Global gram-negative diabetic foot infection prevalence and its associations with climate: a systematic review and meta-analysis

BackgroundBased on limited data, the International Working Group on the Diabetic Foot guidelines recommend antibiotics with anti-gram-negative activity, including against P. aeruginosa, for patients with moderate-to-severe diabetic foot infections (DFIs) who reside in warm climates and state that P. aeruginosa DFIs are more common in North Africa/Asia vs Western Europe/North America. MethodsWe performed a systematic review and meta-analysis of studies of any design and language published between January 1, 2010, and December 15, 2020, that reported the proportion of participants with DFIs and microbiological tests that were positive or negative for Pseudomonas aeruginosa and/or gram-negatives of any species. We calculated the pooled prevalence of P. aeruginosa DFIs (psaDFIs) and overall gram-negative DFIs (gnDFIs) defined as the proportion of DFIs presenting to healthcare facilities with microbiologically-confirmed DFIs using random effects models. This review is registered with PROSPERO (CRD42022279019). FindingsWe identified 246 studies (36,788 participants) reporting on psaDFI prevalence and 55 studies (6,079 participants) reporting on gnDFI prevalence. The psaDFI pooled prevalence in tropical, subtropical, and temperate zones was 19% (95%CI 17-22%), 14% (95%CI 12-17%), and 14% (95%CI 11-17%), respectively. The gnDFI pooled prevalence in tropical, subtropical, and temperate zones was 68% (95%CI 61-74%), 54% (95%CI 45-63%), and 43% (95%CI 35-52%), respectively. The pooled prevalence of psaDFIs and gnDFIs was higher in studies conducted in Asia/North Africa [psaDFI 19% (95%CI 17-21%) and gnDFI 57% (95%CI 51-64%)] compared to studies conducted in North America/Western Europe [psaDFI 13% (95%CI 10-17%) and gnDFI 42% (95%CI 32-52%)]. However, the pooled prevalences of these infections were similar in temperate zones of these regions. Few studies reported data on key risk factors for psaDFIs and gnDFIs, including DFI severity and prior antibiotic exposure, and there was substantial between-study heterogeneity within climate zones and regions. InterpretationpsaDFIs and gnDFIs were more prevalent in tropical zones compared to temperate zones, but not subtropical zones. Climate zones better discriminate DFI microbiology compared to the guideline-proposed regional differences. Available studies lack necessary data to separate the effects of climate from other risk factors for psaDFIs and gnDFIs. FundingNone RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSDiabetic foot ulcers are a leading cause of preventable limb loss globally and diabetic foot infections (DFIs) are generally the terminal step before an amputation. Whether or not to use antibiotics with anti-gram-negative activity, particularly anti-Pseudomonas aeruginosa, is a key DFI management decision. The International Working Group on the Diabetic Foot is an international multidisciplinary organization that issues diabetic foot-related guidelines adopted globally. The latest guidance issued in 2023 states that the decision to use anti-gram-negative and anti-pseudomonal agents should be based on infection severity, recent antibiotic exposure, prior culture data, and the climate and location where the patient resides (table). The climate- and location-related recommendations are based on limited data. We searched PubMed, EMBASE, Web of Science, and World Health Organization databases on December 15, 2020, to identify articles published between January 1, 2010, and December 15, 2020, and repeated the PubMed search on December 30, 2024. Two prior systematic reviews and meta-analysis found higher P. aeruginosa DFI (psaDFI) rates in Asia and Africa compared to the Americas and Europe. We found no prior systematic reviews reporting on the prevalence of psaDFIs and overall gram-negative DFIs (gnDFI) globally stratified by climate zones. Added value of this studyFrom 246 studies (36,788 participants) reporting on psaDFI prevalence and 55 studies (6,079 participants) reporting on gnDFI prevalence, psaDFIs and gnDFIs were more prevalent in tropical settings compared to temperate zones, but there were no substantial differences in the prevalence of these infections between tropical and subtropical, and subtropical and temperate zones. Additionally, we found that climate zones better discriminate the prevalence of these infections compared to the guideline-proposed regional differences. Importantly, studies generally lacked key data needed to understand if the differences in prevalence were related to characteristics other than climate (DFI severity, antibiotic exposure) and there was substantial between-study heterogeneity within climate zones and regions that could not be explained by meta-regression models that included climate, region, or inpatient vs outpatient recruitment (a proxy for DFI severity). Implications of all the available evidenceWell-designed geographically representative cohort studies that contain patient-level data regarding the contribution of location and clinical factors on DFI microbiological profile and treatment outcomes are needed to better guide antimicrobial therapy. Absent further evidence, the future guidelines could state psaDFIs and gnDFIs are more common in tropical zones. O_TBL View this table: org.highwire.dtl.DTLVardef@134d0c5org.highwire.dtl.DTLVardef@7675bborg.highwire.dtl.DTLVardef@12b5382org.highwire.dtl.DTLVardef@1779a27org.highwire.dtl.DTLVardef@1298380_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable:C_FLOATNO O_TABLECAPTIONInternational Working Group on the Diabetic Foot/Infectious Diseases Society of America 2023 recommendations regarding use of anti-gram-negative, including anti-pseudomonal, antibiotics. C_TABLECAPTION C_TBL