Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures

  • Review
  • Intervention

Authors


Abstract

Background

Wound infection and other hospital-acquired infections cause significant morbidity after internal fixation of fractures (osteosynthesis). The administration of antimicrobial agents (antibiotics) may reduce the frequency of infections.

Objectives

To determine whether the prophylactic administration of antibiotics in patients undergoing surgical management of hip or other long bone fractures reduces the incidence of wound and other hospital acquired infections.

Search strategy

We searched the The Cochrane Library, Issue 3 2000; MEDLINE, EMBASE, LILACS, Current Contents, Dissertation Abstracts, and Index to UK Theses to August 2000. Bibliographies of identified articles were screened for further relevant trials. No language restriction was applied.

Selection criteria

Randomised or quasi-randomised controlled trials involving -
Participants: Any patients with a hip or other closed long bone fracture undergoing surgery for internal fixation or replacement arthroplasty.
Interventions: Any regimen of systemic antibiotic prophylaxis administered at the time of surgery.
Outcome measures: Wound infection (deep and superficial), urinary tract infection, respiratory tract infection, adverse effects of prophylaxis, economic evaluations.

Data collection and analysis

Two reviewers independently screened papers for inclusion, assessed trial quality using an eight item scale, and extracted data. Additional information was sought from two trialists. Pooled data are presented graphically.

Main results

Data from 8307 participants in 22 studies were analysed. In patients undergoing surgery for closed fracture fixation, single dose antibiotic prophylaxis significantly reduced deep wound infection (risk ratio 0.40, 95% CI 0.24 to 0.67) superficial wound infections, urinary infections, and respiratory tract infections. Multiple dose prophylaxis had an effect of similar size on deep wound infection (risk ratio 0.40, 95% CI 0.24 to 0.67), but significant effects on urinary and respiratory infections were not confirmed. Economic modelling using data from one large trial indicates that single dose prophylaxis with ceftriaxone is a cost-effective intervention. There are limited data for the incidence of adverse effects, but as expected they appear to be more common in those receiving antibiotics, compared with placebo or no prophylaxis.

Authors' conclusions

Antibiotic prophylaxis should be offered to those undergoing surgery for closed fracture fixation.
On ethical grounds, further placebo controlled randomised trials of the effectiveness of antibiotic prophylaxis in closed fracture surgery are unlikely to be justified. Trials addressing the cost-effectiveness of different effective antibiotic regimens would need to be very large.

Plain language summary

Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures

Wound infection and other hospital acquired infections can be life threatening in people following surgery for thigh and other long bone fractures. Antibiotics have been given routinely since the 1970s in an effort to reduce infections from bacteria such as staphylococcus. The review of trials found that antibiotics are effective in reducing the incidence of infection, both at the wound site and in the chest and urine. The effect of a single dose is similar to those from multi-doses if the antibiotic chosen is active through the period from the beginning to the end of surgery.

Background

The principles of prophylaxis against post-surgical infection were established in the laboratory in the early 1960s (Burke 1961). The administration of antibiotic prior to surgery is now widely accepted. The period of administration of prophylaxis has been reduced but the optimal duration remains uncertain. Antibiotic prophylaxis during the operative management of closed fractures has been claimed to reduce infection rates from around five per cent to less than one per cent (Bodoky 1993). As the pathogenesis of post-surgical infection is similar after osteosynthesis of any closed fracture, it has been suggested that combining data from similar prophylactic regimens used during different surgical procedures is quite appropriate (Platt 1991).

Closed hip fractures in the elderly are common, and surgical management is normal in the developed world. The majority of studies of the efficacy of antibiotic prophylaxis in closed fracture fixation have focused on this group of patients. Early randomised trials completed in the 1970s suggested a small but definite prophylactic effect. These trials were individually small, and some used prolonged courses of antibiotic. Many further trials have been reported over the following 25 years. These have addressed a range of issues: duration of administration, route of administration, and antimicrobial spectrum.

A number of descriptive reviews of antibiotic prophylaxis in orthopaedic surgery have been published (Doyon 1989; Norden 1991), in which some attempt has been made to assess methodological quality and include this in the interpretation of results. However, there is sufficient persisting uncertainty about the efficacy, optimal duration, and cost-effectiveness of antibiotic prophylaxis during the surgical treatment of hip and other long bone fractures to justify a systematic review of the evidence from randomised trials.

Objectives

The objective of this review is to determine whether the prophylactic administration of antibiotics in patients undergoing surgical management of hip or other closed long bone fractures reduces the incidence of wound and other hospital acquired infections.

The following hypotheses are tested:

1. Antibiotic prophylaxis leads to a reduction in the proportion of patients developing a wound infection, either deep or superficial, compared with those given a placebo or no prophylaxis.

2. 'Single dose' antibiotic prophylaxis leads to a significant reduction in the proportion of patients developing a wound infection compared with those given 'longer duration' prophylaxis.

3. There is a significant reduction in the proportion of patients with a post-operative wound infection who receive prophylaxis using broad-spectrum antibiotics when compared with those who receive narrow spectrum agents.

4. Antibiotic prophylaxis leads to a significant reduction in the proportion of patients developing septicaemia, respiratory or urinary tract infection, compared with those given a placebo or no prophylaxis.

5. 'Single dose' antibiotic prophylaxis leads to a significant reduction in the proportion of patients developing septicaemia, respiratory, or urinary tract infection after surgical management of a hip or other long bone fracture compared with those given three or more doses.

6. Oral administration of a prophylactic regimen leads to a significant reduction in the proportion of participants experiencing a wound infection, respiratory or urinary tract infection, or adverse drug effect, compared with those receiving parenteral prophylaxis.

7. There is a significant increase in the proportion of patients with conditions such as gastro-intestinal symptoms or skin reactions in those allocated antibiotic prophylaxis when compared with those receiving placebo or no prophylaxis.

Methods

Criteria for considering studies for this review

Types of studies

The predetermined inclusion criteria were broad so as to include any controlled study testing a prophylactic antibiotic in closed fracture surgery.

1. The study must test some method of antibiotic prophylactic intervention aimed at reducing the wound infection rate in closed fracture surgery and compare it against a placebo or alternative intervention group.

2. The study must be a controlled study, randomised or quasi-randomised.

3. The study population must be defined to enable identification of the operative intervention, ideally with relevant subgroups given if more than one.

4. Wound infection must be one of the primary outcome measures.

Types of participants

Any person undergoing surgery for internal fixation or replacement arthroplasty as treatment for a closed fracture of the proximal femur, or any other long bone.

Types of interventions

Any regimen of systemic antibiotic prophylaxis administered at the time of surgery.

Types of outcome measures

1. Wound infection. The reference definition of wound infection for quality assessment was:
Deep wound infection -
A surgical wound infection which occurs within one year, if an implant is in place and infection involves tissues or spaces at or beneath the fascial layer.
Superficial wound infection -
A surgical wound infection which occurs at the incision site within 30 days after surgery and involves the skin subcutaneous tissue, or muscle located above the fascial layer. In the assessment of methodological quality, more weight was given to studies in which wound infection had been confirmed by microbiological analyses.
2. Urinary tract infection
3. Respiratory tract infection
4. Adverse reaction to antibiotic (gastro-intestinal symptoms, skin reactions)
5. Cost-effectiveness outcomes - length of hospital stay
- reoperation due to infection.

Search methods for identification of studies

Trials were identified by searches up to the end of August 2000.

i. The Cochrane Central Register of Controlled Trials, The Cochrane Library, Issue 3, 2000 was searched.
ii. MEDLINE (1966-October 2000); OVID web (see Appendix 1)
iii. EMBASE (to October 2000), OVID web (see Appendix 1)
iv. LILACS, Current Contents, Dissertation Abstracts, and Index to UK Theses were searched to the end of August 2000.
v. The bibliographies of identified literature reviews, original articles, and relevant chapters of published books were examined for undetected articles.
vi. Contacts were made in person or by mail with identified trialists and other experts in the field.

