TEMPO ATÉ O INÍCIO DA ANTIBIOTICOPROFILAXIA E O RISCO DE INFECÇÃO EM FRATURAS EXPOSTAS: UMA REVISÃO SISTEMÁTICA

Marchiori, João Guilherme Tavares; Nunes, Ana Paula Ferreira

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Acta Ortopédica Brasileira

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Systematic Review Article/Orthopedic Trauma • Acta Ortop Bras 32 (2) • 2024 • https://doi.org/10.1590/1413-785220243202e263176 copiar

TEMPO ATÉ O INÍCIO DA ANTIBIOTICOPROFILAXIA E O RISCO DE INFECÇÃO EM FRATURAS EXPOSTAS: UMA REVISÃO SISTEMÁTICA

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

As fraturas expostas são lesões altamente incidentes, intimamente relacionadas à vida moderna, na qual os acidentes causados por veículos automotores ou outros aparatos transmitem alta energia ao tecido ósseo. A morbidade individual é representada pelo comprometimento funcional resultante de infecção, não-união ou cicatrização viciosa. Há enormes custos envolvidos no tratamento dessas fraturas em termos de saúde pública, principalmente quanto as complicações. Uma das questões críticas no tratamento de fraturas expostas é o uso de antibióticos, incluindo as decisões sobre quais agentes específicos devem ser administrados, a duração e o momento ideal para a primeira dose profilática. Embora as diretrizes recentes tenham recomendado o início da profilaxia antibiótica o mais rápido possível, essa recomendação parece se basear em evidências insuficientes. Em vista disso, realizamos uma revisão sistemática, incluindo estudos que abordaram o impacto do tempo até o primeiro antibiótico e o risco de resultados infecciosos. Foram selecionados 14 estudos, dos quais apenas quatro concluíram que o início precoce do tratamento com antibióticos é capaz de prevenir infecções. Todos os estudos tinham riscos importantes de viés. Os resultados indicam que essa questão permanece em aberto, sendo necessários mais estudos prospectivos e metodologicamente sólidos para orientar as práticas e políticas de saúde relacionadas a esse assunto. Nível de Evidência II; Estudos Terapêuticos que Investigam o Nível de Resultados do Tratamento.

Descritores:
Agentes Antibacterianos; Fraturas Ósseas; Controle de Infecções

Study Year of publication Design	Inclusion	Sample data Timing to first ATB	Outcome definition	Risk of bias	Study risk of bias
Dellinger et al. 1988¹⁵15 Dellinger EP, Miller SD, Wertz MJ, Grypma M, Droppert B, Anderson PA. Risk of infection after open fracture of the arm or leg. Arch Surg. 1988;123(11):1320-7. doi:10.1001/archsurg.1988.01400350034004. https://doi.org/10.1001/archsurg.1988.01... Retrospective cohort	Femur, humerus, leg bones, forearm bones All classifications Multicentric > 14y No comorbidities	N= 240 (263 fx) Minimum follow-up 21d Gt I: 25% Gt II: 47% Gt IIIA: 19% Gt IIIB: 5% Gt IIIC: 5% Method of counting time to first ATB undefined	Clinical criteria	A=M B=L C=S D=L E=S F=S G=M	S
Patzakis et al. 1989¹⁶16 Patzakis MJ, Wilkins J. Factors influencing infection rate in open fracture wounds. Clin Orthop Relat Res. 1989;(243):36-40. Prospective cohort	Any age Any bone	N= 1.104 or 1.390? Undefined follow-up Method of counting time to first ATB undefined	Clinical criteria, confirmed by microbiology	A=S B=S C=NI D=L E=C F=M G=M	C
