RESULTS: Complete clearance of warts was observed in 52.6%, partial response in 36.8%, and no response in 10.5% of the patients in the acyclovir group. Partial response was reported in 16.7%, and no response in 83.3% of the patients in the control group. A high statistically significant difference was found between the treatment and control groups (P < .01). Adverse effects included pain during injection in 89.5%, blistering in 52.6% and erythema in5.3% of the patients. No recurrence was detected during the follow-up period. CONCLUSION: Intralesional acyclovir can be an effective and well-tolerated treatment modality for cutaneous warts.

Rheological and in vitro release measurements of manufactured acyclovir 5% creams: confirming sensitivity of the in vitro release.

Previous evaluation of marketed acyclovir 5% creams using in vitro release testing (IVRT) and its correlation with the qualitative composition confirmed the discriminative characteristics of this methodology. This was in line with the principles of Topical drug Classification System (TCS). For the current research, experimental formulations were designed and prepared by applying controlled changes in manufacturing process, sources of raw materials, and amount of the excipients. The topical semisolids were representative for the four classes of TCS. The outcome of the IVRT and rheological assessments was evaluated in relation with the nature of the change and the functional role of the excipients. The variations in propylene glycol content from 5% to 40% impacted both the in vitro release rates (gradual decrease from 16.23 to 8.97 µg/cm2/min0.5) and the microstructural characteristics (proportional increase of yield stress from 17.98 to 46.40 Pa). The inert excipients e.g. cetostearyl alcohol or white soft paraffin altered majorly the rheological behavior, as their functionality is mainly related to vehicle properties. IVRT was discriminative for the microstructural differences induced by both categories of excipients according to TCS dichotomy. This simple, reliable, and reproducible test reflected the impact of difference in quantitative composition and characteristics of excipients.

Bi-polymeric Spongy Matrices Through Cross-linking Polymerization: Synthesized and Evaluated for Solubility Enhancement of Acyclovir.

In this study, two hydrophilic polymers hydroxypropyl methyl cellulose and beta-cyclodextrin (ß-CD) are used to synthesize highly responsive and spongy polymeric matrices. Porous and stimulus-responsive polymeric network was developed to improve the solubility of acyclovir (ACV) at significant level. Grafting was successfully carried out by free radical polymerization technique. Spongy matrices were characterized by percentage entrapment efficiency, drug loading, solubility studies, FTIR, powder X-ray diffraction, TGA, DSC, XRD, SEM, swelling studies, and in vitro studies. Acute oral toxicity studies were conducted to determine the safety of oral administration of prepared HPMC-ßCD-g-poly(AMPS) formulation. Porous and spongy structures were depicted in SEM images. Complex formation and thermal stability of constituents and drug (ACV) were analyzed by FTIR, TGA, and DSC spectra. XRD analysis revealed reduction in acyclovir crystallinity in spongy matrices. Particle size of optimized formulation was found in the range of 197 ± 2.55 nm. The momentous difference with reference product committed that drug solubility and release characteristics were markedly enhanced by the developed spongy matrices. Toxicity studies endorsed that developed spongy matrices were non-toxic and compatible to biological system. The efficient method of preparation, enhanced solubility, excellent physico-chemical characteristics, high dissolution, and non-toxic HPMC-ßCD-g-poly(AMPS) spongy matrices may be a promising approach for oral delivery of poorly soluble drugs.

Acute Kidney Injury During Treatment with Intravenous Acyclovir for Suspected or Confirmed Neonatal Herpes Simplex Virus Infection.

OBJECTIVE: To describe the epidemiology of and risk factors associated with acute kidney injury (AKI) during acyclovir treatment in neonates and infants. STUDY DESIGN: We conducted a multicenter (n = 4), retrospective cohort study of all hospitalized infants age <60 days treated with intravenous acyclovir (≥1 dose) for suspected or confirmed neonatal herpes simplex virus disease from January 2011 to December 2015. Infants with serum creatinine measured both before acyclovir (baseline) and during treatment were included. We classified AKI based on changes in creatinine according to published neonatal AKI criteria and performed Cox regression analysis to evaluate risk factors for AKI during acyclovir treatment. RESULTS: We included 1017 infants. The majority received short courses of acyclovir (median, 5 doses). Fifty-seven infants (5.6%) developed AKI during acyclovir treatment, with an incidence rate of AKI at 11.6 per 1000 acyclovir days. Cox regression analysis identified having confirmed herpes simplex virus disease (OR, 4.35; P = .002), receipt of ≥2 concomitant nephrotoxic medications (OR, 3.07; P = .004), receipt of mechanical ventilation (OR, 5.97; P = .001), and admission to an intensive care unit (OR, 6.02; P = .006) as risk factors for AKI during acyclovir treatment. CONCLUSIONS: Among our cohort of infants exposed to acyclovir, the rate of AKI was low. Sicker infants and those exposed to additional nephrotoxic medications seem to be at greater risk for acyclovir-induced toxicity and warrant closer monitoring.

Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfusion.

PURPOSE: Dermal open flow microperfusion (dOFM) has previously demonstrated its utility to assess the bioequivalence (BE) of topical drug products in a clinical study. We aimed to characterize the sources of variability in the dermal pharmacokinetic data from that study. METHODS: Exploratory statistical analyses were performed with multivariate data from a clinical dOFM-study in 20 healthy adults evaluating the BE, or lack thereof, of Austrian test (T) and U.S. reference (R) acyclovir cream, 5% products. RESULTS: The overall variability of logAUC values (CV: 39% for R and 45% for T) was dominated by inter-subject variability (R: 82%, T: 91%) which correlated best with the subject's skin conductance. Intra-subject variability was 18% (R) and 9% (T) of the overall variability; skin treatment sites or methodological factors did not significantly contribute to that variability. CONCLUSIONS: Inter-subject variability was the major component of overall variability for acyclovir, and treatment site location did not significantly influence intra-subject variability. These results support a dOFM BE study design with T and R products assessed simultaneously on the same subject, where T and R treatment sites do not necessarily need to be next to each other. Localized variation in skin microstructure may be primarily responsible for intra-subject variability.

Neonatal Herpes Simplex Virus-1 Recurrence with Central Nervous System Disease in Twins after Completion of a Six-Month Course of Suppressive Therapy: Case Report.

Seventeen-day-old twins were hospitalized for neonatal herpes simplex virus 1 (HSV-1) with central nervous system disease and internal capsule and thalamic lesions on magnetic resonance imaging (MRI). They were treated with the usual intravenous (IV) treatment and oral therapy for 6 months. The clinical course was good in both children with negative HSV polymerase chain reaction on completion of IV therapy. The neurological condition recurred in one child with new radiological lesions at 7 months of age, 2 weeks after discontinuation of oral treatment. Cerebral lesions highlighted on the MRI scan are specific to the neonatal period and impact long-term prognosis. The likely genetic predisposition in this case is interesting and requires further investigation. In addition, this case raises questions about the duration of oral acyclovir suppressive therapy.

Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2.

Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF's active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5-100 µmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC50 value of 4.91 µmol/L. TER (5 µmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells' uptake of acyclovir and increased the plasma concentration.

Carrageenan-Based Acyclovir Mucoadhesive Vaginal Tablets for Prevention of Genital Herpes.

Women are the most affected by genital herpes, which is one of the most common sexually transmitted infections, affecting more than 400 million people worldwide. The application of vaginal microbicides could provide a safe method of protection. Acyclovir is a safe and effective medication for vaginal administration, and numerous benefits have been observed in the treatment of primary or recurrent lesions due to genital herpes. Vaginal tablets based on a combination of the polymers iota-carrageenan and hydroxypropyl methylcellulose were developed for the controlled release of acyclovir. Swelling, mucoadhesion and drug release studies were carried out in simulated vaginal fluid. The tablets, containing a combination of iota-carrageenan and hydroxypropyl methylcellulose, have an adequate uptake of the medium that allows them to develop the precise consistency and volume of gel for the controlled release of acyclovir. Its high mucoadhesive capacity also allows the formulation to remain in the vaginal area long enough to ensure the complete release of acyclovir. These promising formulations for the prevention of genital herpes deserve further evaluation.

Determination of acyclovir in renal microdialysis fluid and confirmation of renal function index.

Acyclovir (ACV) is a nucleoside antivirus-free agent that was developed and marketed by Burroughs Well-come of the United States. Renal damage from ACV has been a major factor limiting its clinical application. Thus, the renal toxicity mechanism of ACV requires systematic study. In our previous study, we speculated that the nephrotoxicity of ACV may be associated with oxidative stress. In addition to the study of ACV's toxic effect in vivo, it is also necessary to explore the absorption and distribution of ACV in the body to further investigate the changes to ACV in the body. In this study, the toxicokinetics ACV in the kidney of the rat were explored using microdialysis, and the renal function of rats was measured. The results showed that high-dose ACV is associated with renal toxicity after a single intravenous injection or successive administration.

Effect of benzylpenicillin on intravenous pharmacokinetics of acyclovir in red-eared slider turtles (Trachemys scripta elegans).

