Acute Renal Failure Related to High Doses of Acyclovir (15 mg/kg/8 h) during Treatment of Varicella Zoster Virus Encephalitis

Abstract

Varicella zoster virus (VZV) is less susceptible than herpes simplex virus to acyclovir. The optimal acyclovir regimen during VZV encephalitis remains unknown. We report two cases of acute renal failure after an increase in acyclovir dosage from 10 mg to 15 mg/kg/8 h during the treatment of VZV encephalitis according to French guidelines.

Introduction

Encephalitis, a life-threatening infection of the central nervous system, requires urgent therapeutic management. Varicella zoster virus (VZV) is the second leading cause of meningoencephalitis (ME) in France after type 1 herpes simplex virus (HSV) [1]. The French recommendations for the management of infectious encephalitis in adults emphasize the need for rapid early initiation of treatment including acyclovir (10 mg/kg/8 h) combined with amoxicillin 200 mg/kg/24 h [2]. Where VZV is identified, amoxicillin is immediately discontinued and the acyclovir dosage, due to a higher 50% inhibitory dose (ID50) of acyclovir on VZV virus, is increased to 15 mg/kg/8 h for a total of 14 days [2,3]. However, in the literature, recommendations vary from 10 mg/kg to 15 mg/kg and these high doses confer a potentially increased risk of renal or neurological toxicity. We report two cases of patients with VZV encephalitis complicated with acute renal failure (ARF) following a change in acyclovir posology from 10 mg/kg/8 h to 15 mg/kg/8 h in accordance with French recommendations.

Case Reports

Case 1

A 77-year-old woman weighing 80 kg (body mass index [BMI] 28.7) was admitted for febrile encephalitis on 9 May 2017 with behavioural disturbances and loss of stool. Her medical history was characterized by type 2 diabetes mellitus, hypertension, Horton's disease and substituted hypothyroidism. Cerebrospinal fluid (CSF) analysis revealed 116 leukocytes/mm³ with 87% lymphocytes, 1% polymorphonuclear leukocytes (PMN) and 12% monocytes, protein 1.94 g/l, lactates 5.2 mmol/l and glucose 7.1 mmol/l. In-serum C-reactive protein (CRP) level was 61 mg/l, procalcitonin level was 0.12 ng/l and creatinine level was 85 mmol/l. Her uninjected CT and brain MRI were normal. The patient was initially treated with acyclovir 10 mg/kg/8 h (750 mg/8 h), amoxicillin 12 g/day and a dose of gentamycin 240 mg. Upon her admission, nephrotoxic treatments and metformin were withdrawn. The initial evolution was favourable. Her PCR returned positive for VZV (11 May 2018) and amoxicillin was discontinued and acyclovir was increased to 15 mg/kg/8 h (that is, 1.1 g/8 h diluted in 250 ml of serum saline [resulting in a final concentration of acyclovir of 4.8 mg/l]). On 13 May 2018 the patient presented with ARF with creatinine at 209 mmol/l (Figure 1), and in-urine protein at 0.6 g/l, but without blood or crystal, motivating the discontinuation of acyclovir. The patient was transferred to an intensive care unit in a state of major agitation with rapid intubation. Secondary evolution was favourable with the recovery of renal function and the regression of confusion. Treatment with acyclovir was resumed at 750 mg/8 h until 25 May 2018, with a favourable outcome.

Figure 1

Creatinine values according to acyclovir dosages

Case 2

A 64-year-old man weighting 81 kg (BMI 27.4) with a medical history of type 2 diabetes mellitus treated by metformin was hospitalized on 29 March 2018 complaining of headache, vertigo, hallucinations and chills. His EEG and MRI were normal. His CSF analysis revealed 1,100 leukocytes/mm³, with 94% lymphocytes, 4% PMN, and 2% monocytes, protein 3.18 g/l, glucose 4.1 mmol/l and lactates 4.2 mmol/l. In-serum CRP result was 1 mg/l and creatinine was 59 μmol/l. The patient was treated with acyclovir 500 mg/8 h and amoxicillin 12 g/day. There was a clear improvement in his clinical state. The VZV PCR returned positive, and we discontinued the amoxicillin and increased the acyclovir to 15 mg/kg/8 h (that is, 3^*1.2 g), rapidly lowered because of digestive discomfort and dizziness after 3 doses, to 750 mg/8 h before a subsequent increase to 3x1 g with good evolution. The patient returned home at his request on 4 April 2018 with the continuation of his treatment of 3^*1 g acyclovir diluted in 300 ml of serum saline (3.33 mg acyclovir/ml). He was readmitted on 6 April 2018 with aphasia, difficulty in walking, confusion and speech disorder. Blood analyses revealed ARF with creatinine at 459 μmol/l (Figure 1). There were no protein, red cells/ml or crystals in his urine, his brain MRI remained unchanged and his CSF analysis was improving, with 125 leucocytes/mm³. We permanently discontinued acyclovir and rehydrated him with alkalization. The evolution was rapidly favourable and resulted in the normalization of renal function and regression of neurological disorders.

