Original Article Prophylactic use of gentamicin ... use of gentamicin/flucloxacillin versus...

Int J Clin Exp Med 2015;8(10):17856-17867www.ijcem.com /ISSN:1940-5901/IJCEM0012428

Original ArticleProphylactic use of gentamicin/flucloxacillin versus cefuroxime in surgery: a meta analysis of clinical studies

Shaoning Luo1, Yu Lai2, Chunxin Liu1, Yi Chen3, Xiaoyu Qiao1

1Emergency Department, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe District, Guangzhou 510000, China; 2Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-Sen University, Tianhe District, Guangzhou 510000, China; 3Department of Breast Surgery, Sun Yat-Sen Menorial Hospital, Sun Yat-Sen University, Tianhe District, Guangzhou 510000, China

Received July 5, 2015; Accepted September 5, 2015; Epub October 15, 2015; Published October 30, 2015

Abstract: Purpose: To conduct meta-analyses of all available studies comparing efficacies of prophylactic cefurox-ime and prophylactic gentamicin/flucloxacillin (Gen/Flu) in preventing post-operative wound infections and their association with risks of Clostridium difficile infections and post-operative renal impairment. Methods: Published studies including both prophylactic cefuroxime and prophylactic Gen/Flu used in surgery were included for meta analysis. Outcomes were analyzed using a random-effect model or a fixed-effect model depending on the heteroge-neity across the included studies. Results: Gen/Flu prophylaxis showed similar efficacy as cefuroxime prophylaxis in preventing post-operative wound infections and was associated with a significantly lower risk of Clostridium dif-ficile infection, but it was associated with a higher risk of post-operative renal impairment, especially in orthopedic surgery. Conclusions: Our findings that Gen/Flu prophylaxis was associated with significantly higher risk of post-operative renal impairment dictate that benefits and risks of Gen/Flu prophylaxis should be carefully assessed and balanced, and each patient should be evaluated individually so that a proper antibiotic prophylaxis regimen could be chosen.

Keywords: Cefuroxime, gentamicin, flucloxacillin, prophylaxis, surgery, infection, meta-analysis

Introduction

Prophylactic antibiotics have been shown to reduce the incidence of post-operative wound infection and are routinely administered to patients undergoing surgery. [1, 2]. Cepha- losporin antibiotics such as cefuroxime have often been used because of their broad spec-trum [3]. however, their use has been associat-ed with increased risk of Clostridium difficile infection [4]. As a result, in order to reduce rates of Clostridium difficile infection, prophy-lactic gentamicin in combination with flucloxa-cillin has recently been widely used to replace prophylactic cefuroxime [2, 3, 5-8]. Gentamicin was chosen because it has good antibiotic activity against gram-negative bacteria and is also potent against Staphylococcus aureus, especially in combination with a beta-lactam antibiotic such as flucloxacillin [9]. Therefore,

gentamicin in combination with flucloxacillin was considered proper prophylactic antibiotic regimen and is currently used by many surgical teams around the world.

Despite the advantage of the broad spectrum of antibacterial coverage provided by the com-bination of gentamicin and flucloxacillin, there are concerns about the risk of renal impairment associated with their use as prophylactic antibi-otics because both gentamicin and flucloxacil-lin are known to be nephrotoxic in some patients [10, 11]. Coincidentally, there are reports of a probable increase in the incidence of acute kid-ney injury (AKI) after arthroplasty and of neph-rotoxicity associated with gentamicin and dicloxacillin in 163 patients with intertrochan-teric hip fracture [12, 13]. It remains inconsis-tent whether prophylactic gentamicin and flu-cloxacillin is associated with an increased risk

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Prophylactic use of gen/flu vs. cefuroxime in surgery

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of renal impairment compared to prophylactic cefuroxime [2, 3, 5, 6, 8].