Al-Arabi et al. 2008¹⁷17 Al-Arabi YB, Nader M, Hamidian-Jahromi AR, Woods DA. The effect of the timing of antibiotics and surgical treatment on infection rates in open long-bone fractures: a 9-year prospective study from a district general hospital. Injury. 2007;38(8):900-5. doi:10.1016/j.injury.2007.02.043. Erratum in: Injury. 2008;39(3):381. https://doi.org/10.1016/j.injury.2007.02... Prospective cohort	Femur, humerus, leg bones, forearm bones All classifications	N=133 Undefined follow-up Method of counting time to first ATB undefined	Clinical criteria (edema, erythema, discharge, pain), cultures when possible	A=C B=C C=S D=L E=C F=S G=M	C
Enninghorst et. al 2011¹⁸18 Enninghorst N, McDougall D, Hunt JJ, Balogh ZJ. Open tibia fractures: timely debridement leaves injury severity as the only determinant of poor outcome. J Trauma. 2011;70(2):352-7. Prospective cohort	> 18y, trauma center, all classifications of open diaphyseal tíbia fx	N=89 Gt I: 25% Gt II: 30% Gt IIIA: 20% Gt IIIB: 24% Gt IIIC: 1% Follow-up: 12m	Surgical debridement indication or long term systemic ATB	A=M B=L C=S D=L E=NI F=S G=M	S
Thomas et al. 2013¹⁹19 Thomas SH, Arthur AO, Howard Z, Shear ML, Kadzielski JL, Vrahas MS. Helicopter emergency medical services crew administration of antibiotics for open fractures. Air Med J. 2013;32(2):74-9. doi:10.1016/j.amj.2012.06.007. https://doi.org/10.1016/j.amj.2012.06.00... Prospective cohort	Any age, extremity open fractures	N= 138 Follow-up: 6m 60 patients: ATB pre-hospital (helicopter) 78 patients: ATB hospital Method of counting time to first ATB: time of admission and time of trauma	Composite Endpoint (superficial or deep infection or nonunion)	A=C B=L C=S D=L E=C F=C G=M	C
Leonidou et al. 2014²⁰20 Leonidou A, Kiraly Z, Gality H, Apperley S, Vanstone S, Woods DA. The effect of the timing of antibiotics and surgical treatment on infection rates in open long-bone fractures: a 6-year prospective study after a change in policy. Strategies Trauma Limb Reconstr. 2014;9(3):167-71. doi:10.1007/s11751-014-0208-9. https://doi.org/10.1007/s11751-014-0208-... Prospective cohort	Open long bones fractures	N= 212 (220 fx) Analysis for first ATB included 139 patients Follow-up: until bone healing or a procedure for nonunion or infection Gt I: 36,6% Gt II: 19,9% Gt IIIA: 24,8% Gt IIIB: 18,6% Method of counting time to first ATB: time of admission and time of trauma	Purulent discharge from deep fascia, dehiscence; "radiological evidence" or cultures	A=C B=L C=S D=L E= C F=S G=M	C
Weber et al. 2014²¹21 Weber D, Dulai SK, Bergman J, Buckley R, Beaupre LA. Time to initial operative treatment following open fracture does not impact development of deep infection: a prospective study of 736 subjects. J Orthop Trauma. 2014;28(11):613-9. Prospective cohort	Long bones open fx of adults. All classifications	N=686 (737 fx) Gt I: 29% Gt II: 37% Gt IIIA: 21% Gt IIIB: 12% Gt IIIC: 1% Follow-up: 90d or phone interview at 12m	Surgical debridement indication or long term systemic ATB	A=M B=L C=S D=L E=S F=S G=M	S
Zumsteg et al. 2014²²22 Zumsteg JW, Molina CS, Lee DH, Pappas ND. Factors influencing infection rates after open fractures of the radius and/or ulna. J Hand Surg Am. 2014;39(5):956-61. doi:10.1016/j.jhsa.2014.02.008. https://doi.org/10.1016/j.jhsa.2014.02.0... Retrospective cohort	18y Radius and/or ulna open fx	N=200 Variable follow-up (max 6m) Gt I: 22% Gt II: 24% Gt III: 55% Data from medical records	Deep infection as an indication or surgical debridement, assessed from medical records or phone calls	A=S B=C C=S D=L E=S F=C G=M	C
