A Detailed Study of Infection Following Custom-Made Porous Hydroxyapatite Cranioplasty: Risk Factors and How to Possibly Avoid Device Explantation

<b>Background/Objectives:</b> Postoperative infection is a significant complication following cranioplasty procedures. This study aimed to assess infection risk factors and clinical outcomes in patients undergoing cranioplasty with custom-made porous hydroxyapatite (PHA) implants, with a particular focus on treatment strategies used to manage infections and avoid implant explantation. <b>Methods:</b> This retrospective multicenter analysis included 984 patients who underwent PHA cranioplasty as part of a post-market clinical follow-up. Clinical data included demographics, surgical characteristics, infection features, microbiological results, infection management strategies, and outcomes. Associations with infection risk and implant explantation were assessed using chi-square tests. <b>Results:</b> Seventy-six patients (7.7%) developed postoperative infections. Infection risk was significantly associated with second-line procedures (<i>p</i> = 0.011) and implant location (<i>p</i> = 0.037). Most infections were superficial (92.1%) and early-onset (≤2 months from the surgery, 61.9%), with <i>Staphylococcus</i> spp. as the predominant pathogens. Explantation occurred in 77.6% of infected cases. The infection management strategy-whether initial conservative treatment with antibiotics alone (n = 18 of which 11.1% explanted) or surgical reoperation (n = 58 of which 93.8% explanted)-along with surgical cleaning and local (in situ) antibiotic use alone, was significantly associated with explantation outcomes (all <i>p</i> < 0.001). Among 18 patients treated with systemic antibiotics alone, 88.9% retained their implants. Notably, all successful cases had received broad-spectrum antibiotics for at least 4 weeks. Local antibiotic therapy was administered in 13 patients; no explants occurred among those who also received prolonged systemic treatment. Pathogen type was not significantly associated with the risk of explantation. <b>Conclusions:</b> Prolonged systemic antibiotic therapy, especially when combined with local treatment, may allow implant retention in selected infections, supporting individualized, conservative management strategies.