Discussion

Acyclovir is an antiviral with anti-HSV-1/anti-HSV-2 and anti-VZV activity. The recommended dosage for HSV encephalitis is 10 mg/kg/8 h. Nevertheless, VZV is less sensitive to acyclovir, motivating the French recommendations of a higher regimen of acyclovir 15 mg/kg/8 h for 14 days in VZV encephalitis. These recommendations are, however, theoretical and do not rely on a comparison of the doses in a clinical trial. Data from the literature on the dosages and duration of acyclovir in VZV MEs are discordant, relying only on case reports and small series [4]. The Australian and New Zealand recommendations are 10 mg/kg/8 h to 12.5 mg/kg/8 h for patients aged over 12 years, the American recommendations of the Infectious Diseases Society of America are 10 mg/kg/8 h to 15 mg/kg/8 h for 10 days to 14 days, while the French recommendations are 15 mg/kg/8 h for 14 days [2,4,5].

Acyclovir is a nephrotoxic drug often implicated in ARF [6,7] by a mechanism of precipitation (crystals) and acute tubular necrosis. Reports of ARF are frequent [8–13] and are accompanied by classical risk factors: high dose administration, water-soluble depletion and combination with other nephrotoxic drugs, leading to a recommendation for slow infusion administration with hydration. In patients with renal insufficiency, dosage reduction is required. ARF usually develops rapidly after the beginning of therapy with acyclovir, similar to that which occurred in our patients, and is a characteristic of acyclovir nephropathies. ARF related to acyclovir is often accompanied by preserved diuresis, with leukocyturia and crystalluria. Functional recovery after cessation is rapid. Pathological data show nonspecific obstructive tubular lesions, and sometimes cellular infiltration is noted. In rats, the infusion also caused vasoconstriction. The Koren team at the Hospital for Sick Children in Toronto has published a retrospective analysis of a single-centre case series (n=126) over a 6-month period focusing on identifying risk (concomitant use of nephrotoxic drugs), and alteration of glomerular filtration rate flow [14]. Reporting on human proximal tubular cell cultures, they also showed the metabolism of acyclovir via alcohol dehydrogenase to acyclovir aldehyde, a metabolite potentially causing kidney damage [15]. Pharmacological parameters of which practitioners are poorly informed - such as a too rapid perfusion rate (less than 1 h) and a final solution too concentrated (over 5 mg/ml) are also implicated in ARF [2]. Clinical and biological decline occurred in our two patients after dosage increase, but in both cases with a perfusion rate of acyclovir solution of 1 h and a final concentration of under 5 mg/ml. The dosage increase of 15 mg/8 h did lead to high doses of acyclovir (≥1 g/8 h) in both cases. One paediatric study, however, did not find overtoxicity to be indicated at a high dosage but concerns regarding this population are hardly comparable to those of an adult population with VZV encephalitis [16]. Many case studies report the sometimes severe symptoms in obese adults [17,18]. In our study, both patients presented a weight over 80 kg and were overweight, but not obese (BMI >25<30) and acyclovir was thus not administered at the dosage recommended for the ideal body weight (IBW). However, the precise optimal regimen for use in obese patients remains unclear and use of IBW can lead to lower systemic exposure [19]. In our two cases, the patients presented clinical improvement without toxicity at initial doses of 10 mg/kg/8 h and thus the increase to 15 mg/kg/8 h is questionable. It is noteworthy that acyclovir has neurological toxicities and this toxicity is favoured by ARF [20], as seen in our cases which may be difficult to analyse during encephalitis.

A regimen of high dosage of acyclovir is by itself a risk factor for renal dysfunction [9,12], and nephrotoxicity must remain a concern regardless of the recommendations, especially in the elderly [7]. The high doses of acyclovir during VZV ME lead to an increased risk of renal toxicity and an evaluation of the benefit of this increase deserves a complementary evaluation of the risk-benefit ratio of this increase. Ideally, a prospective study could validate the best acyclovir regimen. Practitioners should be particularly aware of these risks and the need for adequate dilution of acyclovir, adapting the acyclovir regimen (10 mg/kg/8 h versus 15 mg/kg/8 h) on a case by case basis using various parameters - including good evolution with the initial dose of 10 mg/kg/8 h, weight of patients, including overweight and other factors of nephrotoxicity. In all cases the adapted speed of infusion, acyclovir final concentration and adapted hydration should be carefully monitored.