No language restriction was applied.

Data collection and analysis

Selection of studies

All identified studies were read. We included all randomised or quasi-randomised controlled trials reporting the results of antibiotic prophylaxis in patients undergoing hip or other long bone fracture surgery with wound infection as one of the primary outcome measures. Reports in which participants were not allocated at enrolment in a randomised or quasi-randomised fashion into treatment or control groups were excluded.

Quality Assessment

Methodological assessment was undertaken by two raters, using the criteria described in Appendix 2, supplemented by a pre-designed coding manual. Disagreement was resolved by discussion between raters.

Data extraction

Data were independently extracted by two reviewers and adjudicated by a third using a data extraction tool which had undergone prior testing. We approached two groups of trialists for clarification of data relevant to the review.

Data synthesis

Using Review Manager, for each study, risk ratios and 95 per cent confidence intervals were calculated for dichotomous outcomes. For comparable groups of trials pooled odds ratios with 95 per cent confidence intervals were derived, and where appropriate absolute risk reduction was calculated.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

The search strategy identified 48 trials in which antibiotic prophylaxis had been compared with no treatment, a placebo, or another antibiotic regimen in orthopaedic surgery. Twenty-five of these were excluded either because the participants had sustained an open fracture prior to the administration of antibiotics, because participants had not sustained a fracture, or because no usable data were reported for a fracture fixation subgroup in a wider study. In 23 studies, data were available for patients undergoing closed fracture surgery. We were unable to assess one study (Chiu 1993), which has been reported only in abstract. The remaining 22 studies are described in detail in the 'Characteristics of included studies' table. Some reported more than one comparison.

The comparisons evaluated were:

1. A pre-operative dose and two or more post-operative doses of parenteral (injected) antibiotic compared with a placebo or with no treatment. There were 10 trials in this category, in seven of which the participants underwent hip fracture surgery (Ericson 1973; Boyd 1973; Tengve 1978; Burnett 1980; Hedstrom 1987; Buckley 1990; Bodoky 1993), and in three of which (Bergman 1982; Gatell 1984; Paiement 1994) other closed fracture fixation procedures were carried out.

2. A single preoperative dose of parenteral antibiotic compared with a placebo or no treatment. There were seven trials in this category, in five of which (Buckley 1990; Hjortrup 1990; Luthje 2000; McQueen 1990; Kaukonen 1995) the participants underwent hip fracture surgery, and in two of which a range of closed fracture fixation procedures were carried out (Hughes 1991; Boxma 1996).

3. A single dose of parenteral antibiotic compared with multiple doses of the same agent. There were two trials in this category, in one of which (Buckley 1990) the participants underwent hip fracture surgery, and in the other (Gatell 1987), a range of different closed fracture fixation procedures were carried out.

4. A single dose of parenteral antibiotic using an agent with a long half-life, compared with multiple doses of other agents with shorter half lives. There were three trials in this category, of which one (Garcia 1991) included both participants undergoing hip fracture surgery and others undergoing other closed fracture surgery. In Karachalios 1987 the participants underwent hip fracture surgery, and in Jones 1987 B a range of different closed fracture fixation procedures were carried out.

5. Multiple doses of parenteral antibiotic administered over 24 hours or less, compared with a longer period of administration. Two trials (Nelson 1983; Hedstrom 1987) whose participants underwent hip fracture surgery reported comparisons in this category.
6. Oral administration of antibiotic compared with parenteral administration. There was one trial (Nungu 1995) in this category.

Risk of bias in included studies

The quality of most studies as reported was poor to moderate. The score for each attribute is recorded for each trial in the 'Characteristics of included studies' table. Only four of the 22 published trials were adequately powered to test the research hypothesis with confidence. In seven trials the description of the randomisation process indicated that prior concealment of allocation was satisfactory, in 12 it was unclear, and in three assignment was inadequately concealed. Placebos were used appropriately in 12 trials, and were not employed where their use would have been appropriate in 10 trials. In trials with a short (inadequate) follow up, analysis by intention to treat was usually possible, but in those in which follow up would have been likely to identify late onset post-operative infection, losses were larger. The trialists' reported definitions of outcome measures varied. In most reports, the definition of wound infection was clinical and did not require microbiological confirmation, although it was often sought. Blinding of the outcome assessor was rarely mentioned, although it could be assumed in those studies which were fully placebo controlled.

Effects of interventions

Results in each comparison category are shown in the analyses. We accepted that there was variation between studies in the reported definition of the main outcome measures, but considered that these definitions were clinically sufficiently consistent to permit pooling. Also, although the regimens of antibiotic prophylaxis within each category also varied in respect of the agent and the details of timing, we found that all reported trials employed agents likely to be widely effective at the time of the study against Staphylococcus aureus, the principal organism implicated in post-operative wound infection.

1. A pre-operative dose and two or more post-operative doses of parenteral (injected) antibiotic compared with a placebo or with no treatment.

Data from 1896 participants from 10 trials (11 datasets) were pooled. Regimens in this category significantly reduced the incidence of deep wound infection (risk ratio (RR) 0.36, 95% confidence intervals (CI) 0.21, 0.65), and of superficial wound infection (RR 0.48, 95% CI 0.28 to 0.81), and reduced the incidence of infection of the urinary tract (RR 0.66, 95% CI 0.43 to 1.00). There was no significant reduction in the rate of respiratory infection (RR 0.81, 95% CI 0.41 to 1.63). Adverse effects were rarely reported but appeared more common in participants given antibiotics (RR 1.83, 95% CI 0.96 to 3.50). The absolute risk of deep wound infection in the control patients was 4.3% (0.043), and the risk difference -0.03, (95% CI -0.04 to -0.01).

2. A single preoperative dose of parenteral antibiotic compared with a placebo or no treatment.

Data were pooled from seven trials, including one large multi-centre trial of good quality (Boxma 1996). Regimens in this category reduced the incidence of deep wound infection (RR 0.40, 95% CI 0.24 to 0.67), superficial wound infection (RR 0.69, 95% CI 0.50 to 0.95), urinary tract infection (RR 0.63, 95% CI 0.53 to 0.76), and respiratory infection (RR 0.46, 95% CI 0.33 to 0.65). The absolute risk of deep wound infection in the control patients was 3% (0.03), and the absolute risk reduction -0.02 (95% CI -0.03 to -0.01).

3. A single dose of short-acting parenteral antibiotic compared with multiple doses of the same agent.

Data were pooled from two trials, one of which (Gatell 1987) dominates the analysis by virtue of its size. This trial is of moderate quality. The analysis indicates that a single dose, in the circumstances described in Gatell 1987 was less effective (with marginal statistical significance) in preventing deep wound infection (risk ratio 7.89, 95% CI 1.01 to 61.98), superficial wound infection (RR 4.82, 95% CI 1.08 to 21.61) and urinary tract infection (RR 1.81 to 95% CI 1.01 to 3.23) after surgery for closed fracture than a multiple dose regimen (see 'Discussion').

4. A single dose of parenteral antibiotic using an agent with a long half-life, compared with multiple doses of other agents with shorter half life.

Data were pooled from three trials in this category. One of these (Garcia 1991) was a large trial of moderate quality, but despite its size, analysis of the pooled data failed to show a significant difference between the two types of regimen for the outcomes of deep wound infection (RR 0.57, 95% CI 0.20 to 1.64), superficial wound infection (RR 1.01, 95% CI 0.35 to 2.93), urinary tract infection (RR 0.69, 95% CI 0.37 to 1.32), or respiratory infection (RR 0.31, 95% CI 0.04 to 2.48).

5. Multiple doses of parenteral antibiotic administered over 24 hours or less, compared with a longer period of administration.

Data were pooled from the two small trials in this category. There was no evidence of difference between the two types of regimen for the outcomes of deep (RR 1.10, 95% CI 0.22 to 5.34) or superficial wound infection (RR 0.57, 95% CI 0.17 to 1.93).

