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A meta-analysis of the use of amoxycillin-clavulanic acid in surgical prophylaxis
Journal of Hospital Infection (1992) 22 (Supplement A), 9 21
A m e t a - a n a l y s i s of the use of a m o x y c i l l i n - c l a v u l a n i c acid in surgical prophylaxis A. P. R. Wilson, S. S h r i m p t o n a n d M. Jaderberg
Department of Clinical Microbiology, University College Hospital, London and SmitkKline Beecham Pkarmaceuticals, Brentford, Middlesex, UK. Summary: T h e efficacy of amoxycillin clavulanic acid as antibiotic prophylaxis in surgery has been assessed in numerous clinical studies, chiefly in abdominal and gynaecological surgery. A meta-analysis of 21 trials covering 2685 patients given amoxycillin-clavutanic acid and 2220 patients given comparator regimens is presented. Monotherapy with amoxycillin clavula-
nic acid was as effective as the comparators, including combination regimens utilizing gentamicin or metronidazole, in preventing wound infections (median wound infection rates were 6% and 10% respectively). The antibacterial activity of amoxycillin-clavulanic acid covers the broad range of aerobic Gram-negative and anaerobic organisms that have a major role in postoperative infections. In addition, amoxycillin clavulanic acid may have benefits in terms of convenience, tolerance and cost.
Keywords: Antimicrobial prophylaxis; amoxycillin-clavulanic acid; wound infection; meta-analysis.
Introduction T h e use of a n t i b i o t i c s for the p r e v e n t i o n of surgical sepsis has been s h o w n to be effective w h e n t h e o p e r a t i o n involves a site w i t h a n o r m a l bacterial flora, e.g. the c o l o n or vagina, and in patients w i t h i n c r e a s e d s u s c e p t i b i l i t y to infection u n d e r g o i n g p r o c e d u r e s , s u c h as g a s t r o d u o d e n a l or biliary s u r g e r y , t I n m a n y cases p l a c e b o - c o n t r o l l e d trials are no l o n g e r c o n s i d e r e d ethical and a s s e s s m e n t s of n e w p r o p h y l a c t i c a n t i b i o t i c s have to be m a d e in c o m p a r a t i v e trials w i t h e s t a b l i s h e d r e g i m e n s . T h e n u m b e r s of p a t i e n t s r e c r u i t e d into m o s t trials are i n a d e q u a t e to d e m o n s t r a t e a n y b u t the m o s t gross differences in efficacy b e t w e e n p r o p h y l a c t i c r e g i m e n s . M e t a - a n a l y s i s aims to c o m b i n e results f r o m different trials to increase statistical p o w e r and to p r o v i d e a s t r u c t u r e d a n d critical review of the existing m e d i c a l literature. 2 A m o x y c i l l i n c l a v u l a n i c acid ( ' A u g m e n t i n ' , S m i t h K l i n e B e e c h a m ) has been w i d e l y used as a p r o p h y l a c t i c a n t i b i o t i c in a b d o m i n a l and g y n a e c o l o g i c a l s u r g e r y . 3 Its s p e c t r u m of activity i n c l u d e s Staphylococcus aureus, Enterococcus faecalis, Esckerickia coli, Proteus mirabilis, and m o s t strains of Bacteroides fragilis. H o w e v e r , it is not active a g a i n s t Correspondence to: Dr A. P. R. Wilson, Department of Clinical Microbiology, University College tlospital, Grafton Way, London WC1E 6AU, UK. 0195 67(11/92/I)A0009 ~ 13 $08.00/0
"l;~ 1992 "l'hc I Iospital Injection Society
9
10
A. P. R. W i l s o n e t al.
amoxycillin-resistant strains of E n t e r o b a c t e r spp., S e r r a t i a m a r c e s c e n s or spp. 3 T h e aim of this study was to determine if any conclusion as to the relative efficacy of amoxycillin-clavulanic acid v s . other antibiotic regimens could be drawn from the literature.