The aim of this study was to determine the effect of benzylpenicillin on the pharmacokinetics of acyclovir in red-eared slider turtles (Trachemys scripta elegans). Six clinically healthy red-eared slider turtles weighing 400 and 580 g were used for the study. Acyclovir (40 mg/kg) and benzylpenicillin (30 mg/kg) were administered intravenously to turtles. In the study, the cross-pharmacokinetic design (2 × 2) with a 30-day washout period was performed in two periods. Plasma concentrations of acyclovir were assayed using the high-performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated by two-compartment open pharmacokinetic model. Following the administration of acyclovir alone, elimination half-life (t1/2 ß ), area under the plasma concentration-time curve (AUC), total clearance (ClT ), and volume of distribution at steady-state (Vdss ) were 20.12 hr, 1,372 hr * µg/mL, 0.03 L hr-1  kg-1 , and 0.84 L/kg, respectively. Benzylpenicillin administration increased t1/2 ß , AUC, and Vdss while decreased ClT of acyclovir. These results showed that benzylpenicillin changed the pharmacokinetics of acyclovir following simultaneous administration in turtles. However, further research is needed to determine molecular mechanism of interaction in turtle.

Fifteen-minute consultation: Prevention and treatment of chickenpox in newborns.

There are inconsistencies in how newborns are managed following exposure to varicella, ranging from reassurance and observation to administration of varicella zoster immunoglobulin (VZIG) and admission to hospital for varying length courses of intravenous aciclovir.Hospitalised preterm babies exposed to varicella should receive VZIG. Administration can otherwise be limited to pregnant non-immune women or to newborns if there is development of maternal chickenpox from 5 days prior to delivery up to 48 hours postdelivery. Intravenous aciclovir is only recommended in cases of newborn disease despite VZIG or in severe disease. The use of VZIG may not prevent varicella but may reduce severity of disease.In this article, we review the evidence for risk to non-immune mothers, the fetus and newborns who had different types of exposure to varicella, with recommendations for management and treatment of confirmed neonatal chickenpox.

PEGylated Lipid Polymeric Nanoparticle-Encapsulated Acyclovir for In Vitro Controlled Release and Ex Vivo Gut Sac Permeation.

Currently, pharmaceutical research is directed wide range for developing new drugs for oral administration to target disease. Acyclovir formulation is having common issues of short half-life and poor permeability, causing messy treatment which results in patient incompliance. The present study formulates a lipid polymeric hybrid nanoparticles for antiviral acyclovir (ACV) agent with Phospholipon® 90G (lecithin), chitosan, and polyethylene glycol (PEG) to improve controlled release of the drugs. The study focused on the encapsulation of the ACV in lipid polymeric particle and their sustained delivery. The formulation developed for the self-assembly of chitosan and lecithin to form a shell encapsulating acyclovir, followed by PEGylation. Optimisation was performed via Box-Behnken Design (BBD), forming nanoparticles with size of 187.7 ± 3.75 nm, 83.81 ± 1.93% drug-entrapped efficiency (EE), and + 37.7 ± 1.16 mV zeta potential. Scanning electron microscopy and transmission electron microscopy images displayed spherical nanoparticles formation. Encapsulation of ACV and complexity with other physical parameters are confirmed through analysis using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. Nanoparticle produced was capable of achieving 24-h sustained release in vitro on gastric and intestinal environments. Ex vivo study proved the improvement of acyclovir's apparent permeability from 2 × 10-6 to 6.46 × 10-6 cm s-1. Acyclovir new formulation was achieved to be stable up to 60 days for controlled release of the drugs. Graphical abstract.

Severe Herpes Zoster Requiring Intravenous Antiviral Treatment in Allogeneic Hematopoietic Cell Transplantation Recipients on Standard Acyclovir Prophylaxis.

Allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk for varicella zoster virus (VZV) reactivation and associated complications. The incidence, timing, and risk factors for severe herpes zoster (HZ) are not well described in the era of acyclovir (ACV) prophylaxis. We performed a retrospective cohort study of all patients who underwent first allogeneic HCT between October 2006 and December 2015 at our institution. Patients were followed until December 2017 for the development of severe HZ, defined as necessitating administration of i.v. antiviral medication. Out of 2163 patients who underwent allogeneic HCT, 22 (1.0%) developed severe HZ at a rate of 1 per 228 person-years, including dermatomal/multidermatomal disease (n = 5), disseminated skin disease (n = 5), HZ ophthalmicus (n = 4), meningitis/encephalitis (n = 4), pneumonia (n = 2), viremia (n = 1), and erythema multiforme (n = 1). Severe HZ infection occurred in a bimodal distribution during the early peri-HCT period and at 12 to 24 months post-HCT (median, 12.7 months). Twelve patients (54.5%) were compliant with ACV prophylaxis at the time of HZ diagnosis. Eleven patients (50%) died during the study period, only 2 of whom (9.1%) with active VZV infection. Mortality was higher in patients on immunosuppressive therapy (62.5% versus 16.7%; P = .045) and with concurrent graft-versus-host disease (75.0% versus 35.7%; P= .044). These data suggest that severe HZ remains an important consideration despite ACV prophylaxis.