6. Oral administration of antibiotic compared with parenteral administration.

Only one small trial (Nungu 1995) has evaluated this comparison for the outcomes of deep and superficial wound infection, and urinary infection. No significant difference between the routes was demonstrated (deep infection: RR 0.29, 95% CI 0.01 to 7.07; superficial infection: RR 0.17, 95% CI 0.02 to 1.47; urinary infection: RR 1.10, 95% CI 0.62 to 1.94). This trial was underpowered to identify any difference between oral and parenteral routes of administration.

Discussion

Antibiotic prophylaxis has been widely used in fracture surgery since the 1970s. The 22 trials reported span over quarter of a century. In the early studies, penicillins effective against gram positive cocci were used. As resistant organisms appeared, subsequent generations of penicillins, and then cephalosporins have been trialed in prophylaxis, both against placebo or no treatment, and against other agents. As cephalosporins have a wider antimicrobial spectrum than the penicillins used in the early studies, their efficacy in reducing the occurrence of infections of the urinary and respiratory tracts, which were secondary outcome measures in many of the included trials, may be superior.

Over time, shorter durations of prophylaxis have been used. For effective prophylaxis, the minimum inhibitory concentration (MIC) of the antibiotic in the tissues must be exceeded for at least the period from incision to wound closure (Burke 1961). In practice, this initially meant using regimens with several consecutive doses, and the pooled data support their effectiveness. The availability of agents with a long elimination half life has allowed single dose prophylaxis reliably to meet Burke's prerequisite. Amongst published trials the large multi-centre Netherlands trial (Boxma 1996), which used an antibiotic which provided concentrations exceeding MIC for 12-24 hours, dominates the analysis in this category. This trial supported the hypothesis that single dose intravenous prophylaxis is effective in reducing the incidence of deep wound infection, superficial wound infection, and urinary and respiratory tract infections. The effect sizes are similar to those of from multi-dose prophylaxis.

Despite the lack of power in many of the individual studies, pooling of the accumulated evidence supports the hypothesis of effectiveness of antibiotic prophylaxis. Boxma 1996 included an economic evaluation based on the effectiveness data which indicates a cost saving of a little under 500US dollars per patient given prophylaxis. This may be conservative as the evaluation does not appear to take into account the costs of urinary and respiratory infections prevented. Albers and colleagues (Albers 1994) have calculated that antibiotic prophylaxis for closed fracture surgery is cost effective if the absolute risk reduction is 0.25% or more; the pooled estimates for absolute risk reduction for single dose or multiple dose prophylaxis in this review exceed that. Therefore, without taking into account the effects of wide adoption of prophylactic regimens on the development of antibiotic resistance, antibiotic prophylaxis appears cost-effective.

Direct comparisons of multiple and single dose prophylaxis have also been conducted by Gatell 1987 and Buckley 1990. Buckley 1990 was underpowered to distinguish between the two regimens tested. Gatell 1987, a large single centre study, concluded that single dose prophylaxis was inferior , but the statistical significance is marginal. Also, the tissue MIC may not have been reliably exceeded throughout the procedure for all participants in Gatell 1987, in which an agent (cefamandole 2g) with a short half life was administered 30 minutes prior to the planned onset of surgery.

Authors' conclusions

Implications for practice

1. Antibiotic prophylaxis for closed fracture surgery is an effective intervention. Application of cost-modelling to the effectiveness data has indicated that it also appears to be cost-effective, in the absence of any data on the impact on the development of antibiotic resistance.
2. Single dose intravenous prophylaxis is effective if the agent used provides tissue levels exceeding the minimum inhibitory concentration over a 12 hour period.
3. If the antibiotic chosen has a short half-life which may not allow minimum inhibitory concentrations to be exceeded throughout the period from incision to wound closure, the use of multiple dose regimens using a 12 hour dosage schedule is a satisfactory alternative.

Implications for research

1. Further placebo controlled trials to evaluate the effectiveness of antibiotic prophylaxis in closed fracture surgery would be unlikely to be ethical.
2. Further trials comparing different antibiotic regimens would require to be very large to confirm differences between candidate regimens.
3. Modelling of cost effectiveness (purchase price, adverse effects) will be important in making choices as established agents lose their efficacy due to resistance, and new agents become available.

Acknowledgements

The authors acknowledge the help of the following who assisted with searching, retrieval of studies, and methodological assessment: Dr Helen Handoll, Mrs Lesley Gillespie, Dr Chris Hoffman. We would also like to thank the following for useful comments from the initial editorial review in 1998: Dr Helen Handoll, Dr Rajan Madhok, Prof Gordon Murray and Dr Antony Berendt.

Data and analyses

Download statistical data

Comparison 1. Antibiotic agent (mulitple dose) versus placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep wound infection101896Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.21, 0.65]
1.1 Hip fracture fixation4526Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.07, 0.75]
1.2 Hip endoprosthesis114Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.03, 11.57]
1.3 Unspecified hip fracture procedure3770Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.21, 1.04]
1.4 Operative management of other or unspecified closed fracture3586Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.10, 1.24]
2 Superficial wound infection71366Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.28, 0.81]
3 Urinary tract infection2500Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.43, 1.00]
4 Respiratory infection2500Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.41, 1.63]
5 Adverse drug effects2882Risk Ratio (M-H, Fixed, 95% CI)1.83 [0.96, 3.50]
5.1 Gastro-intestinal symptoms2441Risk Ratio (M-H, Fixed, 95% CI)2.05 [0.99, 4.25]
5.2 Skin reactions2441Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.30, 5.22]
Analysis 1.1.

Comparison 1 Antibiotic agent (mulitple dose) versus placebo or no treatment, Outcome 1 Deep wound infection.

Analysis 1.2.

Comparison 1 Antibiotic agent (mulitple dose) versus placebo or no treatment, Outcome 2 Superficial wound infection.

Analysis 1.3.

Comparison 1 Antibiotic agent (mulitple dose) versus placebo or no treatment, Outcome 3 Urinary tract infection.

Analysis 1.4.

Comparison 1 Antibiotic agent (mulitple dose) versus placebo or no treatment, Outcome 4 Respiratory infection.

Analysis 1.5.

Comparison 1 Antibiotic agent (mulitple dose) versus placebo or no treatment, Outcome 5 Adverse drug effects.

Comparison 2. Antibiotic agent (single dose) versus placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep wound infection73500Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.24, 0.67]
1.1 Unspecified hip fracture procedure51251Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.28, 1.66]
1.2 Operative management of other or unspecified closed fracture22249Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.17, 0.60]
2 Superficial wound infection73500Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.50, 0.95]
3 Urinary tract infection42975Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.53, 0.76]
4 Respiratory infection42975Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.33, 0.65]
Analysis 2.1.

Comparison 2 Antibiotic agent (single dose) versus placebo or no treatment, Outcome 1 Deep wound infection.

Analysis 2.2.

Comparison 2 Antibiotic agent (single dose) versus placebo or no treatment, Outcome 2 Superficial wound infection.

Analysis 2.3.

Comparison 2 Antibiotic agent (single dose) versus placebo or no treatment, Outcome 3 Urinary tract infection.

Analysis 2.4.

Comparison 2 Antibiotic agent (single dose) versus placebo or no treatment, Outcome 4 Respiratory infection.

Comparison 3. Single dose short-acting versus multiple dose - same agent
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep wound infection2921Risk Ratio (M-H, Fixed, 95% CI)7.89 [1.01, 61.97]
1.1 Unspecified hip fracture procedure1204Risk Ratio (M-H, Fixed, 95% CI)Not estimable
1.2 Operative management of other or unspecified closed fracture1717Risk Ratio (M-H, Fixed, 95% CI)7.89 [1.01, 61.97]
2 Superficial wound infection1717Risk Ratio (M-H, Fixed, 95% CI)4.82 [1.08, 21.61]
3 Urinary tract infection1717Risk Ratio (M-H, Fixed, 95% CI)1.81 [1.01, 3.23]
Analysis 3.1.