Pseudomonas
Methods
Meta-analysis followed the m e t h o d of L ' A b b + e t a l . 2 T h e criteria for inclusion of studies in the review were that they were randomized comparative trials of the efficacy of anaoxycillin-clavulanic acid v s . other antibiotic regimens in the prevention of surgical w o u n d infection. Randomization had to be performed in a m a n n e r that precluded knowledge of the next treatment assignment. Antibiotic prophylaxis had to be administered prior to skin incision. Studies were rejected on the basis of methods not results. Relevant studies were identified by a c o m p u t e r search on 'Medline' from 1983 to 1991, by reviewing the references in the trials found and in other reviews. 3 T o find studies that were only partially published, the records of the m a n u f a c t u r e r were consulted. Data extraction was performed i n d e p e n d e n t l y by two of the authors. Inter-observer agreement was recorded and any differences resolved by discussion. Assessment of quality was similarly performed by two of the authors using a published method. 4 Differences in efficacy were expressed by the odds ratio (OR) and results were pooled by the m e t h o d of Mantel-Haenszel. 2's T h e pooled OR gave an estimate of the relative risk of w o u n d infection in patients given amoxycillin-clavulanic acid or a comparator antibiotic in groups of trials covering, for example, a surgical speciality. Heterogeneity was tested graphically 2 and by the m e t h o d of W o o l f using an adjustment for small subsets, s Confidence intervals were calculated for the individual trials and for the combined data, using the m e t h o d of Cornfield. 6 T h e effect of inclusion of the quality index 4 was examined by the m e t h o d of Klein et al. 7 Where possible, efficacy was examined for specific surgical specialities: colorectal, gynaecological and biliary surgery. Comparison was made with regimens containing cephalosporins or aminoglycosides. One study showed a significant difference between amoxycillin-clavulanic acid and metronidazole in gynaecological surgery as a result of infections caused by aerobic Gram-negative bacteria. 8 T h e effects of exclusion of this trial were examined. Results Literature
review
T h e literature search identified 30 studies. ~ 37 Nine trials were excluded, including two duplicate publications (references 14 and 29, and references
Meta-analysis of surgical prophylaxis
11
19 and 30) and one that did not indicate in which antibiotic group infections occurred. 31 One study was excluded because it gave no indication of patient randomization. 32 It claimed a significant i m p r o v e m e n t in the rate of sepsis after amputation in patients given amoxycillin-clavulanic acid (three of 31 patients), compared to those given penicillin (9 of 13 patients) ( P < 0"001). Three trials were placebo-controlled 33'34'3: and two compared different regimens of amoxycillin-clavulanic acid. 3S'36 For the remaining 21 trials, the characteristics of the patients, and the dosage and duration of the test and control regimens are shown in "Fable I. T h e criteria for w o u n d infection and results are shown in Table II. All except two studies used control regimens effective against G r a m - n e g a t i v e bacteria. ~'16 Control regimens for contaminated surgery usually included metronidazole or clindamycin but, with one exception, 25 amoxycillinclavulanic acid was given as a 'single' agent. T w o studies were double-blind, three observer-blind and two patient-blind. T h e r e were 20 (7%) points of disagreement between the two authors in Tables I and II. These were all resolved by discussion. Statistically significant differences in favour of amoxycillin-clavulanic acid vs. comparator regimens were present in two trials. In one the excess of infections was caused by Gram-negative aerobes as the comparator was metronidazole alone (2% vs. 11%, difference in proportions 95% C1 0.03-0"15). s T h e other study compared amoxycillin-clavulanic acid with metronidazole plus gentamicin in paediatric surgery (5% vs. 25%, difference in proportions 95% confidence limits 0"08-0-33). 