Emergence of cross-resistant herpes simplex virus following topical drug therapy in rabbit keratitis.
The acquisition of drug resistance in vivo was investigated by 7 serial passages (from P0 to P7) of herpes simplex virus (HSV-1) in rabbit cornea treated with either IUdR (idoxuridine), IDC (idoxycytidine), ACV (acyclovir), TFT (trifluridine), or Ara A (adenine arabinoside). Therapeutic failure was acquired gradually: at P3 for IUdR, at P4 for ACV and at P5 for TFT. At P7, viral thymidine kinase (TK) activity was reduced to 5.6% of the parental strain for IUdR, to 7.5% for ACV and to 4.6% for TFT treatment. No signs of clinical unresponsiveness occurred with IDC or Ara A. The in vitro determination of antiviral drug sensitivity performed by the dye-uptake assay on HSV isolates at each passage showed a correlation between the increase in the 50% effective dose (ED50) and the increase of ulcer area grade at each passage under antiviral drug (p less than 0.1). Both IUdR- and TFT-resistant HSV1 developed cross-resistances to TK dependent drugs. However ACV-resistant HSV1 did not show cross-resistance to other antiviral TK dependent drugs. The acquisition of the cross-resistances is discussed, and the practical implications in case of therapeutic failures are suggested.
Fardeau
C
C
Unité de Recherches d'Ophtalmologie, INSERM U 86, Hôtel-Dieu, Paris, France.
Langlois
M
M
Mathys
B
B
Rafales
P
P
Nugier
F
F
Godard
V
V
Aymard
M
M
Denis
J
J
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004352:Drug Resistance, Microbial; D005260:Female; D007635:Keratitis, Dendritic / Q000188:drug therapy*; D007928:Lethal Dose 50; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D018139:Simplexvirus / Q000187:drug effects* / Q000302:isolation & purification; D014776:Virus Cultivation
D000998:Antiviral Agents