There has been no meta-analysis comparing the efficacies of prophylactic cefuroxime and prophylactic gentamicin and flucloxacillin (Gen/Flu) in preventing post-operative wound infec-tions, and their association with risk of Clostridium difficile infection and renal impair-ment. The main aim of the current study was to perform meta-analyses of all available studies comparing the efficacies of prophylactic cefu-roxime and prophylactic Gen/Flu in preventing post-operative wound infections and their asso-ciation with the risks of Clostridium difficile infections and post-operative renal impairment in order to assess the relative advantages and disadvantages of prophylactic Gen/Flu when compared with prophylactic cefuroxime, such assessment could potentially help surgeons choose a proper prophylactic antibiotic regi-men based on different patients’ needs.

Materials and methods

Search strategy

All published studies including both gentamicin in combination with flucloxacillin and cefurox-ime were identified by searching PubMed (Medline), Google Scholar and Web of Science databases (Web of Knowledge, Wok) up to November 2013 using the search keywords: “cefuroxime”, “gentamicin”, “flucloxacillin”, “An- aptivan”, “Biociclin”, “Biofurex”, “Cefurin”, “Du- xima”, “Novocef”, “Zinacef”, “Alcomicin”, “Brista- gen”, “Cidomycin”, “Duragentam”, “Garamycin”, “Garasol”, “Genoptic”, “Gentacidin”, “Gentacin”, “Gentaglyde”, “Gentalyn”, “Gentamicin C Com- plex Citrate”, “Gentibioptal”, “Genticin”, “Gen- tocin”, “Gentogram”, “Gent-Ophtal” and “Geta- lline”.

Inclusion and exclusion criteria

Published studies (criterion 1) reporting effica-cies of prophylactic cefuroxime and prophylac-tic Gen/Flu in preventing post-operative wound infections, or their associations with the risks of Clostridium difficile infection or renal impair-ment (criterion 2) on all ethnic groups were all considered eligible for inclusion in the meta-analyses. Reviews and meeting abstracts were excluded.

Two of the participating authors (JZ and JF) selected studies for possible inclusion in the

current meta-analyses independently by reviewing titles and abstracts identified from the search independently followed by examin-ing independently the full text of all studies con-sidered to be possibly relevant. Any disagree-ment regarding whether a particular study should be included was resolved by discussion participated by all authors followed by a con-sensus reached by all.

Data extraction

Two authors (JF and XL) extracted data inde-pendently and any disagreement between the two authors were resolved by discussion. The following information was extracted: author(s), year of publication, methodology details such as sample size for both prophylactic cefuroxime and prophylactic Gen/Flu, diagnostic tools for renal impairment and Clostridium difficile infec-tions whenever the information was available, types of post-operative wound infections, and sample characteristics including gender ratio, mean age and the numbers of patients having and not having post-operative wound infec-tions, Clostridium difficile infections, and/or post-operative renal impairment in both groups whenever the information was available.

Quality of studies

Quality of each studies included in the current meta-analyses was assessed by two methods. First, we evaluated the adequacy of each study in three key areas: methodological, clinical and statistical; we then screened each study with the Newcastle-Ottawa Scale [14].

Statistical analysis

The efficacies of prophylactic cefuroxime and prophylactic Gen/Flu in preventing post-opera-tive wound infections, and their associations with the risk of Clostridium difficile infection and post-operative renal impairment were com-pared by calculating their respective Odds Ratios (ORs) and their corresponding 95% con-fidence intervals (95% CIs) as the effect size measurement for the analyses. The ORs with their corresponding 95% CIs were calculated with the Cochrane Review Manager (RevMan, version 5.2). Because heterogeneity among the studies was expected, pooled ORs with their corresponding 95% CIs were calculated first using a random-effect model that assumes a genuine diversity in the results of the included


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studies and therefore incorporates a between-studies variance into the calculation [15]. Z test was used to assess the statistical significance of the pooled ORs, further, between-studies heterogeneity was assessed using chi-square (x2) test based on Cochran Q statistic [16]. I2 index was used to quantify the between-stud-ies heterogeneity, wherein a I2 value around 25%, 50% or 75% indicated low, moderate or large heterogeneity, respectively [17]. When there was no between-studies heterogeneity, data was analyzed using a fixed-effect model. A P value <0.05 was considered to be statistically significant except for the Q statistics wherein a P<0.10 was considered to be statistically significant.