13 C u l t u r e of wound exudate usually produced a mixed growth and the n u m b e r of patients with positive cultures in each group was not given. However, there were eight isolates of S. a u r e u s and four of E n t e r o c o c c u s spp. after the comparator regimen compared with none after amoxycillin-clavulanic acid. T h e likelihood of a T y p e II error (i.e. of failing to detect a significant difference) was discussed in three trials but, in two, the n u m b e r s needed were t h o u g h t impractical. 24'27 T h e third designed the trial to recruit sufficient numbers to detect a 50% reduction in the rate of sepsis with a power of 0"8. 2~ T w o other trials were of sufficient size to detect a 50-60% reduction but recruited patients in a 2:1 ratio. 2s'26 Bacterial isolates were c o m m o n l y mixed and the n u m b e r of isolates, rather than patients, were given, making statistical differentiation of antibacterial efficacy difficult. Quality
assessment
Quality scores varied from 25% to 89% and the difference between the assessors was largely d e p e n d e n t on the interpretation of the criteria. F u r t h e r criteria for the answering of these questions were decided as previously reported. 3s T h e resulting mean difference in score was 0.01 with a range of - 0'05 0"06. These differences were resolved by discussion. I n f o r m a t i o n on the outcome of patients withdrawn from study was given in only one study. 2s
12
A. P. R. W i l s o n e t a L
"Fable I. Characteristics of comparative trials of amoxycillin-clavulanic acid (ACA) in the
prevention of surgical wound prevention Trial/ indication
Blind
Exclusions
Quality
Age (years) ACA/comparator
Sex
Abri '~ Colon
NB
NK
0-40
NK
NK
Ashall '~ General
NB
NK
0.46
NK
NK
Bernard ~' Colorectal
PB
NK
0.51
65+2 67 4- 1-5
Beytout ~2 Abdominal
NB
NK
0.34
NK
Brereton ~3 paediatric, Abdominal
NB
M i n o r surgery, recent antibiotics, sepsis, allergy, C S F shunts, < 10% risk of w o u n d infection
0'69
0-13 0-13
33M 22M
18F 16F
0 9
20M
13F
18M 12M
14F 17F
NK
Brown* Hysterectomy
NB
Allergy, recent antibiotics, renal failure, infection, diabetes, steroids, a u t o i m m u n e disease
0"77
26 74 25 80
Dieterich TM Vascular
NB
Liver disease, allergy, recent antibiotics
0.46
24-86 23-78
D o m b r o v i c h 's Hysterectomy
NB
NK
0.25
NK
NK
D r u m m u' OB Appendicectomy (a) n o n gangrenous (b) g a n g r e n o u s
< 12 years, recent antibiotics, allergy
076
(a) N K NK (b) N K NK
NK
E1 M u f t i ' : NB Cholecystectomy
Allergy
0"54
22 75 16-67
4M 2M
El M u f t i TM Biliary
NB
Allergy
0"41
18-73 18-72
IlM 13M
Friese t'' Gynaecological
NB
Allergy, < 16 years, recent antibiotics, malignancy, pregnancy
0.71
Allergy, < lg years, lactation, pregnancy, renal failure, infection, inflammatory bowel disease, e m e r g e n c y
0.70
Hall > Colorectal
NB
394- 15 to 62 + 14 38• to 5 9 • 13 18 90 18-92
138F 142F
57M 56M
15f: 13F
NK
46t: 48F 89F 87F
199F 196t; 59M 46M
1231," 131F
Meta-analysis of surgical prophylaxis Table I. Trial/ indication
Blind
13
(continued)
Exclusions
Quality
Age (years) ACA/comparator
Sex
Menzies 21 PB Abdominal (a) clean (b) c o n t a m i n a t e d
< 14 years, allergy, renal or liver failure, pregnancy, recent antibiotics
0"74
(a) 19-81 20-88 (b) 18-88 20-88
27M 25M 32M 38M
35F 42F 31F 28F
M e u n i e r 22 Abdominal (carcinoma)
NB
Neutropenia
0'35
24-84 40-80
10M
16F
13M
14F
Mosimann > Colorectal
NB
NK
0.45
NK
Palmer 24 Abdominal
OB
< 12 years, allergy, o t h e r antibiotics, infection, pregnancy, renal or hepatic failure, previous entry
0"78
12-96 13--96
103M l15M
127F ll0F
Playforth 2s Abdominal
DB
< 1 2 years, allergy, hernias, mistaken administration
0.85
>12<89
173M
180F
>12<89
95M
NK
91F
Tehan > General and gynaecological
DB
Allergy, recent antibiotics, hepatic or renal failure, pregnancy, lactation, emergency
0.79
16-89 18-92
156M 84M
553F 264F
Weersink 27 Abdominal
OB
< 18 years, infection, other antibiotics, allergy, pregnancy
0.74
26-86
26M
33F
22-85
19M
24F
NK
0.25
Wenzel 2s Colorectal
NB
NK
NK
NK = not known; I)B = double-blind; OB = observer blind; I'B = patient blind; NB = not blinded.