Lack et al. 2015²³23 Lack WD, Karunakar MA, Angerame MR, Seymour RB, Sims S, Kellam JF, et al. Type III open tibia fractures: immediate antibiotic prophylaxis minimizes infection. J Orthop Trauma. 2015;29(1):1-6. doi:10.1097/BOT.0000000000000262. Erratum in: J Orthop Trauma. 2015;29(6):e213. https://doi.org/10.1097/BOT.000000000000... Retrospective cohort	Type III open tibia fractures	N=137 Follow-up 90d Gt IIIA: 52% Gt IIIB/IIIC: 48% Method of counting time to first ATB: time of admission and time of trauma	CDC	A=M B=L C=S D=L E=L F=S G=M	S
Johnson et al 2017.²⁴24 Johnson JP, Goodman AD, Haag AM, Hayda RA. Decreased Time to Antibiotic Prophylaxis for Open Fractures at a Level One Trauma Center. J Orthop Trauma. 2017;31(11):596-9. doi:10.1097/BOT.0000000000000928. https://doi.org/10.1097/BOT.000000000000... Cross-sectional	> 18y Limb and axial bones All classifications Data from medical records	N=100 1 group N= 50 before early ATB protocol. 1 group N=50 after protocol institution Undefined follow-up	Surgery indication	A=S B=C C=S D=L E=S F=S G=M	C
Assunção ALF, Oliveira de ST. 2020²⁵25 Assunção ALF, Oliveira de ST. Clinical Audit of Primary Treatment of Open Fractures: Antibiotic Treatment and Tetanus Prophylaxis. Rev Bras Ortop (Sao Paulo). 2020;55(3):284-92. doi:10.1055/s-0039-3402470. https://doi.org/10.1055/s-0039-3402470... Prospective cohort	> 18y, trauma center, data from medical records.	N=241 Gt I: 20% Gt II: 19% Gt III: 21,6% NC: 39,4% Time from admission to first ATB	NS	A=C B=C C=S D=C E=M F=S G=M	C
Hendrickson et al 2020²⁶26 Hendrickson SA, Donovan R, Harries L, Wright TC, Whitehouse MR, Khan U. Time to intravenous antibiotic administration (TIbiA) in severe open tibial fractures: Impact of change to national guidance. Injury. 2020;51(4):1086-90. doi:10.1016/j.injury.2020.03.005. https://doi.org/10.1016/j.injury.2020.03... Retrospective cohort	Type IIIB open tíbia fx	N= 156 (159 fx) Minimum follow-up 1y Median 26 m (IQR 18-39) Method of counting time to first ATB: time of trauma	Deep infection confirmed by microbiology	A=M B=L C=L D=L E=L F=M G=M	M
Roddy et al. 2020²⁷27 Roddy E, Patterson JT, Kandemir U. Delay of Antibiotic Administration Greater than 2 Hours Predicts Surgical Site Infection in Open Fractures. Injury. 2020;51(9):1999-2003. doi:10.1016/j.injury.2020.04.031. https://doi.org/10.1016/j.injury.2020.04... Retrospective cohort	Upper and lower limb open fx, all classifications, data from medical records	N= 230 Minimum follow-up: 30d, endpoint assessment at 90d	CDC NHSN	A=M B=L C=S D=L E=S F=S G=M	S
Zuelzer et al. 2021²⁸28 Zuelzer DA, Hayes CB, Hautala GS, Akbar A, Mayer RR, Jacobs CA, et al. Early Antibiotic Administration Is Associated with a Reduced Infection Risk When Combined with Primary Wound Closure in Patients with Open Tibia Fractures. Clin Orthop Relat Res. 2021;479(3):613-9. doi:10.1097/CORR.0000000000001507. https://doi.org/10.1097/CORR.00000000000... Retrospective cohort	> 18y, trauma center, data from medical records, rescue sheets, Gustilo I, II, IIIA	N=127 Gt I: 27,6% Gt II: 48,8% Gt IIIA: 23,6% Minimum follow-up: 6w	CDC	A=M B=L C=S D=L E=M F=S G=M	S

Study	Analysis	Results	Comments	Earl ATB: recommendation x usual practice
