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Infectious complications in tissue expander (TE) breast reconstruction can be devastating and costly. Therefore, to optimize care, we examined patient’s demographics, microbiology of TE infections, and the efficacy of empiric antimicrobial regimens and thereafter generated an algorithm for the treatment of these complex infections.We retrospectively reviewed all patients who underwent TE breast reconstruction between 2003 and 2012 and analyzed those patients who developed a “definite” device-related infection leading to TE explantation and had a positive intraoperative culture.A total of 3,082 patients underwent immediate breast reconstruction with TE. Of these, 378 patients (12.3%) developed an infection, 189 (6.1%) eventually proceed with explantation, and 118 (3.8%) had a positive intraoperative culture. Gram-positive organisms caused 73% of infections, and Gram-negative organisms caused 27% of infections. Narrow-spectrum empiric antimicrobials with predominantly Gram-positive coverage were deemed appropriate in only 62% of cases, and those with Gram-negative coverage were appropriate in 46%. Broad-spectrum antimicrobials were used in 47% of cases, mainly recommended by infectious disease specialists, and were considered appropriate in >90% of the occasions.Current empiric antibiotic regimens do not cover the vast spectrum of organisms causing TE infections. To increase the salvage rate of an infected TE, at the first sign of infection, in addition to benefiting with an infectious diseases consultation, empiric coverage with broad-spectrum antibiotics active against biofilm-embedded organisms should be administered.