Pooling of trial results The 21 trials covered 2685 patients given amoxycillin-clavulanic acid and 2220 patients given comparator regimens with median rates of postoperative wound infection of 6 and 10% respectively (Table III). The pooled OR for wound infection in the 21 trials was 0-84 (95% confidence limits 0.68 1.03) by Mantel-Haenszel, not significantly different from 1"0 but with a trend in favour of amoxycillin-clavulanic acid (Table I I I; Figure 1). By including the quality index, this trend was lost and the pooled OR became 0"89 (95% confidence limits 0'7-1"2). Excluding the two trials in which the comparator was metronidazole alone, s'16 the pooled odds ratio
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was 0-93 (95% confidence limits 0"7-1"2) (Z x= 0"4, P > 0"5), becoming 1"00 (95% confidence limits 0"8-1"3) when quality was included. With the exception of gynaecological surgery, the pooled results did not suggest any difference in efficacy between amoxycillin-clavulanic acid and comparator antibiotics. Nine studies gave separate results for colorectal surgery, including 705 patients given amoxycillin-clavulanic acid and 628 given comparator regimens. 9'2~ T h e rates of post-operative w o u n d infection were similar and the pooled O R was not significantly different from 1"0 (Table III). Pooling the four studies reporting biliary surgery 17dS'24,2s gave a similar result (3 % v s . 4% infection). T h e pooled ratio of the four studies of gynaecological surgery 8'1s,19'26 was distorted by the inclusion of the trial of Brown e t a l . 8 and was not significantly different from 1-0 when trial quality was included. Nine trials c o m p a r e d w o u n d infections in a total of 1685 patients given amoxycillin-clavulanic acid with 1232 given a cephalosporin with/without metronidazole.m,11,14,17 19,24-26 T h e r e was no significant difference in efficacy in the pooled results (odds ratio 1"0), the median rate of infection being 6% in both cases (Table III). Six trials included gentamicin in the comparator regimen but again efficacy was similar (odds ratio 0"98). 12'13'20'22'23'27 T h e r e was a significant heterogeneity amongst these trials ()r 13, P < 0 " 0 2 5 ) but this was lost when the quality index was included (X2= 7"6, P > 0 " I ) . Fourteen trials compared amoxycillin-clavulanic acid as m o n o t h e r a p y with a combination of two or more antibiotics. T h e pooled odds ratio was very close to 1"0, despite inclusion of 2053 v s . 1581 patients (Table III). 9'1~176 Eight trials used a single agent as comparator and again there was no evidence of any difference in efficacy (odds ratio 0.94, Table Ill). 8'11'14'16 t8,21,25 Bacteriological efficacy was not interpretable in many trials as the n u m b e r of w o u n d s from which isolates derived was not given. In nine trials, covering 1438 test patients and 985 controls, the odds ratio was 0"83 (95% confidence limits 0"5-1'2) (Z 2= 0-8, P > 0"3). Six studies reported adverse events following amoxycillin clavulanic acid or comparator. 8'1~ 9/128 v s . 3/126, 2/47 v s . 2/36, 2/138 v s . 0/142, 2/72 v s . 3/69, 10/521 v s . 2/251 and 2/59 v s . 2/43. T h e pooled odds ratio was 1"87 (95% confidence limits 0"9-4) (Z2=2"6, P > 0 " I ) with or without the quality index. T h e r e was no significant heterogeneity. Discussion
T h e meta-analysis suggests that there is no statistically significant difference in efficacy between amoxycillin clavulanic acid and comparator regimens of similar antimicrobial s p e c t r u m in the prevention of w o u n d infection. Both single and combination comparator regimens showed similar efficacy to amoxycillin clavulanic acid. T h e incidence of adverse events following amoxycillin-clavulanic acid was not significantly different from that of other regimens.