Sub-population analyses were performed for orthopedic surgery on efficacies of prophylactic cefuroxime and prophylactic Gen/Flu in pre-venting post-operative wound infections, and their associations with the risk of Clostridium difficile infection and post-operative renal impairment. Sensitivity analysis examining the effect of excluding a particular study was also performed which used a stepwise process, wherein a single study included in the meta-analysis was excluded each time to assess its influence on the pooled OR. Funnel plots were used to assess publication bias in the meta-analyses.

were included in the current meta-analyses and their data were extracted, [2, 3, 5-8] among them, 4 were included in the meta-analysis of prophylactic antibiotic regimens and post-oper-ative wound infections, [2, 3, 5, 7] were includ-ed in the meta-analysis of prophylactic antibi-otic regimens and Clostridium difficile infec-tions, [2, 3, 5, 7, 8] and 5 were included in the meta-analysis of prophylactic antibiotic regi-mens and post-operative renal impairment [2, 3, 5, 6, 8]. All eligible studies were of adequa- tely high quality.

The characteristics of the 6 studies included in the meta-analyses were described in Tables 1-4, including name of the first author, year of publication, sample sizes in each group (pro-phylactic cefuroxime and prophylactic Gen/Flu), gender ratio, mean age, numbers of sub-jects developing or not developing post-opera-tive wound infections in each group (for the 4 studies included in the meta-analysis of pro-phylactic antibiotic regimens and post-opera-tive wound infections), numbers of subjects developing or not developing Clostridium diffi-cile infection in each group (for the 5 studies included in the meta-analysis of prophylactic antibiotic regimens and Clostridium difficile infection); and number of subjects developing or not developing post-operative renal impair-ment in each group (for the 5 studies included

Figure 1. Flow diagram of the publication selection process.

Results

Eligible studies and study characteristics

Figure 1 described the search process flow and results. From a total of 15 potentially eligible studies, 9 were excluded because they were not relevant to the study questions, [18-24] or review [25]. From the 7 studies eligible for inclusion, 1 was exclud-ed because no detailed numbers of patients having or not having post-operative wound infection, Clostridium difficile infec-tions, or post-operative renal impairment were given [26]. A total of 6 studies


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Table 1. Characteristics of studies included in the meta-analyses

First authorSubjects receiving prophylactic cefuroxime Subjects receiving prophylactic gentamicin and flucloxacillin

Total sample (N) Male/Female Mean age Subjects Total sample (N) Male/Female Mean age Subjects

Al-Obaydi 2010 [7]

625 (231 in trauma group; and 394 in elective group)

196/429 (55/176 for trauma group; 141/253 for elective group)

83 for trauma group; and 70 for elective group

Subjects (trauma or elective hip or knee arthroplasty group)

706 (216 for trauma group; 490 for elective group)

258/448 (68/148 for trauma group; 190/300 for elective group)

82 for trauma group; 70 for elective group

Subjects (trauma or elective hip or knee arthroplasty group)

Challagundla 2012 [5]

100 36/64 70.4 Subjects undergoing elective hip or knee replacement surgery

98 (52 in high-dose group; 46 in low dose group)

45/53 (22/30 for high-dose flucloxacillin with gentamicin [HD] group; 23/23 for low-dose flucloxacillin with gentamicin group)

70.5 Subjects undergoing elective hip or knee surgery

Craxford 2013 [3]

200 (100 total hip replace-ment [THR] and 100 total knee replacement [TKR])

- 68.3 Subject undergoing THR or TKR

200 (100 THR and 100 TKR)

- 68.2 Subject undergoing THR or TKR

Ross 2013 [6]

124 (74 for THR; 50 for TKR) 55/69 72.3 Subject undergoing THR or TKR

149 (98 for THR, 51 for TKR)

