1 Background

Up to 6 million bone fractures occur yearly in the United States and it is estimated that the lifetime risk for sustaining a traumatic fracture is 1 in 2 up to the age of 65. Nearly 3 % of those fractures are estimated to be open. Open fractures are those that involve the penetration of bone through the surface of the skin leading to the bone's direct contact with the external environment.^1–5

Due to the nature of these injuries, infection is a major concern.^6–8 Infected fractures put a significant cost on the patient both financially and physically.⁹ Infected fractures have shown to increase financial healthcare costs by as much as 6-fold, mostly due to extended length of stay.⁹ Physically, infection may delay wound healing, cause non-union, necessitate further surgery to prevent the spread of the pathogen which can include amputation, and in severe cases can even result in death.^6–8 Early administration of antibiotics, irrigation and debridement, and fracture stabilization are essential components of management employed to decrease infection risk.^6–8,10 Although infection rates have improved due to antibiotic use and surgical technique, there is still room for optimization of antibiotic guidelines.

Guidelines published by the Eastern Association for the Surgery of Trauma (EAST) stipulate that Gustilo-Anderson type I and type II open fractures should receive first-generation cephalosporins (e.g. cefazolin) for gram-positive coverage and type IIIA-C open fractures should receive both a first-generation cephalosporin for gram-positive coverage and an aminoglycoside (e.g. gentamycin) for gram-negative coverage.¹¹ Certain cases that require anaerobic or aquatic coverage may also utilize penicillin or fluoroquinolones, respectively.¹¹ While effective and generally safe, first-generation cephalosporins have an increased risk of antibiotic resistance.^12,13 Additionally, aminoglycosides pose the risk of ototoxicity, reported in up to 2–45 % of patients, and nephrotoxicity, reported in up to 10–25 % of patients.¹⁴

Multiple studies have proposed the use of Piperacillin/Tazobactam (PT) as an alternative treatment due to its safety profile and combined gram-positive, gram-negative, and anaerobic coverage in a single-dose administration method.^15–18 In addition, PT is often administered from a convenient ready-to-administer package in contrast to the weight-based dosage used in cephalosporins and aminoglycosides.¹⁶ The purpose of this systematic literature review is to evaluate the hypothesis that PT antibiotic prophylaxis does not differ in clinical outcomes as compared to the current guidelines in the treatment of open fractures.

2 Methods

The following research question was posed: Does prophylactic Piperacillin/Tazobactam administration differ in clinical outcomes as compared to current guidelines in open fractures? Using the Participants/Population, Interventions, Comparator/Control, Outcomes (PICO) framework, inclusion, and exclusion criteria were identified (Table 1) (see Table 2).

PubMed, Embase, Cochrane Libraries, Scopus, and ClinicalTrials.Gov were queried for articles relevant to antibiotic administration for open fractures. The following search terms were used: (Cephalosporin OR Cefalexin OR Cefazolin OR Antibiotic OR Prophylaxis) AND (Zosyn OR Piperacillin OR Tazobactam OR Penicillin) AND (Open OR Fracture). A total of 7305 articles were identified. All articles published prior to August 4, 2024 were analyzed. After removing 341 duplicates, 6964 articles were reviewed by title and or abstract. A 2-author screening process was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines as shown in the PRISMA flow diagram (Fig. 1). A total of 4 studies were included in the systematic review.

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Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses showing search and selection criteria for the systematic review of PT vs current guidelines in the treatment of open fractures.

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Only comparative studies of current antibiotic prophylactic guidelines for PT treatment for open fractures were included. No articles were excluded based on age, language, sex, race/ethnicity, or duration of treatment.

Recorded data included study characteristics such as publication year, design, site, period, regimen, and number of patients. Patient demographics included age, sex, fracture type, diabetes, injury severity score (ISS), and time to antibiotic administration. Outcome measures included surgical site infection (SSI), acute kidney injury (AKI), length of stay (LOS), return to the operating room, 1-year mortality, non-union, and development of resistant pathogens. Any discrepancy between the two review authors was resolved by a third senior author. The level of evidence was described for each article using the Oxford criteria, which classifies research strength based on study type from Level 1 (strongest) to 5 (weakest).