Dellinger et. al. 1988¹⁵15 Dellinger EP, Miller SD, Wertz MJ, Grypma M, Droppert B, Anderson PA. Risk of infection after open fracture of the arm or leg. Arch Surg. 1988;123(11):1320-7. doi:10.1001/archsurg.1988.01400350034004. https://doi.org/10.1001/archsurg.1988.01...	Chi-square Fisher Student's t Kaplan-Meier Logistic regression	Time to 1°ATB < 3h: 16% infected; > 3h: 17% infected. p=0,9784 Mean time to 1º ATB in infected: 2,0h (+-1,1h); non-infected: 2,2h (+-1,4h)	Method of counting the time to first ATB not informed 22% lost to follow-up at 6m	No mention about recommendation or practice
Patzakis et al. 1989¹⁶16 Patzakis MJ, Wilkins J. Factors influencing infection rate in open fracture wounds. Clin Orthop Relat Res. 1989;(243):36-40.	Chi-square	Time to first ATB <3h (364 fx): 4,7% infected. . >3h (661 fx): 7,4% infected p= 0,087 (Yates 0,114)	No information on follow-up No control for confounding variables Method of counting the time to first ATB not informed. Dichotomization of time to first ATB variable. No information on time as a continuous variable Divergence regarding composition of the cohort (1.104 ou 1.390?) No apparent distinction between superficial and deep infection	Recommends ATB as soon as possible after lesion
Al-Arabi et al. 2007¹⁷17 Al-Arabi YB, Nader M, Hamidian-Jahromi AR, Woods DA. The effect of the timing of antibiotics and surgical treatment on infection rates in open long-bone fractures: a 9-year prospective study from a district general hospital. Injury. 2007;38(8):900-5. doi:10.1016/j.injury.2007.02.043. Erratum in: Injury. 2008;39(3):381. https://doi.org/10.1016/j.injury.2007.02...	Fisher Linear Regression	Time to first ATB < 6h: 5,7% infected > 6h: 22,2% infected p=0,1144	No control for confounding variables No information regarding central tendency measures for follow-up Method of counting the time to first ATB not informed A non-specified number of more severe fx (IIIB and IIIC) lost to follow-up, with no information on their basal characteristics 80% statistical power for a reduction of 10% in infection rate	No mention about recommendation or practice
Enninghorst et al. 2011¹⁸18 Enninghorst N, McDougall D, Hunt JJ, Balogh ZJ. Open tibia fractures: timely debridement leaves injury severity as the only determinant of poor outcome. J Trauma. 2011;70(2):352-7.	Means Student's t Mann-Whitney U Chi-square Univariate, bivariate, multiple regression	Cohort mean: 1,2h (+-0,3h) Incidence of infection: 16,8% No difference in time to first ATB between infected and non-infected	Indefinition regarding classification of intervention and outcome No missing data information	No mention about recommendation or practice
Thomas et al. 2013¹⁹19 Thomas SH, Arthur AO, Howard Z, Shear ML, Kadzielski JL, Vrahas MS. Helicopter emergency medical services crew administration of antibiotics for open fractures. Air Med J. 2013;32(2):74-9. doi:10.1016/j.amj.2012.06.007. https://doi.org/10.1016/j.amj.2012.06.00...	Fisher Chi-square Kruskal-Wallis	Pre-hospital ATB group: 60 patients (13 completed follow-up) 1 outcome (infection or nonunion [7,7%]) Hospital ATB group: 78 patients. (70 completed follow-up) 9 outcomes nonunion [12,9%]) P=1,0 60,2% lost to follow-up	No control for confounding variables Inconsistencies in classification of intervention, without proper control (potentially affects internal validity) High losses to follow-up Meticulous statistical analysis and discussion about limitations	No mention about recommendation or practice