63/86 72.5 Subject undergoing THR or TKR

Vooght 2013 [8]

202 - - Subject undergoing elective or trauma hip and knee surgery

210 - - Subject undergoing elective or trauma hip and knee surgery

White 2013 [2]

1725 1275/450 64.3 Subject undergoing cardiac surgery

1695 1278/417 64.8 Subject undergoing cardiac surgery

Table 2. Studies included in the meta-analysis of prophylactic antibiotic regimens and post-operative wound infections

First author

Subjects receiving prophylactic cefuroxime Subjects receiving prophylactic gentamicin and flucloxacillin

P value Type(s) of post-operative wound infections

Number of Subjects developing post-oper-ative wound infections (N)

Number of subjects not developing post-operative wound infections (N)

Total Number (N)

Number of Subjects developing post-oper-ative wound infections (N)

Number of subjects not developing post-operative wound infections (N)

Total Num-ber (N)

Al-Obaydi 2010 [7]



625 (231 in trauma group; and 394 in elective group

16 (8 for trauma groups; and 8 for elective group)



0.46 for trauma group; 0.90 for elective group

early deep wound infections


10 (all superficial wound infection)

90 100 5 (3 in the high-dose group; 2 in the low-dose group) (all superficial wound infection)

93 (49 in high-dose group; 44 in low-dose group).


- Bacteriologically positive superficial wound infection; or deep infection either during admission or in the first 6 months after surgery

Craxford 2013 [3]

3 (2 SSI and 1 RTT) 197 200 (100 THR and 100 TKR)

4 (3 SSI and 1 RTT) 196 200 (100 THR and 100 TKR)

1 (1 for SSI and 1 for RTT)

Surgical site infection (SSI); Return to theatre for infection (RTT)

White 2013 [2]

56 1669 1725 46 1649 1695 0.36 SSI diagnosed according to a proforma based on ASEPSIS5 and clinical assessment


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Table 3. Studies included in the meta-analysis of prophylactic antibiotic regimens and Clostridium difficile infection

First author

Subjects receiving prophylactic cefuroxime Subjects receiving prophylactic gentamicin and flucloxacil-lin

P value Diagnostic tool of Clostridium difficile infection

Number of subjects having Clostridium difficile infection (N)

Number of subjects not having Clostridium difficile infection (N)

Total Number (N)

Number of Subjects having Clostridium difficile infection (N)

Number of subjects not having Clostridium difficile infection (N)

Total Number (N)

Al-Obaydi 2010 [2]


602 (212 for trauma group; 390 for elec-tive group)

625 (231 in trauma group; and 394 in elective group




0.004 (0.02 for trauma group; 0.27 for elective group)

Examination of diarrhoeal faecal specimens


0 100 100 0 98 (52 in high-dose group; 46 in low dose group)


- Clostridium difficile associated diahhroea (CDAD)

Craxford 2013 [3]

0 200 (100 THR and 100 TKR)

200 (100 THR and 100 TKR)

0 200 (100 THR and 100 TKR)

200 (100 THR and 100 TKR)

1 CDAD diagnosed where a patient had documented diarrhoea and a stool sample positive for C. difficile toxin

Vooght 2013 [8]

3 (all with hip fracture) 199 202 (80 hip fracture)

0 210 210 0.04 -

White 2013 [2] 9 1716 1725 1 1694 1695 0.021 -

Table 4. Studies included in the meta-analysis of prophylactic antibiotic regimens and post-operative renal impairment

First author

Subjects receiving prophylactic cefuroxime Subjects receiving prophylactic gentamicin and flucloxacillin

P value Diagnostic tool of renal impairment Number of Subjects developing renal impairment (N)

Number of subjects not developing renal impairment (N)

Total Number (N)

Number of Subjects developing renal impairment (N)

Number of subjects not developing renal impairment (N)

Total Number (N)


11 developed any form of AKI by RIFLE criteria

89 100 37 (27 in the high-dose group; 10 in the lose-dose group) developed any form of AKI by RIFLE criteria