Due to inconsistency in statistical reporting, all data presented as median and interquartile range were converted into mean and standard deviation according to a method developed by Wan et., al. to assist systematic reviews and meta-analyses in combining data.¹⁹ Chi-square test, Fisher Exact test, and t-tests were used to compare PT to control groups. All analyses were conducted with all fracture types combined. All analyses were conducted with a first-generation cephalosporin and a first-generation cephalosporin plus an aminoglycoside combined as control treatment. All analyses were performed on SPSS version 28.0.0. A p-value <0.05 was considered significant. Due to an insufficient sample size, a true meta-analysis was not performed.

Methodologic index for non-randomized studies (MINORS) criteria was used to objectively assess the methodologic quality of the studies reviewed. MINORS uses 12 scored items for comparative studies. A perfect score of 24 fulfills all criteria. A score of 0 does not fulfill any criteria.

3 Results

4 Discussion

The present systematic review evaluated the hypothesis that PT antibiotic prophylaxis does not differ in clinical outcomes as compared to the current guidelines in the treatment of open fractures. The statistical analysis of this study supports this hypothesis.

Antibiotic prophylaxis is key in minimizing the risks associated with open fractures.⁸ Early intervention with antibiotics significantly decreases negative patient outcomes including SSI and length of stay.^20,21 Our analysis showed that nearly all major outcomes associated with the PT and control group showed no differences. The similarity in SSI, AKI, 1-year mortality, non-union, and resistant pathogen development indicates that it is possible to obtain the safety profile benefits of PT without sacrificing the effectiveness of a cephalosporin or combined cephalosporin and gentamicin regimen. Surprisingly, the length of hospital stay was greater in the PT group. This may be explained by the greater ISS of this group. Kashkoee et al. and Yousefzadeh et al. both determined that injury severity is the best predictor for the length of stay.^22,23

McMurtrie et al. found that the use of PT for type II and III open fractures does not increase the risk of SSI or AKI in patients.¹⁵ They conclude that PT can be safely used as a monotherapy in these patients. One limitation of this study is that it does not have long-term follow-up with patients.¹⁵ To effectively determine infection rates, Zalavras et al. proposes that 1-year follow-up is preferable to the typical 90-day follow-up because most SSIs develop after the 90-day period. Following patients for shorter than 1-year may cause physicians to miss infection development.²⁴ Another important limitation in this study to consider is that the time to administration of antibiotics was significantly shorter in the PT group than in the control group (304 min vs 395 min).¹⁵ Longer time to administration is typically associated with higher rates of surgical site infection so the conclusions of this study must be evaluated with caution.²⁰

Frantz et al. concluded that PT may lower the risk of surgical site infection and nephrotoxicity for type II and III open fractures.¹⁶ This is in contrast to other studies that show no trends in the improvement of these outcomes.^15,17,18 A key finding from Franz et al. is that there is a decrease in nephrotoxicity when comparing PT to cefazolin plus an aminoglycoside.¹⁶ Another key finding from Franz et al. is that the return to the operating room was greater for the cefazolin alone group but not the cefazolin plus an aminoglycoside group when compared to PT, highlighting one of the negative outcomes of cefazolin alone.¹⁶ Although, this finding may be complicated by the inconsistency in fracture-type reporting. Intraoperatively, fracture types were changed from type II to III or type III to II, leading to inconsistent administration of cefazolin or cefazolin plus an aminoglycoside to its guideline-concordant fracture type. One limitation of this study is the 60-day follow-up. Another limitation of this study is that the times recorded in the electronic medical records were assumed to be true but in emergency scenarios, events may have occurred at different times, therefore, time measurements should be evaluated with caution.

Redfern et al. concluded that the use of PT may be safely used as an alternative treatment for patients with type III open fractures.¹⁷ One strength of this study is the 1-year follow-up with patients, which is significantly longer than other studies evaluated. One limitation of this study is that the time to antibiotic administration was not recorded, which may have played a role in the development of infection. Additionally, this study did not assess AKI, a key outcome when assessing the safety of the regimen. The nephrotoxic characteristics of aminoglycosides were a major consideration when conducting this study, therefore, it would have been beneficial to perform this analysis as well.