Leonidou et al. 2014²⁰20 Leonidou A, Kiraly Z, Gality H, Apperley S, Vanstone S, Woods DA. The effect of the timing of antibiotics and surgical treatment on infection rates in open long-bone fractures: a 6-year prospective study after a change in policy. Strategies Trauma Limb Reconstr. 2014;9(3):167-71. doi:10.1007/s11751-014-0208-9. https://doi.org/10.1007/s11751-014-0208-...	Fisher	Time to 1°ATB < 3h: 14% infected; > 3h: 12,5% infected. p=1,0	No control for confounding variables No information regarding central tendency measures for follow-up 39,6% lost to follow-up Inconsistencies in classification of intervention, without proper control (potentially affects internal validity) Inconsistencies in information of sample composition and in records of losses	Usual practice: ATB in less than 3 hours from lesion
Weber et al. 2014²¹21 Weber D, Dulai SK, Bergman J, Buckley R, Beaupre LA. Time to initial operative treatment following open fracture does not impact development of deep infection: a prospective study of 736 subjects. J Orthop Trauma. 2014;28(11):613-9.	Medians Mann-Whitney U Simple and multiple regression	6% of infection Median to 1° ATB among infected: 2h37min. Median to first ATB among non-infected: 3h5min p=0,67 Logistic regression: OR 1,0 (IC95% 0,95-1,05)	Sound methodology Method of counting the time to first ATB not informed Few losses to follow-up. Intervention not known in 15% of patients No definite conclusion on the association of early ATB and infection, as most patients received late ATB	Usual practice
Zumsteg et al. 2014²²22 Zumsteg JW, Molina CS, Lee DH, Pappas ND. Factors influencing infection rates after open fractures of the radius and/or ulna. J Hand Surg Am. 2014;39(5):956-61. doi:10.1016/j.jhsa.2014.02.008. https://doi.org/10.1016/j.jhsa.2014.02.0...	Wilcoxon Fisher Chi-square Logistic Regression	32% lost to follow-up, with no information on their basal characteristics Mean time to 1° ATB: 1,6 +− 0,9h among infected; 2,6 +− 2,2 horas among noninfected ATB < 3h: 159 patients (6% infected). ATB > 3h: 41 patients (2% infected p=0,40 10 infections (5%), on average 118 days after first stabilization	Many confounders not controlled Inconsistencies in classification of intervention High losses to follow-up Upper limb open fractures have less risk of getting infected, so big samples may be needed to investigate such associations.	No mention about recommendation or practice
Lack et al. 2015²³23 Lack WD, Karunakar MA, Angerame MR, Seymour RB, Sims S, Kellam JF, et al. Type III open tibia fractures: immediate antibiotic prophylaxis minimizes infection. J Orthop Trauma. 2015;29(1):1-6. doi:10.1097/BOT.0000000000000262. Erratum in: J Orthop Trauma. 2015;29(6):e213. https://doi.org/10.1097/BOT.000000000000...	Chi-square Student's t Logistic Regression	Time to 1°ATB < 66min: 7% infected; > 66min: 25% infected p=0,0063 ROC: 66min (AUC=0,63 p=0,03) Logistic regression: ATB > 66min: OR = 3,78 (CI95% 1,26-14,11 p= -0,016)	Sound methodology and analysis Gives a cut-off time to first ATB Sample calculation for a power of 80% Late ATB is a independent predictor of infection Inconsistencies in classification of intervention, without proper control (potentially affects internal validity)	Recommends ATB as soon as possible, preferably at pre-hospital level