61 (25 in the high-dose group; 36 in the low-dose group)


- Acute kidney injury (AKI) classified according to the risk, injury, failure, loss of function and end stage renal disease (RIFLE criteria) [33]

Craxford 2013 [3]

Total AKI: 2 (2 for THR; 0 for TKR)

198 (98 for THR; 100 for TKR)

200 (100 THR and 100 TKR)

Total AKI: 16 (5 for THR; 11 for TKR)

184 (95 THR; 89 TKR)

200 (100 THR and 100 TKR)

<0.01 (0.44 THR; <0.01 TKR)

AKI was defined by a 50 % increase in serum creatinine over baseline and graded as per the RIFLE classification [34]

Ross 2013 [6]

2 122 124 (74 for THR; 50 for TKR)

9 140 149 (98 for THR, 51 for TKR)

0.058 Each patient was also categorised RIFLE clas-sification

Vooght 2013 [8]

10 192 202 23 187 210 0.012 AK classified by severity (AKI Network Criteria)

White 3013 [2]

90 1635 1725 73 1622 1695 0.24 new or worsening renal impairment (defined in the surgical database as creatinine >200 mmol/L (2.26 mg/dL) or requirement for renal replacement therapy)


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in the meta-analysis of prophylactic antibiotic regimens and incidence of post-operative renal impairment). The pooled population was 2,650 subjects receiving prophylactic cefuroxime and 2,699 subjects receiving prophylactic Gen/Flu for the meta-analysis of prophylactic antibiotic regimens and post-operative wound infections; 2,852 subjects receiving prophylactic cefurox-ime and 2,909 subjects receiving prophylactic Gen/Flu the meta-analysis of prophylactic anti-biotic regimens and Clostridium difficile infec-tion; and 2,351 subjects receiving prophylactic cefuroxime and 2,352 subject receiving pro-phylactic Gen/Flu the meta-analysis of prophy-lactic antibiotic regimens and post-operative renal impairment.

Meta-analysis comparing efficacies of prophy-lactic Gen/Flu and prophylactic cefuroxime in preventing post-operative wound infections

A meta-analysis comparing efficacies of pro-phylactic Gen/Flu and prophylactic Cefuroxime in preventing post-operative wound infections was first performed using a random-effect

model and it did not reveal a significant differ-ence between the two regimens (OR=0.87; 95% CI= [0.63, 1.20]; P=0.39; I2=0). Sub-population analysis for Orthopedic surgery including 3 of the 4 studies [3, 5, 7] yielded similar result (OR=0.95; 95% CI= [0.53, 1.69]; P=0.85; I2=0). Because there was no between-studies heterogeneity, a fixed-effect model was then used to perform the meta-analysis and it yielded similar result (OR=0.86; 95% CI= [0.63, 1.20]; P=0.38; I2=0) (Figure 2A). Sub-population analysis for Orthopedic surgery including 3 of the 4 studies [3, 5, 7] using a fixed-effect model also produced similar result (OR=0.94; 95% CI= [0.53, 1.65]; P=0.82; I2=0) (Figure 2A). The results demonstrated that No significant difference in efficacies between the two prophylactic antibiotic regimens.

Sensitivity analysis, between-studies heteroge-neity and publication bias

No study altered the results when removed individually from the meta-analysis during the

Figure 2. A. Forest plot of comparison of efficacies of gentamicin/flucloxacillin (Gen/Flu) prophylaxis and cefuroxime prophylaxis in preventing post-operative wound infections: overall effect for dichotomous outcome (fixed-effect model). The diamond stood for pooled effect. No significant difference between the efficacies of Gen/Flu prophylaxis and cefurox-ime prophylaxis in preventing post-operative wound infections. B. Funnel plot of studies included in the meta-analysis of efficacies of Gen/Flu prophylaxis and cefuroxime prophylaxis in preventing post-operative wound infections. The symmetrical funnel suggested little or no publication bias in the analysis.