Meta-analysis of surgical prophylaxis
19
Individual trials were usually of inadequate size to demonstrate differences of 50% in efficacy. T h e one exception was a trial of amoxycillin clavulanic acid v s . gentamicin plus metronidazole in paediatric surgery. 13 T h e study included a placebo group but the rate of withdrawal from the group was high. Detailed analysis was provided on only 122 of 171 operations but this did not appear to affect the significance of the result. Although statistical analysis of bacteriological efficacy was not possible, the excess of infections with the comparator regimen appeared to be due to S. a u r e u s and enterococci. T h e lack of a consistent trend in colorectal surgery despite the inclusion of 13 33 patients suggests that trials sufficient to show a significant difference would be too large to be practicable. T h e efficacy of regimens including a cephalosporin or an aminoglycoside appeared similar to those with amoxycillin-clavulanic acid, again including large n u m b e r s of patients. Metronidazole alone was inadequate in gynaecological surgery as w o u n d infections due to aerobic Gram-negative bacteria occurred in significant numbers, s Placebo-controlled trials demonstrate a significant reduction in surgical w o u n d infection in patients given amoxycillin-clavulanic acid. W o u n d infections after various procedures in a renal transplant unit were less frequent after 1"2 g amoxycillin-clavulanic acid (0/24 v s . 6/22, P = 0 - 0 1 , Fisher's test). 33 However, there were more transplant patients in the treated group. A double-blind placebo-controlled trial showed amoxycillinclavulanic acid to be effective in reducing clinical infection after animal bites when given between 9 and 24 h after injury but represents early t r e a t m e n t rather than prophylaxis. 34 An observer-blind study in head and neck surgery reported four infections in 16 patients given the antibiotic compared to 12 infections in 16 given placebo ( P = 0"01, Fisher's test). 37 T w o trials compared different regimens of amoxycillin clavulanic acid. One trial failed to show a significant difference in efficacy of a 5-day course and a short course of three doses in vascular surgery (9/56 v s . 12/52). 3s T h e other showed amoxycillin clavulanic acid given subcutaneously along the line of the proposed incision to be associated with fewer w o u n d infections than after the same dose given intravenously (25/296 v s . 52/328, P < 0-01, Z2 test). 36 Amoxycillin-clavulanic acid is effective in the prevention of w o u n d infection in operations where w o u n d infections are likely to develop with Gram-negative, anaerobic or mixed bacteria. This meta-analysis suggests that anaoxycillin-clavulanic acid m o n o t h e r a p y is as effective as single agent or combination regimens and it might be preferred to the latter by virtue of safety, convenience and lower cost. References
1. Guglielmo BJ, Hohn I)C, Koo PJ, Hunt TK, Sweet RI,, Conte JE. Antibiotic prophylaxis in surgical procedures. A r c h Surg 1983; 118:943 955. 2. L'Abb~ K, Detsky AS, O'Rourke K. Meta-analysis in clinical research. A n n Intern M e d 1987; 107: 224-233.