Comparison 3 Single dose short-acting versus multiple dose - same agent, Outcome 1 Deep wound infection.

Analysis 3.2.

Comparison 3 Single dose short-acting versus multiple dose - same agent, Outcome 2 Superficial wound infection.

Analysis 3.3.

Comparison 3 Single dose short-acting versus multiple dose - same agent, Outcome 3 Urinary tract infection.

Comparison 4. Single dose long acting versus any multiple dose regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep wound infection31747Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.20, 1.64]
1.1 Unspecified hip fracture procedure2505Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.12, 3.59]
1.2 Operative management of other or unspecified closed fracture21242Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.13, 2.02]
2 Superficial wound infection21689Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.35, 2.93]
3 Urinary tract infection11489Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.37, 1.32]
4 Respiratory infection11489Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.04, 2.48]
Analysis 4.1.

Comparison 4 Single dose long acting versus any multiple dose regimen, Outcome 1 Deep wound infection.

Analysis 4.2.

Comparison 4 Single dose long acting versus any multiple dose regimen, Outcome 2 Superficial wound infection.

Analysis 4.3.

Comparison 4 Single dose long acting versus any multiple dose regimen, Outcome 3 Urinary tract infection.

Analysis 4.4.

Comparison 4 Single dose long acting versus any multiple dose regimen, Outcome 4 Respiratory infection.

Comparison 5. Operative day only versus longer prophylaxis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep wound infection2224Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.22, 5.34]
1.1 Unspecified hip fracture procedure2224Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.22, 5.34]
2 Superficial wound infection1121Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.17, 1.93]
Analysis 5.1.

Comparison 5 Operative day only versus longer prophylaxis, Outcome 1 Deep wound infection.

Analysis 5.2.

Comparison 5 Operative day only versus longer prophylaxis, Outcome 2 Superficial wound infection.

Comparison 6. Oral versus parenteral administration of antibiotic agent
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep wound infection1452Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.01, 7.07]
1.1 Unspecified hip fracture procedure1452Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.01, 7.07]
2 Superficial wound infection1452Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.02, 1.47]
3 Urinary tract infection1452Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.62, 1.94]
Analysis 6.1.

Comparison 6 Oral versus parenteral administration of antibiotic agent, Outcome 1 Deep wound infection.

Analysis 6.2.

Comparison 6 Oral versus parenteral administration of antibiotic agent, Outcome 2 Superficial wound infection.

Analysis 6.3.

Comparison 6 Oral versus parenteral administration of antibiotic agent, Outcome 3 Urinary tract infection.

Appendices

Appendix 1. Search strategies

MEDLINE (OVID Web)

1 randomized controlled trial.pt.
2 controlled clinical trial.pt.
3 random allocation/
4 double blind method/
5 single blind method/
6 exp Cross-Over Studies/
7 or/1-6
8 ((clinical or controlled or comparative or placebo or prospective$ or randomi#ed) adj3 (trial or study)).tw.
9 (random$ adj7 (allocat$ or allot$ or assign$ or basis$ or divid$ or order$)).tw.
10 ((singl$ or doubl$ or trebl$ or tripl$) adj7 (blind$ or mask$)).tw.
11 (cross?over$ or (cross adj1 over$)).tw.
12 ((allocat$ or allot$ or assign$ or divid$) adj3 (condition$ or experiment$ or intervention$ or treatment$ or therap$ or control$ or group$)).tw.
13 or/8-12
14 or/7,13
15 exp Orthopedic Procedures/
16 exp Orthopedic Equipment/
17 exp Orthopedics/
18 exp Fractures/
19 exp Fracture Healing/
20 exp Amputation, Traumatic/
21 exp Arm Injuries/
22 exp Athletic Injuries/
23 exp Dislocations/
24 exp Hand Injuries/
25 exp Leg Injuries/
26 exp Soft Tissue Injuries/
27 exp Contusions/
28 exp Contusions/
29 exp "Sprains and Strains"/
30 exp Tendon Injuries/
31 exp Arthroscopy/
32 or/15-31
33 (hip$ or femur$ or femoral$ or trochant$ or pertrochant$ or intertrochant$ or subtrochant$ or intracapsular$ or extracapsular$ or condyl$ or shaft$ or diaphys$).tw.
34 (pelvi$ or acetabul$ or knee$ or patell$ or tibia$ or fibula$ or pillon or malleol$ or ankle$ or calcan$ or tarsal$ or talus$ or talar$ or cuneiform$ or navicular$ or cuboid$ or metatars$ or phalang$).tw.
35 (leg$1 or (lower adj limb$) or arm$1 or (upper adj limb$) or shoulder$ or humer$ or radi$ or ulna$ or scapula$).tw.
36 (elbow$ or wrist$ or supracondyl$ or epicondyl$ or metacarpal$ or hand$ or finger$ or trapez$ or hamate$ or capitate$ or scaphoid$ or lunate$ or triquetral$ or pisiform$).tw.
37 ((styloid$ or coronoid$) adj2 process$).tw.
38 (ligament$ or tendon$ or menisc$).tw.
39 or/33-38
40 (fracture$ or injur$ or wound$ or dislocat$ or sublux$ or rupture$ or tear$ or torn).tw.
41 and/39-40
42 (fracture$ adj3 (open or closed)).tw.
43 or/41-42
44 or/32,43
45 14 and 44
46 Animal/ not Human/
47 45 not 46
48 exp Antibiotic Prophylaxis/
49 Surgical Wound Infection/ or Postoperative Complications/ or Wound Infection/
50 (antibiotic$ or antimicrob$).tw.
51 or/48,50
52 infect$.tw.
53 or/49,52
54 and/51,53
55 and/47,54

EMBASE (OVID Web)

1. exp Randomized Controlled trial/
2. exp Double Blind Procedure/
3. exp Single Blind Procedure/
4. exp Crossover Procedure/
5. or/1-4
6. ((clinical or controlled or comparative or placebo or prospective$ or randomi#ed) adj3 (trial or study)).tw.
7. (random$ adj7 (allocat$ or allot$ or assign$ or basis$ or divid$ or order$)).tw.
8. ((singl$ or doubl$ or trebl$ or tripl$) adj7 (blind$ or mask$)).tw.
9. (cross?over$ or (cross adj1 over$)).tw.
10. ((allocat$ or allot$ or assign$ or divid$) adj3 (condition$ or experiment$ or intervention$ or treatment$ or therap$ or control$ or group$)).tw.
11. or/6-10
12. or/10-11
13. Animal/ not Human/
14. 12 not 13
15. exp Orthopedic Surgery/
16. exp Orthopedics/
17. exp Orthopedic Equipment/
18. exp Fracture Healing/
19. exp Avulsion Injury/
20. exp Contusion/
21. exp Limb Injury/
22. exp Musculoskeletal Injury/
23. exp Pelvis Injury/
24. exp Traumatic Amputation/
25. exp Soft Tissue Injury/
26. exp Sport Injury/
27. or/15-26
28. (hip$ or femur$ or femoral$ or trochant$ or pertrochant$ or intertrochant$ or subtrochant$ or intracapsular$ or extracapsular$ or condyl$ or shaft$ or diaphys$).tw.
29. (pelvi$ or acetabul$ or knee$ or patell$ or tibia$ or fibula$ or pillon or malleol$ or ankle$ or calcan$ or tarsal$ or talus$ or talar$ or cuneiform$ or navicular$ or cuboid$ or metatars$ or phalang$).tw.
30. (leg$1 or (lower adj limb$) or arm$1 or (upper adj limb$) or shoulder$ or humer$ or radi$ or ulna$ or scapula$).tw.
31. (elbow$ or wrist$ or supracondyl$ or epicondyl$ or metacarpal$ or hand$ or finger$ or trapez$ or hamate$ or capitate$ or scaphoid$ or lunate$ or triquetral$ or pisiform$).tw.
32. ((styloid$ or coronoid$) adj2 process$).tw.
33. (ligament$ or tendon$ or menisc$).tw.
34. or/28-33
35. (fracture$ or injur$ or wound$ or dislocat$ or sublux$ or rupture$ or tear$ or torn).tw.
36. and/34-35
37. (fracture$ adj3 (open or closed)).tw.
38. or/36-37
39. or/27,38
40. and/14,39
41. antibiotic prophylaxis/ or infection prevention/
42. (antibiotic$ or antimicrobial$).tw.
43. or/41-42
44. hospital infection/ or infection complication/ or postoperative infection/ or surgical infection/ or wound infection/ or "bone and joint infections"/
45. infection$.tw.
46. or/44-45
47. and/43,46
48. and/40,47