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sensitivity analysis with overall P value remain-ing insignificant (data not shown). There was no between-studies heterogeneity (Figure 2A).Further, the funnel plot used to assess publica-tion bias is symmetrical, indicating presence of very little or none publication bias in the meta-analysis (Figure 2B).

Meta-analysis comparing associations of pro-phylactic Gen/Flu and prophylactic cefuroxime with post-operative clostridium difficile infec-tion

A meta-analysis comparing the associations of prophylactic Gen/Flu and prophylactic cefurox-ime with Clostridium difficile infection was first

performed using a random-effect model, and it revealed that compared with prophylactic cefu-roxime, prophylactic Gen/Flu was associated with significant lower risk of Clostridium difficile infection (OR=0.28; 95% CI= [0.14, 0.57]; P=0.0005; I2=0). Sub-population analysis for Orthopedic surgery yielded similar result (OR=0.32; 95% CI= [0.15, 0.68]; P=0.003; I2=0). Because there was no between-studies heterogeneity, a fixed-effect model was then used to perform the meta-analysis and it pro-duced similar result (OR=0.26; 95% CI= [0.13, 0.53]; P=0.0002; I2=0) (Figure 3A). Sub-population analysis for Orthopedic surgery using a fixed-effect model also produced simi-lar result (OR=0.31; 95% CI= [0.15, 0.66];

Figure 3. A. Forest plot of comparison of associa-tions of Gen/Flu prophylaxis and cefuroxime pro-phylaxis with post-operative Clostridium difficile infection: overall effect for dichotomous outcome (fixed-effect model). The diamond stood for pooled effect. Gen/Flu prophylaxis was associated with significantly lower risk of post-operative Clostridium difficile infection. B. Funnel plot of studies included in the meta-analysis of associations of Gen/Flu pro-phylaxis and cefuroxime prophylaxis with post-oper-ative Clostridium difficile infection. The symmetrical funnel suggested little or no publication bias in the analysis.


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P=0.002; I2=0) (Figure 3A). These results sug-gested that prophylactic Gen/Flu was associ-ated with significantly lower risk of Post-Operative Clostridium difficile Infection.


Only one study [7] altered the results for sub-population analysis for Orthopedic surgery when removed individually from the meta-anal-ysis during the sensitivity analysis (OR=0.14; 95% CI= [0.01, 2.64]; P=0.19]. The remaining studies did not alter the result of the analysis when removed individually from the meta-anal-ysis with overall P value remaining significant (data not shown). There was no between-stud-ies heterogeneity (Figure 3A). Further, the fun-nel plot used to assess publication bias is sym-

metrical, indicating presence of very little or none publication bias in the meta-analysis (Figure 3B).

Meta-analysis comparing associations of pro-phylactic gen/flu and prophylactic cefuroxime with post-operative renal impairment

A meta-analysis comparing associations of pro-phylactic Gen/Flu and prophylactic cefuroxime with post-operative renal impairment was per-formed using a random-effect model, and it revealed that compared with prophylactic cefu-roxime, prophylactic Gen/Flu was associated with significant higher risk of post-operative renal impairments (OR=2.85; 95% CI= [1.06, 7.70]; P=0.04; I2=87) (Figure 4A). Sub-population analysis for Orthopedic surgery including 4 of the 5 studies [3, 5, 6, 8] yielded

Figure 4. A. Forest plot of comparison of associations of Gen/Flu prophylaxis and cefuroxime prophylaxis with post-operative renal impairment: overall effect for dichotomous outcome (random-effect model). The diamond stood for pooled effect. Gen/Flu prophylaxis was associated with significantly higher risk of renal impairment. B. Funnel plot of studies included in the meta-analysis of associations of Gen/Flu prophylaxis and cefuroxime prophylaxis with renal impairment. The symmetrical funnel suggested little or no publica-tion bias in the analysis.