20
A. P. R. W i l s o n e t a k
3. Todd PA, Benfield P. Amoxycillin/clavulanic acid. Drugs, 1990; 39: 264-307. 4. Evans M, Pollock AV. A score system for evaluating random control clinical trials of prophylaxis of abdominal surgical wound infection. Br.7 Surg 1985; 72: 256-260. 5. Armitage P, Berry G. Statistical methods in epidemiology. In: Statistical Methods" in Medical Research, 2nd edn. Oxford: Blackwell Scientific Publications 1987: Chapter 16, 459464. 6. Breslow NE, Day NE. Classical methods of analysis of grouped data. In: Statistical ~Iethods in Cancer Research, Vol 1, The Analysis of Case-Control Studies. l,yon: International Agency for Research on Cancer Scientific Publications, No. 32 1980; Chapter 4, 139 140. 7. Klein S, Simes J, Blackburn GI,. Total parenteral nutrition and cancer clinical trials. Cancer 1986; 58:1378 1386. 8. Brown EM, Depares J, Robertson AA et al. Amoxycillin/clavulanicacid (Augmentin) vs. metronidazole as prophylaxis in hysterectomy: a prospective, randomized clinical trial. l:lrJObstet Gynaecol, 1988; 95: 286-293. 9. Abri O, Schulz L, Lohde E, Poschel E, Kraas E. Peri-operative antibiotic prophylaxis in colon surgery; amoxycillin/clavulanic acid versus mezlocillin + metronidazole. Proc 2nd Bienn Conf Ckemother Infect Dis Malig, Montreux, 1989; Poster 41. 10. Ashall G, Mouchizadeh J, Ornstein MH, Pyper RJD, Glazer G. A trial of Augmentin versus cephazolin and metronidazole for antibiotic prophylaxis in general surgery. Proc 4tk Mediterr Congr Chemother, Rhodes, 1984. Chemioterapia 1985; 4 (Suppl. 2): 776-777. 11. Bernard E, Bertrand JC, Dellamonica P. Prophylactic antibiotic treatment on colorectal surgery--a randomized single-blind study of amoxycillin/clavulanic acid versus cefoxitin. Proc 2nd Bienn Con[ Chemotker Infect Dis Mali~, Montreux, 1989: 42. 12. Beytout J, Ferrier C, 1,ointier P, Chipponi J, Boutin-Tranchant ME, Rey M. Antibioth~,rapie prophylactique en chirurgie digestive: r~sultat d'une ~tude randomisfie comparant amoxicilline-a, clavulanique fi gentalline+ornidazole. Proc Reunion Interdiscip Ckemother Anti-infect, Paris, 1987; Abstr. 134/P7, 187. 13. Brereton RJ, Ward HC, Valente A, Ghandour K, Price E, Dale P. A prospective trial of Augmentin (amoxycillin/clavulanic acid) prophylaxis in paediatric abdominal surgery. Proc 6th Mediterr Congr Chemother, Taormina, 1988..,7 Drug Dev, 1989; 2 (Suppl. 1): 95 104. 14. Dieterich H J, Groh J, Behringer K, I,auterjung L, Martin E. The prophylactic activity of amoxycillin/clavulanate and cefoxitin in vascular surgery-- a randomized clinical study, ff Antimicrob Ckemother 1989; 24 (Suppl. B): 209 211. 15. Dombrovicz N, Foidart JM. Use of Augmentin as antibioprophylaxis in hysterectomy: a comparative study. Proc 6tk Mediterr Congr Chemother, Taormina, Italy 1988: Abstr. 238: 139. 16. Drumm J, [)onovan IA, Wise R, Lowe P. Metronidazole and Augmentin in the prevention of sepsis after appendicectomy. IClrJ Surg, 1988; 72:571 573. 17. El Mufti MB, Glessa A. Single-dose clavulanate-potentiated amoxycillin versus three-dose cefotaxime in the prevention of wound infection following elective cholecystectomy: a prospective randomized study. J Int Med Res 1988; 16: 92-97. 18. E1 Mufti M, Rakas FS, Glessa A et al. Ceftriaxone versus clavulanate-potentiated amoxycillin for prophylaxis against post-operative sepsis in biliary surgery: a prospective randomized study in 200 patients. Curr Med Res Opin 1989; 11: 354-359. t9. Friese S, Willems FTC, Loriaux SM, Meewis JMJM. Prophylaxis in gynaecological surgery: a prospective randomized comparison between single dose prophylaxis with amoxycillin/clavulanate and the combination of cefuroxime and metronidazole, ft. Antimicrob Chemother 1989; 24 (Suppl. B): 213 216. 20. Hall C, Curran F, Burdon DW, Keighley MRB. A randomized trial to compare amoxycillin/clavulanate with metronidazole plus gentamicin in prophylaxis in elective colorectal surgery, ff Antirnicrob Chemother 1989; 24 (Suppl. B): 195-202. 21. Menzies D, Gilbert JM, Shepherd M J, Rogers TR. A comparison between amoxycillin/clavulanateand mezlocillin in abdominal surgical prophylaxis. ,7 Antimicrob Chemother 1989; 24 (Suppl. B): 203-208. 22. Meunier F, Legrand JC, Gerard A, Chastel C, Pector JC, Delhaye N. Antibiotic prophylaxis in gastrointestinal surgery. Proc 2nd Bienn Conf Chemother Infect Dis Malign, Montreux, 1989; Poster 60.