Appendix 2. Quality assessment criteria

A. Was the assigned treatment adequately concealed prior to allocation?
1=states random, but no description, or quasi-randomisation (Category C)
2=small but real chance of disclosure of assignment (Category B)
3=method did not allow disclosure of assignment (Category A)

B. Were the outcomes of patients who withdrew described and included in the analysis (intention to treat)?
1=not mentioned
2=states numbers and reasons for withdrawal, but analysis unmodified
3=primary analysis based on all cases as randomised

C. Assessment of outcome. Were assessors of outcome blinded to treatment status?
1=not done or not mentioned
2=moderate chance of unblinding of assessors
3=action taken to blind assessors, or outcomes such that bias is unlikely

D. Comparability of treatment and control groups at entry
1=large potential for confounding or not discussed
2=confounding small; mentioned but not adjusted for
3=unconfounded; good comparability of groups or confounding adjusted for

E. Was a placebo treatment assigned as part of the randomisation?
1=No 3=Yes

F. Were exclusion criteria clearly defined?
1=not defined
2=poorly defined
3=well defined

G. Method of assessment of wound infection.
1=not stated
2= clinical decision, or definite criteria without a microbiological diagnosis
3=definite criteria including a microbiological diagnosis

H. Surveillance for wound infection
1=not stated, or not active
2=active, but less than three months
3=active, and at least one year

Feedback

Comment sent 12 January 1999

Summary

I very much enjoyed reading the new Cochrane review of antibiotic usage in fracture prosthetic surgery. This is full of fascinating information, and is a good marriage of high-quality statistical and clinical input. I have made our Orthopaedic surgeons aware of the review's findings, and have proposed a change to our agreed prophylactic protocols as a result.

The review usefully examined the effects of long- and short-halflife agents, but another common point of debate is the choice of narrow-spectrum (mainly isoxazolyl penicillin) versus broad-spectrum (e.g. cefuroxime, or isoxazolyl penicillin plus gentamicin) prophylaxis. There is a suggestion in the classic Lidwell/MRC study reports that broad spectrum prophylaxis may reduce infection rates (by reducing deep Gram-negative infections), but others have been concerned about costs, side effects (principally Clost. difficile diarrhoea) and induction of resistance associated with broader-spectrum agents. Did the group consider this approach? Could it be examined in the future?

Reply

Many thanks for your interest in our review. We did not identify any trial which compared narrow and broad spectrum agents in the closed fracture population. There are in joint replacement (Pollard 1979, Vainionpaa 1988), and in open fracture management (Patzakis 1977); these studies were in our excluded trials table. If we have missed any that you know about, I would be most interested to hear of them. In Nelson 1983 (a study which we included comparing antibiotic versus placebo), the choice of antibiotic was at the discretion of the treating surgeon, but the trial did not compare these options. There seems to be evidence of a beneficial effect in limiting urinary tract infection when a cephalosporin was compared with a placebo (see the analyses in our review).

Contributors

Comment sent from:
Dr Mark Farrington, Cambridge, UK
Reply from:
Prof William Gillespie, Dunedin, New Zealand
Processed by:
Dr Helen Handoll, Edinburgh, UK
Dr Rajan Madhok, Hull, UK (criticism editor)

What's new

DateEventDescription
5 November 2008AmendedConverted to new review format.

History

Protocol first published: Issue 1, 1995
Review first published: Issue 4, 1998

DateEventDescription
26 November 2000New citation required but conclusions have not changedThis review was updated in Issue 2, 2001. This involved including data from a new randomised controlled trial (Luthje 2000) comparing a single dose antibiotic regimen with no prophylaxis. The conclusions of the review were unchanged.

Contributions of authors

Both reviewers (WJ Gillespie and G Walenkamp) appraised and extracted data from all included papers. WJ Gillespie was respnsible for drafting and for entering modifications to the text. WJ Gillespie is the guarantor of the review.

Declarations of interest

None known

Sources of support

Internal sources

  • HealthCare Otago Endowment Trust, Dunedin, New Zealand.

External sources

  • Chief Scientist Office, Department of Health, The Scottish Office (Original Review), UK.

  • Health Research Council of New Zealand (Update), New Zealand.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bergman 1982

MethodsRCT
Location: University Hospital, Sweden
Recruitment period:1974-1977
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 3
Blinding of outcome assessors: 2
Comparability of treatment groups at entry: 1
Use of placebo: 3
Definition of inclusion and exclusion criteria: 1
Assessment of infection: 2
Duration of surveillance: 1
Losses to follow up: None described
Participants180 analysed (92 women, 88 men, mean age 47 years)
Inclusion criteria: undergoing surgery for closed ankle fracture
Exclusion criteria: None described
Interventionsa. Dicloxacillin 2g pre-operatively and 6 hourly for 48 hrs
b. Benzyl penicillin 3 million international units (IU), same regimen
c. Saline placebo, same regimen.
Outcomes1. Deep wound infection
2. Superficial wound infection
3. Adverse reactions
NotesThis report also contains data for use of the same regimen in 90 open fractures. The total number of individuals given antibiotics was 270 (antibiotic 177, placebo 93); the adverse reaction data are reported and analysed using these denominators.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Bodoky 1993

MethodsRCT.
Location: University Hospital, Switzerland.
Recruitment period: 1984-1987
Adequacy of concealment of assigned allocation: A
Intention to treat analysis: 2
Blinding of outcome assessors: 3
Comparability of treatment groups at entry: 3
Use of placebo: 3
Definition of inclusion and exclusion criteria: 3
Assessment of wound infection 3
Duration of surveillance: 1
Losses to follow up: 45 of 284 (16%)
Participants239 analysed (female 184, male 55, mean age 77 years)
Inclusion criteria: Undergoing internal fixation for intracapsular hip fracture.
Exclusion criteria: Pre-existing infection, Antibiotic allergy, Antibiotic prophylaxis for other reason e.g , valve, Immunosuppression, polytrauma.
Interventionsa. Cefotiam 2g induction; 2g once 12 hours later
b. Placebo induction once; 12 hours later
Outcomes1. "Major" wound infection. In the analysis, considered as "deep"
2. "Minor" wound infection In the analysis, considered as "superficial"
3. Urinary tract infection
4. Pulmonary infection
5. Septicaemia
6. Adverse drug effects
7. Infection related death
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Boxma 1996

MethodsRCT.
Location: Multi-centre study, Netherlands.
Recruitment period: 1989-1991
Adequacy of concealment of assigned allocation: A
Intention to treat analysis: 3
Blinding of outcome assessors: 3
Comparability of treatment groups at entry: 3
Use of placebo: 3
Definition of inclusion and exclusion criteria: 3
Assessment of wound infection: 2
Duration of surveillance: 2
Losses to follow up:None described
Participants2195 analysed (female 1132 mean age 65, male 1063, mean age 44)
Inclusion criteria: undergoing surgery for closed fracture.
Exclusion criteria: External fiation or percutaneous wire fixation, pregnancy, immunosuppressive treatment, known hypersensitivity to cephalosporins, antimicrobial use or symptoms of infection in the week prior to surgery.
Interventionsa. Ceftriaxone 2g given intravenously at induction of anaesthesia for surgery
b. Placebo by same regimen
Outcomes1. Deep wound infection.
2. Superficial wound infection.
3. Respiratory infection
4. Urinary tract infection.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Boyd 1973