Johnson et al. 2017²⁴24 Johnson JP, Goodman AD, Haag AM, Hayda RA. Decreased Time to Antibiotic Prophylaxis for Open Fractures at a Level One Trauma Center. J Orthop Trauma. 2017;31(11):596-9. doi:10.1097/BOT.0000000000000928. https://doi.org/10.1097/BOT.000000000000...	Chi-square Mann Whitney U Student's t	Time to first ATB dropped from 123,1min to 35,7min (p=0,0003). Incidence of infection = 10% for both groups	Time to first ATB counted from admission time (risk of bias due to classification of intervention) Outcome defined as indication of surgery (not precise and subjective) Follow-up not defined Small sample (few outcomes, low power)	Usual practice: first ATB as soon as possible from admission
Assunção ALF, Oliveira de ST. 2020²⁵25 Assunção ALF, Oliveira de ST. Clinical Audit of Primary Treatment of Open Fractures: Antibiotic Treatment and Tetanus Prophylaxis. Rev Bras Ortop (Sao Paulo). 2020;55(3):284-92. doi:10.1055/s-0039-3402470. https://doi.org/10.1055/s-0039-3402470...	Frequencies Chi-square	Infection: ≤ 3h from admission: 15,7% > 3 h from admission: 26,1% p = 0.0350	Confounders and co-interventions not listed	Usual practice (preoperative ATB)
Hendrickson et al. 2020²⁶26 Hendrickson SA, Donovan R, Harries L, Wright TC, Whitehouse MR, Khan U. Time to intravenous antibiotic administration (TIbiA) in severe open tibial fractures: Impact of change to national guidance. Injury. 2020;51(4):1086-90. doi:10.1016/j.injury.2020.03.005. https://doi.org/10.1016/j.injury.2020.03...	Medians and IQR Logistic Regression	Time to 1° ATB: median 162 min (IQR: 120-207) Time to 1° ATB x Infection (regression analysis): Continuous: p=0,431 1h: p=0,099 3h: p=0,848	Sound methodology and analysis Main confounders accounted for, including multicollinearity tests Outcome assessed with objective criteria Potential risk of beta error, as most patients took late ATB (>2h)	Usual practice: early/pre-hospital ATB
Roddy et al. 2020²⁷27 Roddy E, Patterson JT, Kandemir U. Delay of Antibiotic Administration Greater than 2 Hours Predicts Surgical Site Infection in Open Fractures. Injury. 2020;51(9):1999-2003. doi:10.1016/j.injury.2020.04.031. https://doi.org/10.1016/j.injury.2020.04...	Chi-square Mann Whitney U ROC Cox regression	Deep infection: 6% Median to 1° ATB in infected: 83min Median to 1° ATB non-infected: 61min p=0,053 Cut-off 120min ROC (AUC 0.62, 95% CI [0.50 – 0.75], p = 0.042) OR 2,4 [CI95% 1,1-5,7] p=0,036.	Sound methodology and analysis Gives a cut-off time to first ATB CI of AUC do not show a definitive benefit of cut-off found Small sample (low power) 130 patients missed (29%) e 78 with no information on time to first ATB (17%)	Recommends ATB as soon as possible
Zuelzer et al. 2021²⁸28 Zuelzer DA, Hayes CB, Hautala GS, Akbar A, Mayer RR, Jacobs CA, et al. Early Antibiotic Administration Is Associated with a Reduced Infection Risk When Combined with Primary Wound Closure in Patients with Open Tibia Fractures. Clin Orthop Relat Res. 2021;479(3):613-9. doi:10.1097/CORR.0000000000001507. https://doi.org/10.1097/CORR.00000000000...	Chi-square Fisher ANOVA Binary regression Logistic regression ROC curve	Infection: ≤ 150 from admission: 3% > 150 from admission: 20% Odds Ratio 5.6 [95% CI 1.4 to 22.2]; p = 0.01	Sound methodology, detection bias risk, risk of bias due to classification of intervention (non-standardized sources of data)	ATB as soon as possible after lesion (practice and recommendation)

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[1] Correspondence: João Guilherme Tavares Marchiori. 60/1102, Taciano Abaurre Street, Enseada do Suá, Vitória, ES, Brasil. 29050470. joaogtm@yahoo.com.br