Stratum Corneum Sampling to Assess Bioequivalence between Topical Acyclovir Products.

PURPOSE: To examine the potential of stratum corneum (SC) sampling via tape-stripping in humans to assess bioequivalence of topical acyclovir drug products, and to explore the potential value of alternative metrics of local skin bioavailability calculable from SC sampling experiments. METHODS: Three acyclovir creams were considered in two separate studies in which drug amounts in the SC after uptake and clearance periods were measured and used to assess bioequivalence. In each study, a "reference" formulation (evaluated twice) was compared to the "test" in 10 subjects. Each application site was replicated to achieve greater statistical power with fewer volunteers. RESULTS: SC sampling revealed similarities and differences between products consistent with results from other surrogate bioequivalence measures, including dermal open-flow microperfusion experiments. Further analysis of the tape-stripping data permitted acyclovir flux into the viable skin to be deduced and drug concentration in that 'compartment' to be estimated. CONCLUSIONS: Acyclovir quantities determined in the SC, following a single-time point uptake and clearance protocol, can be judiciously used both to objectively compare product performance in vivo and to assess delivery of the active into skin tissue below the barrier, thereby permitting local concentrations at or near to the site of action to be determined.

A co-infection of varicella-zoster virus and Pneumocystis jirovecii in a non-HIV immunocompromised patient: a case report.

BACKGROUND: Varicella-zoster virus (VZV) causes herpes zoster. Pneumocystis jirovecii (PJ) also causes pneumonia in immunocompromised hosts. Although both cause opportunistic infections, it is rare to have a co-infection in a non-human immunodeficiency virus carrier. CASE PRESENTATION: An 84-year-old woman with hemolytic anemia referred because of acute respiratory failure. She had received prednisolone without PJ pneumonia prevention. She developed dyspnea and desaturation while eating, and thus was treated based on a presumptive diagnosis of aspiration pneumonia. Physical examination revealed a vesicular rash on the left side of her neck suggesting herpes zoster infection. Polymerase chain reaction of her sputum for PJ and VZV was positive, which confirmed a diagnosis of pneumonia due to PJ and VZV co-infection. Despite acyclovir and sulfamethoxazole and trimethoprim administration, she died on hospital day 19. CONCLUSIONS: Clinicians should suspect PJP when patients on systemic corticosteroids develop pneumonia and they have not received prophylactic treatment for PJP in non-HIV carriers. When such patients have a VZV rash, clinicians should aggressively seek signs of opportunistic infections. Our case hereby highlights the importance of recognizing the possibility of a VZV and PJ co-infection.

Effectiveness of acyclovir prophylaxis against varicella zoster virus disease after allogeneic hematopoietic cell transplantation: A systematic review and meta-analysis.

BACKGROUND: Varicella zoster virus (VZV) disease is a common complication after hematopoietic cell transplantation (HCT). The mortality rate for disseminated VZV infection is 34%. Acyclovir has been used for the prophylaxis of VZV disease after HCT, but the effectiveness of prophylaxis is controversial. We conducted a meta-analysis of the incidence of VZV disease within the first 1 year after acyclovir prophylaxis had been discontinued and assessed the risk of VZV disease during acyclovir prophylaxis. METHODS: Medline, EMBASE plus EMBASE classics, and the Cochrane Central Register of Controlled Trials were used for a systematic search. The inclusion criteria were both randomized controlled trials and cohort studies that described the effectiveness of acyclovir as prophylaxis against VZV disease after allogeneic HCT. RESULTS: We included seven studies involving a total of 2265 patients. No mortality by VZV was identified. Acyclovir prophylaxis significantly reduced the rate of VZV infection within the first 1 year after discontinuation (risk ratio: 0.38, 95% confidence interval (CI): 0.29-0.51). The risk of VZV disease during acyclovir prophylaxis was also reduced (risk ratio: 0.17, 95% CI: 0.12-0.24). Both short-term and long-term prophylaxis reduced the incidence of VZV infection (RR: 0.51, 95% CI: 0.30-0.86 vs RR: 0.34, 95% CI: 0.22-0.54). Low-dose acyclovir (<400 mg/d) is sufficient to reduce the risk of VZV disease. CONCLUSION: This study showed that acyclovir prophylaxis reduced VZV infection after HCT with no fatal cases and acyclovir prophylaxis is beneficial. No significant adverse effects occurred and no delayed VZV disease was identified.