MethodsRCT.
Location: University Hospital, Boston USA
Recruitment period:1966-1969.
Adequacy of concealment of assigned allocation: A
Intention to treat analysis: 1
Blinding of outcome assessors: 2
Comparability of treatment groups at entry: 3
Use of placebo: 3
Definition of inclusion and exclusion criteria: 2
Assessment of wound infection: 2
Duration of surveillance: 3
Losses to follow up: 68/348 (20%)
Participants280 analysed (female 203, male 77, age range 40-90+)
Inclusion criteria: undergoing operative treatment for proximal femoral fracture, either fixation or endoprosthesis.
Exclusion criteria: Pre-existing infection, Antibiotic allergy.
Interventionsa. Nafcillin systemically 500mg Theatre call; 500mg 6 hourly im for 48 hours
b. Placebo (glucose in saline ) Theatre call; Same regimen
Outcomes1. Deep infection (All infected haematomas were treated as deep infections in the analysis.)
2. Superficial infection
3. Adverse drug effects
4. Infection related death
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Buckley 1990

MethodsRCT.
Location: University Hospital, Canada.
Recruitment period: 1985-1988.
Adequacy of concealment of assigned allocation: A
Intention to treat analysis: 1
Blinding of outcome assessors: 1
Comparability of treatment groups at entry: 2
Use of placebo: 3
Definition of inclusion and exclusion criteria: 3
Assessment of wound infection: 2
Duration of surveillance: 2
Losses to follow up: 40/352 (12%)
Participants312 analysed (female 225, male 87, mean age 77 years).
Inclusion criteria: undergoing hip fracture surgery.
Exclusion criteria - Cephalosporin allergy, pathologic fracture, previous surgery on fractured hip, antibiotic treatment with other agent, more than 7 days in hospital pre-op.
Interventionsa. Cefazolin 2g iv induction; 1g 6 hourly iv 3 more doses
b. Cefazolin 2g iv induction; placebo (saline) 6 hourly iv 3 doses
c. Placebo (saline) iv induction; placebo (saline) 6 hourly iv 3 doses
Outcomes1. Deep wound infection
2. Superficial wound infection
NotesNumbers of patients allocated to groups a. multiple dose and c. placebo are reversed in some of the text (including the abstract) compared with the tables in the report. We used the numbers which were consistent with the results (percentages etc) given in the report.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Burnett 1980

MethodsRCT.
Location: County hospital, Minneapolis USA.
Recruitment period: 1973-1977.
Adequacy of concealment of assigned allocation: A
Intention to treat analysis: 2
Blinding of outcome assessors: 3
Comparability of treatment groups at entry: 2
Use of placebo: 3
Definition of inclusion and exclusion criteria: 3
Assessment of wound infection: 3
Duration of surveillance: 1
Losses to follow up: 46/307 (15%)
Participants261 analysed (161 women, 100 men, mean age 72 years)
Inclusion criteria: undergoing hip fracture surgery.
Exclusion criteria: history of allergy to cephalosporin, active infection requring therapy, history of previous infection about the involved hip.
Interventionsa. Cephalothin 1g iv 4 hourly for 72 hours
b. Placebo iv 4 hourly for 72 hours
Outcomes1. Deep wound infection
2. Urinary tract infection
3. Pulmonary infection
4. Septicaemia
5. Death from infection
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Ericson 1973

MethodsRCT
Location: University and regional hospital, Sweden.
Recruitment period: 1970-1972.
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 1
Blinding of outcome assessors: 2
Comparability of treatment groups at entry: 1
Use of placebo: 3
Definition of inclusion and exclusion criteria: 1
Assessment of wound infection: 2
Duration of surveillance: 2
Losses to follow up: 59/230 (25%) overall; losses for hip fracture sub-group not described. See notes.
Participants53 analysed. (39 internal fixation of trochanteric fracture, 14 hemiarthroplasty, mean age 70 years).
Inclusion criteria: undergoing hip arthroplasty for arthritis, or hip fracture surgery.
Exclusion criteria: none described.
Interventionsa. Cloxacillin 1g IM, 1 hour before operation and for three further doses at six hourly intervals. Thereafter 1g orally 6 hourly, with probenecid 1g twice daily until day 14.
b. Placebo to same regimen.
Outcomes1. Wound infection (interpreted as deep infection)
2. Adverse drug reactions
NotesThis report also contains data for use of the same regimen in open fractures. The total number of individuals given antibiotics was 171 (antibiotic 83, placebo 88); the adverse reaction data are reported and analysed using these denominators.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Garcia 1991

MethodsRCT.
Location: University hospital, Spain.
Recruitment period: 1987-89.
Adequacy of concealment of assigned allocation: A
Intention to treat analysis: 3
Blinding of outcome assessors: 2
Comparability of treatment groups at entry: 3
Use of placebo: 1
Definition of inclusion and exclusion criteria: 3
Assessment of wound infection: 3
Duration of surveillance: 3
Losses to follow up: No losses described
Participants1489 (976 female, 513 male, mean age 68 years) analysed. Inclusion criteria: undergoing fracture fixation surgery, of which 305 had a Moores arthroplasty inserted, 697 had an Ender nail inserted, and 487 had another device used to fix a closed fracture.
Exclusion criteria: undergoing total joint replacement, known allergy to cephalosporin or penicillin, receiving immunosuppression or antibiotics for other infection, history of infection in the operative field, open fracture.
Interventionsa. Cefonicid 2g iv at induction of anaesthesia
b. Cefamandole 2g iv 3 doses ( 30 minutes pre-op, 2 , 8 hours)
c. Cefamandole 2g iv 5 doses ( 30 minutes pre-op, 2, 8, 14, 20 hours)
Outcomes1. Deep infection
2. Superficial infection
3. Urinary tract infection
4. Respiratory infection
5. Infection related death
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Gatell 1984

MethodsRCT.
Location: University Hospital, Spain.
Recruitment period: not given. Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 2
Blinding of outcome assessors: 3
Comparability of treatment groups at entry: 1
Use of placebo: 1
Definition of inclusion and exclusion criteria: 3
Assessment of wound infection: 2
Duration of surveillance: 3
Losses to follow up: 16 of 300 (6%)
Participants284 analysed (169 female, 145 male, mean age 55 years)
Inclusion criteria: undergoing internal fixation of a long bone fracture.
Exclusion criteria: patients having a total joint replacement or a procedure directly involving the hip joint, patients on immunosuppression or with a history of sensitivity to penicillins or cephalosporins.
Interventionsa. Cefamandole 2g by intravenous injection 30 mins before surgery, and at 2, 8,14 and 20 hours after the start of surgery.
b. Placebo using the same regimen as group a.
Outcomes1. Deep wound infection
2. Superficial wound infection
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Gatell 1987

MethodsRCT.
Location: University Hospital, Spain.
Recruitment period: not described.
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 2
Blinding of outcome assessors: 3
Comparability of treatment groups at entry: 2
Use of placebo: 3
Definition of inclusion and exclusion criteria: 3
Assessment of wound infection: 3
Duration of surveillance: 3
Losses to follow up: 33/750 (4%)
Participants717 analysed (445 female, 272 male, mean age 65 years).
Inclusion criteria: undergoing closed fracture fixation
Exclusion criteria: Open fractures, previous total joint replacement, known allergy to penicillin or cephalosporin, immunosuppressive treatment, previous infection in the operative field, already on antibiotics.
Interventionsa. Single dose of cefamandole 2g by intravenous injection 30 minutes before start of surgery and four doses of placebo at 2, 8,14, and 20 hours.
b. Cefamandole 2g by intravenous injection 30 minutes before the start of surgery and at 2,8,14, and 20 hours.
Outcomes1. Deep infection
2. Superficial infection
3. Urinary tract infection
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Hedstrom 1987