O'Connell et al. determined that the use of PT does not provide significant benefits compared to current guidelines.¹⁸ Key findings from this study include the infection rate for PT is significantly higher than the infection rate for the control group.¹⁸ This finding is contradictory to the other studies evaluated, however, upon multivariable analysis, they found that antibiotic choice did not predict infection.¹⁸ An important limitation of this study is that it was performed over the course of 10 years, which could have led to variability in the care received by patients. Additionally, this study did not assess AKI.

PT treatment compared to other antibiotic protocols has been studied before. Shawar et al. compared PT to tobramycin-based anaphylaxis for type III fractures and found no difference in nephrotoxicity rates with a lower infection rate in the PT group.²⁵ This study supports our findings that PT may be a good alternative treatment for open fractures. D'Angelica et al. compared the prophylactic use of PT to current guidelines in pancreatoduodenectomy procedures and discovered that it decreases infection rates, which further highlights the benefits that PT may provide.²⁶ Despite current guidelines, a systematic survey done by Chang et al. found that physician recommendations greatly vary in the treatment of open fractures.^1,27,28 The majority of physicians recommend only gram-positive coverage for type I and type II fractures but vary greatly in their specific recommendations that extend beyond current protocols.^1,27,28 Some physicians even recommended broad-coverage antibiotics that include carbapenems, third-generation cephalosporins, and others.^1,27,28 For type III fractures, most physicians recommended broad coverage, but once again varied in specific recommendations.^{1, 27, 28}This highlights the variability in current recommendations and supports the need for further research into proper antibiotic care for open fractures.

Although there is support for PT as an effective therapy for open fractures, it may not be warranted. Via et al. investigated the use of cefotetan as a monotherapy for open fractures and concluded that it may provide superior antibiotic stewardship as compared to current protocols.²⁹ A systematic review done by Suzuki et al. found that there was no difference in infection rates when comparing broad-spectrum versus narrow-spectrum antibiotics in type III open fractures.³⁰ This finding is important to note for future open fracture research to determine if there may be a safer narrow-spectrum alternative to the current guidelines.

Overall, this systematic review shows that PT may be a non-inferior alternative to current antibiotic guidelines in the treatment of open fractures. Physicians may consider using PT due to its better safety profile and single-dose administration method. Despite this, further prospective studies must compare the side effect outcomes between PT and the control group given the low numbers in the literature and the findings of this study should be interpreted with this caution.

This study is not without limitations. First, the overall number of studies included (4) is relatively low and as such, a meta-analysis could not be conducted. Second, this review only includes retrospective cohort studies. Retrospective studies have the potential for a greater number of confounding variables and bias compared with prospective studies. This requires readers to evaluate our conclusions with caution. Third, analysis on time to antibiotic administration was not able to be performed due to one study not providing a standard deviation. To reach stronger conclusions, future prospective studies are needed to further analyze PT as an alternative treatment to current guidelines for open fracture care. We also recommend that more studies provide subgroup analyses for fracture type in their comparison of PT to current guidelines. Additionally, we recommend that future studies provide subgroup analyses on control treatments rather than grouping a cephalosporin or a cephalosporin plus an aminoglycoside together. Finally, no studies evaluated type I fractures, therefore, future studies will be needed to evaluate the use of PT for their treatment.

5 Conclusion

The present systematic review determined that there may be no difference in SSI, AKI, return to operating room, 1-year mortality, non-union, and development of resistant pathogens. LOS was significantly longer in the PT group but may be explained by a greater ISS. PT may be a non-inferior alternative to current guidelines due to its better safety profile and single-dose administration method. However, this review is limited by the lack of side effect reporting and underscores the need for larger prospective studies that compare side effect profiles between PT and control groups.

CRediT authorship contribution statement

Eric Kholodovsky: Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Dylan Luxenburg: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. William Marmor: Conceptualization, Project administration, Validation, Visualization, Writing – original draft, Writing – review & editing. Ashleigh Gibula: Visualization, Writing – original draft, Writing – review & editing. Giselle Hernandez: Supervision, Writing – review & editing.

Guardian/patient's consent

Patient consent was not relevant to this study.

Ethics statement

Ethical approval was not relevant for this study

Funding statement

The authors did not receive funding for this project.