Multiple drug hypersensitivity (MDH) is a rare syndrome, characterized by hypersensitivity to two or more structurally unrelated drugs. They may develop simultaneously at first or appear progressively over the years. The initial picture mostly consists of a severe cutaneous adverse reaction with eosinophilia and systemic symptoms (DRESS). Subsequent reactions may be identical to the first reaction or appear in a milder or more severe form. The immunological basis is a T-lymphocyte overstimulation.

We present a series of three cases with a diagnosis of MDH produced simultaneously by almost two structurally different drugs. Two of them consisted on DRESS syndrome, confirmed by patch test (PT) and intradermal test (IDT) in delayed readings. The third case appeared as an exanthema with fever and eosinophilia without criteria of DRESS syndrome and confirmed by PT.

The first DRESS syndrome, sensitization to Ceftriaxone and Carbamazepine was confirmed by PT, been positive to Carbamazepine 10% in dimetilsulfoxide (DMSO) (+++), Oxcarbazepine 10% DMSO(+) and Ceftriaxone 20% petrolatum (pet)(++) with delayed readings at day 2 (D2) and day 4 (D4).  IDT with Ceftriaxone was positive at 24 hours delayed reading.

In the second DRESS syndrome four different structurally drugs as Ceftriaxone, Ritonavir, Enoxaparin, and Hydroxychloroquine were implicated, being positive at PT to Ceftriaxone 20% pet (++), Hydroxychloroquine 5% DMSO (++), Lopinavir 10% DMSO (++), and Ritonavir 10% DMSO (++) at D2 and D4. Bemiparin and Enoxaparin were positive at IDT in 48 and 96 hours readings. The third case presented with fever and eosinophilia due to Ioversol and Piperacillin-Tazobactam and confirmed sensitization by positive IDT with Iopamidol, Ioversol, Iomeprol and Piperacillin-Tazobactam at 24 hours reading. All PT had negative control DMSO.

In all the cases, MDH appears simultaneously in a severe cutaneous reaction to almost two structurally different drugs. In one case, we found sensitization to four unrelated structurally pharmacological group of drugs. In our cases, PT and IDT were diagnosis, suspecting non-immediate type IV hypersensitivity reactions.