MethodsRCT.
Location: University Hospitals, Sweden.
Recruitment period: 1982-1984
Adequacy of concealment of assigned allocation: A
Intention to treat analysis: 1
Blinding of outcome assessors: 3
Comparability of treatment groups at entry: 2
Use of placebo: 3
Definition of inclusion and exclusion criteria : 2
Assessment of wound infection: 2
Duration of surveillance: 1
Losses to follow up: 26/ 147 (18%)
Participants121 analysed (female 87, male 34, mean age 77 years)
Inclusion criteria: undergoing surgery for fixation of trochanteric fracture.
Exclusion criteria: decreased renal function, severe senility, known or suspected allergy to penicillins or cephalosporins.
Interventionsa. 1 day of prophylaxis (cefuroxime 750 mg thrice daily on the operative day followed by 6 days of placebo tablets)
b. 7 days of prophylaxis(cefuroxime 750 mg thrice daily on the operative day followed by cephalexin 0.5g thrice daily orally for 6 days)
Outcomes1. Deep infection
2. Superficial infection
3. Adverse effects
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Hjortrup 1990

MethodsRCT.
Location: Regional Hospital, Denmark.
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 2
Blinding of outcome assessors: 1
Comparability of treatment groups at entry: 1
Use of placebo: 1
Definition of inclusion and exclusion criteria: 2
Assessment of wound infection: 2
Duration of surveillance: 1
Losses to follow up: 15 / 200 (7.5%)
Participants185 analysed (female 142, male 43, mean age 80 years)
Inclusion criteria: Undergoing surgery for hip fracture
Exclusion criteria: history of allergy to penicillin, active infection requiring antibiotic therapy, decreased renal function, patients subjected to arthroplasty.
Interventionsa. Single dose Methicillin 2g intravenously at the start of the operation.
b. No antibiotic prophylaxis
Outcomes1. Deep infection
2. Superficial infection
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Hughes 1991

MethodsRCT.
Location: University Hospital, Scotland.
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 3
Blinding of outcome assessors: 1
Comparability of treatment groups at entry: 3
Use of placebo: 1
Definition of inclusion and exclusion criteria: 1
Assessment of wound infection: 1
Duration of surveillance: 1
Losses to follow up: none described
Participants54 analysed (15 female, 39 male, mean age 44)
Inclusion criteria: undergoing surgery for low energy closed fractures
Exclusion criteria: none described
Interventionsa.Cefuroxime 1.5g at induction of anaesthesia
b. No treatment
Outcomes1. Deep wound infection
2. Superficial wound infection
3. Urinary tract infection
4. Respiratory tract infection
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Jones 1987 B

MethodsRCT.
Location: Prepaid medical care program, Oregon, USA.
Recruitment period: 1984-1985
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 2
Blinding of outcome assessors: 1
Comparability of treatment groups at entry: 1 (see notes)
Use of placebo: 1
Definition of inclusion and exclusion criteria: 2
Assessment of wound infection: 2
Duration of surveillance: 1
Losses to follow up: 122 of 1036 (12%).
Participants914 in study of which a subgroup of 58 who had undergone fracture surgery were analysed for this review. No demographic details for the fracture subgroup.
Inclusion criteria: Main analysis:undergoing elective surgery in a range of specialties. Subgroup- undergoing open reduction and fixation of fracture.
Exclusion criteria: Concurrent antibiotic treatment, history of hypersensitivity to cephalosporins or penicillins, pregnancy, preoperative urinary tract infection, renal or hepatic disease.
Interventionsa. Cefazolin 1g by intravenous injection at onset of anaesthesia, and 8 hourly for 24 hrs.
b. Cefoxitin 2g by intravenous injection at onset of anaesthesia and 6 hourly for 24 hrs.
c. Cefotaxime 1g by intravenous injection at onset of anaesthesia (with second dose if operation time exceeded 2 hours)
Outcomes1. Wound infection. (defined as drainage of purulent material from the wound) within 30 days of operation.
NotesDemographic data available only for the whole group, but wound infection data for a fracture fixation subgroup.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Karachalios 1987

MethodsRCT.
Location: University Hospital, Greece.
Recruitment period: Not described.
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 3
Blinding of outcome assessors: 1
Comparability of treatment groups at entry: 1
Use of placebo: 1
Definition of inclusion and exclusion criteria: 3
Assessment of wound infection: 1
Duration of surveillance: 1
Losses to follow up: None during the 10 day follow up period.
Participants200 analysed. Demographic details not provided.
Inclusion criteria: undergoing internal fixation of proximal femoral fracture.
Exclusion criteria: Known or suspected hypersenitivity to cephalosporins, concomitant or recent antibiotic use, or evidence of pre-existing infection at the time of surgery.
Interventionsa. Ceftriaxone 1g at start of surgery
b. Cefotaxime 1g at start of surgery and every 8 hours for 3 days.
Outcomes1. Deep wound infection.
2. Superficial wound infection
3. Adverse effects
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Kaukonen 1995

MethodsCCT. (Quasi-randomised- allocation based on odd or even year of birth)
Location: Regional Hospital, Finland.
Recruitment period: 1990-1991 Follow up of variable quality depending on hospital length of stay.
Adequacy of concealment of assigned allocation: C
Intention to treat analysis: 2
Blinding of outcome assessors: 1
Comparability of treatment groups at entry: 1
Use of placebo: 1
Definition of inclusion and exclusion criteria: 2
Assessment of wound infection: 1
Duration of active surveillance: 1
Losses to follow up: 13 / 162 (8%).
Participants149 analysed (female 112, male 37, mean age 76 years)
Inclusion criteria: undergoing operative treatment of hip fracture.
Exclusion criteria: antibiotic treatment for active infection at the time of admission.
Interventionsa. Single dose prophylaxis with cefuroxime 3g at the start of the operation.
b. No antibiotic prophylaxis.
Outcomes1. Deep wound infection
2. Superficial wound infection.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?NoC - Inadequate

Luthje 2000

MethodsRCT.
Location: Multicentre.
University and Community Hospitals, Finland.
Recruitment period:1994-1998.
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 3
Blinding of outcome assessors:1
Comparability of treatment groups at entry: 3
Use of placebo: 1
Definition of inclusion and exclusion criteria: 2
Assessment of wound infection 2
Duration of surveillance: 2
Losses to follow up: None
Participants224 analysed (female 157, male 67, mean age 77 years).
Inclusion criteria: undergoing operative osteosynthesis (internal fixation) of hip fracture.
Exclusion criteria: antibiotic treatment for active infection at the time of admission,history of penicillin/ cephalosporin allergy, immunosuppressive medication, open fracture, pathological fracture, under 15 years of age.
Interventionsa. Single dose prophylaxis with cefuroxime 2g IV 1-2 hours preoperatively.
b. No antibiotic prophylaxis.
Outcomes

1. Deep wound infection
2. Superficial wound infection.
3. Respiratory infection.
4. Urinary infection.

Also reported, but not
included in this review, were thrombo-embolic events, decubitus ulcers, fixation failure, and death.