Meta-analysis of surgical prophylaxis
21
23. Mosimann F, Cornu P, Chikhi S. Amoxycillin/ctavulanic acid versus gentamicin/clindamycinas prophylaxis in elective colorectal surgery: a randomized trial. Proc 7th Mediterr Congr Ckemotker, Barcelona 1990: Abstr. 12. 24. Palmer BV, Mannur KR, Ross WB. An observer blind trial of Augmentin versus cefuroxime plus metronidazole in the prevention of post-operative wound infection after general surgery. (In press). 7th Mediterr Congr Ckemother, Barcelona 1990: Abstr. 220. 25. Playforth M J, Smith GMR, Evans M, Pollock AV. Single-dose intravenous antibiotics for the prophylaxis of abdominal surgical wound infection: a trial of amoxycillin/clavulanate against tatamoxef. Surg Res Comm, 1987; 1: 173-180. 26. Tehan S, Whittaker J. A multi-centre double blind prospective study comparing the efficacy and tolerance of Augmentin with the combination of cephradine plus metronidazole as surgical prophylaxis. Surg Res Commun 1989; 6:97 105. 27. Weersink A, Visser M, Vos Aet al. Amoxycillin/clavulanateprophylaxis against wound infections after clean-contaminated surgery. Eur.7 Surg 1991; 157:271 275. 28. Wenzel M. Oral enoxacin/metronidazole versus intravenous amoxycillin/clavulanic acid for antibiotic prophylaxis in colorectal surgery. Proc 17th ICC, Berlin 1991 ; Abstr. ! 793. 29. Dieterich H J, Groh J, Behringer K, Lauterjung L. Prophylactic activity of Augmentin (amoxycillin/clavulanic acid) and cefoxitin in vascular surgery--a randomized clinical study. Proc 6th Mediterr Congr Chemother, Taormina, 1988; J Drug Dev 1989; 2 (Suppl. 1): 105 106. 30. Friese S, Pricker G J, Willems FTC, I,oriaux SM. Single-dose prophylaxis in gynaecological surgery: amoxycillin/clavulanic acid versus the combination of cefuroxime and metronidazole in a randomized prospective comparison. Eur ff Obstet Gynaeeol Reprod Biol, 1988; 27:313 317. 31. van der Linden M, Ruijs G, van Erp E, Holm J, Meewis J. Amoxycillin/clavulanate versus cefuroxime/metronidazole in the prophylaxis of infection following gynaecological surgery. Proc 7tk Mediterr Congr Ckemotker, Barcelona, 1990; Abstr. 18. 32. Huizinga WKJ, Robbs JV, Kritzinger NA. Prevention of wound sepsis in amputations by peri-operative cover with an amoxycillin/clavulanic acid combination. S A Med ff 1983; 63: 71-73. 33. Evans CM, Purohit S, Colbert JW et al. Amoxycillin/clavulanic acid (Augmentin) antibiotic prophylaxis against wound infections in renal failure patients, ff Antimicrob Ckemother 1988; 22: 363--369. 34. Brackenbury PH, Muwanga CA. comparative double-blind study of amoxycillin/clavulanate versus placebo in the prevention of infection after animal bites. Arch Emerg Med, 1989; 6:251 256. 35. Earnshaw JJ, Hopkinson BR, Slack RCB, Makin GS. Risk factors in vascular surgical sepsis. Ann Roy Coll Surg Eng 1988; 70: 139--143. 36. Pollock AV, Evans M, Smith GMR. Preincisional Augmentin in abdominal operations. Ann Roy Coll Nurg Eng 1989; 71: 97-100. 37. Raine CH, Bartzokas CA, Stell PM, Gallway A, Corkhill JE. Chemoprophylaxis in major head and neck surgery, ff Roy Soc 2VIed 1984; 77: 1006-1009. 38. Meijer WS, Schmitz PIM, Jeekel J. Meta-analysis of randomized controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. Br ff Surg 1990; 77: 283-290.