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similar result (OR=3.85; 95% CI= [2.35, 6.30]; P<0.00001; I2=4). (Figure 4A). Therefore, we concluded that prophylactic Gen/Flu was asso-ciated with significantly higher risk of post-operative renal impairment.


4 of the 5 included studies [3, 5, 6, 8] altered the results for the overall analysis when removed individually from the meta-analysis during the sensitivity analysis (OR=2.29; 95% CI= [0.82, 6.39]; P=0.11; I2=88) with [3] removed, (OR=2.40; 95% CI= [0.84, 6.86]; P=0.10; I2=83] with [5] removed, (OR=2.70; 95% CI= [0.89, 8.17]; P=0.08; I2=90) with [6] removed, and (OR=3.11; 95% CI= [0.84, 11.59]; P=0.09; I2=90) with [8] removed. The remain-ing study [2] did not alter the result of the analy-sis when removed from the analysis with overall P value remaining significant (data not shown). There was high degree of between-studies het-erogeneity for the overall analysis with I2=87 and low degree of between-studies heteroge-neity for the sub-population analysis for Orthopedic surgery with I2=4 (Figure 4A). Further, the funnel plot used to assess publica-tion bias is symmetrical, indicating presence of very little or none publication bias in the meta-analysis (Figure 4B).

Discussion

In this first meta-analysis in literature, we ana-lyzed and compared the efficacy of cefuroxime prophylaxis and gentamicin/flucloxacillin pro-phylaxis in preventing post-operative wound infections and their associations with post-operative Clostridium difficile infection and renal impairment. Our meta-analyses revealed that although prophylactic Gen/Flu was associ-ated with a significantly lower risk of Clostridium difficile infection compared with prophylactic cefuroxime, it was associated with a significant-ly higher risk of post-operative renal impair-ment than prophylactic cefuroxime, further there was no significant difference in their effi-cacy in preventing post-operative wound infection.

Surgical teams around the world moved away from cefuroxime prophylaxis and chose genta-micin/flucloxacillin prophylaxis due to reports of association of cefuroxime prophylaxis with

Clostridium difficile infection [2, 3, 5-8] and our meta-analysis confirmed that prophylactic Gen/Flu did significantly reduce the risk of post-operative Clostridium difficile infection, since Clostridium difficile infections such as Clostridium difficile associated diarrhea (CDAD) confers mortality, especially in frail elderly peo-ple wherein CDAD confers a mortality of up to 25%, [27] by reducing the risk of Clostridium difficile infection while having similar efficacy in preventing post-operative wound infections, Gen/Flu prophylaxis does have obvious advan-tages over cefuroxime prophylaxis.

On the other hand, the advantage of Gen/Flu prophylaxis comes with a cost, our meta-analy-sis showed that Gen/Flu prophylaxis was asso-ciated with significantly increased risk of renal impairment such as AKI, since AKI is associat-ed with increased morbidity and mortality, [9] said cost needs careful consideration. Flucloxacillin-related renal impairment is not common, there are only a couple of case reports that linked flucloxacillin specifically to acute interstitial nephritis [28-30]. Gentamicin is more often associated with acute tubular necrosis [31]. Challagundla et al. reported that renal impairment induced by Gen/Flu prophy-laxis implicated flucloxacillin because 6 our of the 7 patients with AKI RIFLE Class F were tak-ing high-dose flucloxacillin and also because when the dose of flucloxacillin is reduced by half, the incidence of AKI dropped significantly [5].

Further the sub-population analysis for renal impairment associated with Gen/Flu prophy-laxis and cefuroxime prophylaxis showed that the increased risk of renal impairment associ-ated with Gen/Flu prophylaxis only happened in Orthopedic surgery, while in cardiac surgery, there was no significant difference between the two prophylactic regimens (OR=0.82; 95%= [0.60, 1.12]; P=0.21) (Figure 4A), this, coupled with the fact that Gen/Flu prophylaxis in cardi-ac surgery had similar efficacy in preventing post-operative wound infections (OR=0.83; 95% CI= [0.56, 1.24]; P=0.36) (Figure 2A) and was associated with significantly lower risk of Clostridium difficile infection (OR=0.11; 95% CI= [0.01, 0.89]; P=0.04) (Figure 3A), suggest-ed that Gen/Flu prophylaxis was clearly prefer-able over cefuroxime prophylaxis in cardiac sur-gery, however, since there is only one relevant study comparing cefuroxime prophylaxis and


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Gen/Flu prophylaxis in cardiac surgery and it is a retrospective study, [2] it is clear that more studies are needed to confirm this finding.