NotesThis paper contains a multivariate analysis of the most important factors predicting complications in this cohort of hip fracture patients, and an economic analysis of the cost-effectiveness of prophylaxis using this regimen.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB- unclear

McQueen 1990

MethodsRCT.
Location: University Hospital , Scotland.
Recruitment period: 1985-1986
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 2
Blinding of outcome assessors: 2
Comparability of treatment groups at entry: 1
Use of placebo: 3
Definition of inclusion and exclusion criteria: 1
Assessment of wound infection: 3
Duration of surveillance: 1
Losses to follow up: Not described
Participants502 analysed (434 female, 68 male, mean age 79 yrs)
Inclusion criteria: undergoing surgical management of hip fracture
Exclusion criteria: none described
Interventionsa. Cefuroxime 1.5g by intravenous injection at start of operation
b. Placebo by intravenous injection at start of operation
Outcomes1. Deep wound infection
2. Superficial wound infection
3. Urinary tract infection
4. Pulmonary infection
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Nelson 1983

MethodsCCT. (Quasi-randomised by last digit of hospital number: odd or even).
Location: University Hospital, USA.
Recruitment period: Not described.
Adequacy of concealment of assigned allocation: C
Intention to treat analysis: 1
Blinding of outcome assessors: 1
Comparability of treatment groups at entry: 1
Use of placebo: 1
Definition of inclusion and exclusion criteria: 1
Assessment of wound infection: 2
Duration of surveillance: 3
Losses to follow up: 6 / 358 (2%).
Participants103 men and women undergoing hip fracture surgery analysed. Subgroup within a larger study which also included a further 255 joint replacement patients. No demographic details provided.
Inclusion criteria: undergoing hip fracture surgery
Exclusion criteria: none described
Interventionsa. Intravenous antibiotics for 24 hours (either nafcillin or cefazolin 500mg 6 hourly, choice being surgeon dependent)
b. Intravenous antibiotics (same agent and dose as in group a) or three days intravenously, and for a subsequent 4 days orally.
Outcomes1. Deep wound infection
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?NoC - Inadequate

Nungu 1995

MethodsRCT.
Location: Multi-centre recruitment from University and regional Hospitals, Sweden.
Recruitment period: 1991 - 1993.
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 2
Blinding of outcome assessors: 1
Comparability of treatment groups at entry: 1
Use of placebo: 1
Definition of inclusion and exclusion criteria: 2
Assessment of wound infection: 3
Duration of surveillance: 2
Losses to follow up: 107/559 (19%)
Participants559 randomised (412 women, 147 men, mean age 81 years). No demographic details for the 452 analysed.
Inclusion criteria: undergoing internal fixation for an extracapsular fracture of the hip.
Exclusion criteria: current antibiotic treatment, known allergy to penicillin or cephalosporin.
Interventionsa.Oral prophylaxis with cefadroxil 1g 2hours before surgery and again at 12 hours.
b. Intravenous prophylaxis with cefuroxime. Regimen was 750 mg at 8 hour intervals in three participating hospitals, and 1.5g as a single dose in one centre.
Outcomes1. Deep wound infection
2. Superficial wound infection
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Paiement 1994

MethodsRCT
Location: Two University Hospitals, USA and Canada
Recruitment period: 1989-1990
Adequacy of concealment of assigned allocation: B
Intention to treat analysis: 2
Blinding of outcome assessors: 1
Comparability of treatment groups at entry: 3
Use of placebo: 3
Definition of inclusion and exclusion criteria: 3
Assessment of wound infection: 2
Duration of surveillance: 3
Losses to follow up:3/125 (2%)
Participants122 analysed (64 female, 58 male , mean age 43 yrs)
Inclusion criteria: Undergoing surgery for isolated closed fracture
Exclusion criteria: Aged less than 18 years, concomitant infection, surgery delayed over 72 hours, extensive skin blistering, history of allergy to penicillin or cephalosporin, receiving antibiotic or immunosuppression.
Interventionsa. Cephalotin 1g at least 7 minutes before application of surgical tourniquet, and 6 hourly for 24 hours.
b. Placebo, same regimen
Outcomes1. Deep infection
2. Superficial infection.
3. Adverse drug reactions (none)
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Tengve 1978

  1. a

    g = gram
    iv = intravenous
    im = intra-muscular

MethodsCCT (Quasi-randomised -allocation by year of birth).
Location: Regional Hospital, Sweden.
Recruitment period: 1973-74
Adequacy of concealment of assigned allocation: C
Intention to treat analysis: 1
Blinding of outcome assessors: 1
Comparability of treatment groups at entry: 1
Use of placebo: 1
Definition of inclusion and exclusion criteria: 2
Assessment of wound infection: 2
Duration of surveillance: 2
Losses to follow up: 13 / 140 (9%).
Participants127 analysed (table states 38 women, 89 men, average age 77 years). Female/male ratio is reversed from that expected, and may be an error in the report.
Inclusion criteria: undergoing surgery for trochanteric hip fracture
Exclusion criteria: none described.
Interventionsa.Cephalothin 2g at start of anaesthesia, at two hours, and every six hours until tolerating oral intake; thereafter 1g cephalexin orally 6 hourly for total of 48 hours/
b. No prophylaxis.
Outcomes1. Deep infection
2. Superficial infection
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?NoC - Inadequate

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Benson 1983CCT. Open fracture management. One comparison is of antibiotic management.
Braun 1987RCT. Open extremity fractures only. Comparison: cloxacillin and placebo.
Centulio 1988RCT. Comparison of single dose of ceftriaxone with 3 days of ceftriaxone. Uncemented joint replacement used in hip surgery. 13 hip fracture patients included but no usable data for this subgroup.
De Benedictis 1984RCT. Comparison: cefonicid versus cefazolin. Joint replacement patients only.
Dellinger 1988RCT. Open fracture management. Comparison between one day of antibiotic prophylaxis with a cephalosporin, and five days (2 groups - each a different cephalosporin).
Evrard 1988RCT. Comparison of 5 days of cefazolin versus two days of cefamandole .. Hip replacement data only.
Gunst 1984RCT. Comparison: parenteral cefamandole and no antibiotic. Total hip replacement data only.
Henley 1986RCT. Comparison: intravenous cefamandole versus placebo. 130 of 743 participants had fracture surgery, but no usable data for this group are available.
Hill 1981RCT. Comparison: cefazolin by injection over 5 days versus placebo. Total joint replacement patients only.
Johnson 1988RCT. Antibiotic management in open tibial fractures.
Jones 1985RCT. Participants 30 patients undergoing lower limb fracture surgery. Conducted to evaluate levels of three cephalosporins in serum, muscle and haematoma. No usable data on clinical outcomes.
Jones 1987 ARCT. Comparison: single dose cefoperazone versus two doses of cefotaxime. Participants included subgroup undergoing joint replacement and other unspecified orthopaedic procedures. No usable data on fracture fixation.
Knapp 1996RCT. Antibiotic management of open fractures caused by gunshot wounds.
Lidwell 1984RCT. Participants: hip and knee replacement. Randomised to clean air or not.
Mauerhan 1994RCT. Comparison one day of cefuroxime compared with three days of cefazolin. Total joint replacement only.
Mollan 1994RCT. Comparison: single dose teicoplanin versus 4 doses of cephamandole over 24 hrs. Total joint replacement patients only.
Patzakis 1977RCT. Comparison of antibiotic regimens in the management of open fractures.
Pavel 1974RCT. Comparison: cephaloridine versus placebo. Participants were undergoing clean orthopaedic surgery, the procedures being unspecified. It is likely that closed fracture patients were amongst these, but there are no usable data.
Periti 1989RCT comparing single dose prophylaxis using ceftriaxone with multi-dose prophylaxis using cefamandole. Only 9 of 883 participants underwent fracture surgery, and no usable data were available.
Periti 1992RCT. Comparison: single dose teicoplanin versus multiple dose cefazolin. All participants underwent total hip or knee replacement.
Pollard 1979RCT. Comparison: 3 doses of cephaloridine versus 14 days of flucloxacillin. Joint replacement patients only.
Schulitz 1980RCT. Joint replacement patients only.
Vainionpaa 1988RCT comparing narrow-spectrum agent (cloxacillin) with a broad spectrum agent (cefamandole). Joint replacement patients only included.
Van Meirhaeghe 1989RCT. Comparison: narrow spectrum antibiotic (flucloxacillin) versus broad spectrum (cefazolin) in clean orthopaedic surgery. A proportion (not described) were fracture fixation but a wide range of other clean orthopaedic operations were included. No usable data for this review.
Visuri 1976CCT (alternation). Narrow spectrum (dicloxacillin) versus broad spectrum (ampicillin) in patients undergoing total joint replacement.
Wymenga 1992RCT. Single dose versus multiple dose of cephalosporin in hip replacement. Some hip fracture patients are included but no data are available for this subgroup.

Characteristics of studies awaiting assessment [ordered by study ID]

Chiu 1993

Methods?RCT
Participants 
Interventions 
Outcomes 
NotesAbstract only. Authors contacted for more information. No reply to date.

Ancillary