Combination of ceftriaxone and acyclovir – an underestimated nephrotoxic potential?

Abstract

Management of meningo-encephalitis often involves the need for antibiotic and antiviral treatment. We report a retrospective analysis over a 6-month period of 17 patients (age range 1-14 years) who were treated with combination therapy of ceftriaxone and acyclovir. Mean acyclovir and ceftriaxone doses were 1,222+/-304 and 2,315+/-509 mg/m(2) per day, respectively. Three patients developed acute renal failure with a peak creatinine of up to 865% above baseline, occurring 2-3 days after starting combination therapy. Patients revealed a tubular proteinuria pattern. Renal biopsy of 1 patient showed a tubulotoxic picture but no evidence of crystals. In 12 of 17 patients (70%) there was a significant increase in serum creatinine. This was significantly greater than literature reports of 16% with acyclovir monotherapy. The degree of renal impairment in our patients correlated significantly with the acyclovir dose, while no correlation was found with the ceftriaxone dose. We conclude that the addition of a second nephrotoxic drug aggravated the extent of renal injury in our patients. The mechanism is tubulotoxicity. Caution should be exercised when using this potentially nephrotoxic cocktail, with clear criteria established for the initiation of combination therapy and close monitoring of serum creatinine.

Acute kidney injury due to acyclovir

“…Clinical evidence of nephrotoxicity in the absence of crystalluria was suggested to be secondary to the direct cytotoxicity effect of the drug to tubular cells and acute interstitial nephritis in our patient, as mentioned in other studies [8,13,14]. Renal biopsy findings of patients with acyclovir toxicity include bulging of tubular cells, dilated tubular lumens, loss of proximal-distal tubular differentiation, flattening and vacuolization of epithelial cells, and epithelial cell mitoses [8,14]. A moderate and patchy tubulointerstitial infiltration of inflammatory cells and focal necrosis of cortical proximal tubules with edema were noted in our patient.…”

Herpes PCR Testing and Empiric Acyclovir Use Beyond the Neonatal Period

“…2 Although often well tolerated by neonates, acyclovir is associated with increases in serum creatinine and glomerular filtration rate in older children, particularly when coadministered with other nephrotoxic medications, such as antibiotics. 3,4 Furthermore, shifts in the factors influencing HSV diagnostic and empirical treatment decisions may represent a more fundamental problem in the current practice of pediatrics.…”

Acyclovir Dosing and Acute Kidney Injury: Deviations and Direction

“…A prospective clinical trial could better capture this, along with which predictive factors contribute to different times of AKI onset and peak. The study by Vomiero et al, 8 did demonstrate a correlation between the rise in Scr and acyclovir dose, with the greatest rise in those with doses at or above 1500 mg/m 2 /d, similar to AKI evaluated by Rao et al 4 Other potential mechanisms of acyclovir-induced AKI expand on these observations. The lack of crystalluria in numerous case reports and histology reflective of tubulopathy in the face of non-oliguric renal impairment 8 have led translational researchers to seek other explanations for AKI, using in-situ kidney preparations and in-vitro testing with transfected human kidney cells.…”

“…7 It would be easy to suggest that high-dose ceftriaxone adds to the solute burden to accelerate that obstruction. Yet, in the study by Vomiero et al, 8 of 17 cases of combined acyclovir and ceftriaxone use, 12 patients has a significant decrease in estimated GFR in 3 to 5 days (median = 3), and the range in the publication by Rao et al is up to 4.4 days in the failure group, and up to 2 weeks in the risk and injury groups. 4 Moreover, renal failure from ceftriaxone alone in 31 patients was noted to occur 5.2 days after initiation, 9 with the pathology (urolithiasis, anuria) and interventional therapy vastly different from the acyclovir-induced severe AKI.…”