In addition, one of the included studies, Craxford et al. [3] showed that when the sub-jects were further divided into separate groups for total hip replacement (THR) and total knee replacement (TKR), the significantly higher risk of renal impairment associated with Gen/Flu prophylaxis remained the same in TKR (P<0.01) while in THR, there was no significant differ-ence between the two regimens (P=0.44) and they hypothesized that ischaemic metabolites production from the used of a pneumatic tour-niquet in the TKR group in combination with gentamicin might induce AKI in some patients. Obviously, more studies are needed to confirm this finding.

Our meta-analyses could provide some guid-ance for surgeon in choosing a proper prophy-lactic regimen. Since our meta-analyses showed that compared with cefuroxime prophy-laxis, although Gen/Flu had the advantage of lowering the risk of Clostridium difficile infec-tion while at the same time having similar effi-cacy in preventing post-operative wound infec-tions, it was associated with significantly increased risk of renal impairment especially when it is used in orthopedic surgery, therefore its use must be carefully considered and its dosage should also be carefully determined so that the risk of renal impairment is minimized without compromising its ability to prevent post-operative wound infections. Further, based on the findings of Craxford et al., [3] it is possible that Gen/Flu prophylaxis is more suit-able for THR than TKR. In addition, White et al. suggests that Gen/Flu prophylaxis is clearly preferable than cefuroxime prophylaxis in car-diac surgery since there was no significant dif-ference between their association with risk of renal impairment [2]. Finally, as part of the effort to choose a proper prophylactic antibiotic regimen for a particular patient, patients at high risk of developing significant renal impair-ment should be identified by identifying factors such as high body mass index, hypertension, chronic obstructive pulmonary disease and congestive cardiac failure prior to admission [6, 32] and Gen/Flu prophylaxis should not be used on these patients.

Our meta-analyses have some limitation. First, the number of available relevant studies eligi-

ble for inclusion into the meta-analyses is rela-tively low. Secondly, all of the included studies are retrospective studies rather than prospec-tive, randomized controlled trials, therefore we can not completely exclude risk of bias and seasonal effect. Since the shift from cefurox-ime prophylaxis to Gen/Flu prophylaxis is fairly recent, we expect there will be more relevant prospective, randomized controlled studies in the future, this will help confirm our findings. Further our meta-analysis on associations of the prophylactic regimens with renal impair-ment only included post-operative, immediate renal impairment, but did not assess long-term outcome, therefore, it is unclear whether the renal impairment associated with Gen/Flu pro-phylaxis could be reversed over time, this is an important point in considering which antibiotic prophylaxis regimen to choose, more long-term studies are needed to elucidate this point.

In conclusion, our meta-analyses showed that compared with cefuroxime prophylaxis, although Gen/Flu prophylaxis had similar efficacy in preventing post-operative wound infections and was associated with significantly lower risk of Clostridium difficile infection, it had the dis-advantage of being associated with significant-ly higher risk of post-operative renal impair-ment especially in orthopedic surgery, there-fore its benefits and risk should be carefully assessed and each patient should be evaluat-ed individually so that a proper antibiotic pro-phylaxis regimen could be chosen. Further, more relevant prospective, randomized con-trolled trial studies are needed to confirm our findings.

Disclosure of conflict of interest

None.

Address correspondence to: Dr. Xiaoyu Qiao, Emergency Department, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Tianhe District, Guangzhou 510000, China. Tel: 86-20-85253010; E-mail: [email protected]

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