A m e t a - a n a l y s i s of the use of a m o x y c i l l i n - c l a v u l a n i c acid in surgical prophylaxis A. P. R. Wilson, S. S h r i m p t o n a n d M. Jaderberg
Department of Clinical Microbiology, University College Hospital, London and SmitkKline Beecham Pkarmaceuticals, Brentford, Middlesex, UK. Summary: T h e efficacy of amoxycillin clavulanic acid as antibiotic prophylaxis in surgery has been assessed in numerous clinical studies, chiefly in abdominal and gynaecological surgery. A meta-analysis of 21 trials covering 2685 patients given amoxycillin-clavutanic acid and 2220 patients given comparator regimens is presented. Monotherapy with amoxycillin clavula-
nic acid was as effective as the comparators, including combination regimens utilizing gentamicin or metronidazole, in preventing wound infections (median wound infection rates were 6% and 10% respectively). The antibacterial activity of amoxycillin-clavulanic acid covers the broad range of aerobic Gram-negative and anaerobic organisms that have a major role in postoperative infections. In addition, amoxycillin clavulanic acid may have benefits in terms of convenience, tolerance and cost.
Keywords: Antimicrobial prophylaxis; amoxycillin-clavulanic acid; wound infection; meta-analysis.
Introduction T h e use of a n t i b i o t i c s for the p r e v e n t i o n of surgical sepsis has been s h o w n to be effective w h e n t h e o p e r a t i o n involves a site w i t h a n o r m a l bacterial flora, e.g. the c o l o n or vagina, and in patients w i t h i n c r e a s e d s u s c e p t i b i l i t y to infection u n d e r g o i n g p r o c e d u r e s , s u c h as g a s t r o d u o d e n a l or biliary s u r g e r y , t I n m a n y cases p l a c e b o - c o n t r o l l e d trials are no l o n g e r c o n s i d e r e d ethical and a s s e s s m e n t s of n e w p r o p h y l a c t i c a n t i b i o t i c s have to be m a d e in c o m p a r a t i v e trials w i t h e s t a b l i s h e d r e g i m e n s . T h e n u m b e r s of p a t i e n t s r e c r u i t e d into m o s t trials are i n a d e q u a t e to d e m o n s t r a t e a n y b u t the m o s t gross differences in efficacy b e t w e e n p r o p h y l a c t i c r e g i m e n s . M e t a - a n a l y s i s aims to c o m b i n e results f r o m different trials to increase statistical p o w e r and to p r o v i d e a s t r u c t u r e d a n d critical review of the existing m e d i c a l literature. 2 A m o x y c i l l i n c l a v u l a n i c acid ( ' A u g m e n t i n ' , S m i t h K l i n e B e e c h a m ) has been w i d e l y used as a p r o p h y l a c t i c a n t i b i o t i c in a b d o m i n a l and g y n a e c o l o g i c a l s u r g e r y . 3 Its s p e c t r u m of activity i n c l u d e s Staphylococcus aureus, Enterococcus faecalis, Esckerickia coli, Proteus mirabilis, and m o s t strains of Bacteroides fragilis. H o w e v e r , it is not active a g a i n s t Correspondence to: Dr A. P. R. Wilson, Department of Clinical Microbiology, University College tlospital, Grafton Way, London WC1E 6AU, UK. 0195 67(11/92/I)A0009 ~ 13 $08.00/0
"l;~ 1992 "l'hc I Iospital Injection Society
9
10
A. P. R. W i l s o n e t al.
amoxycillin-resistant strains of E n t e r o b a c t e r spp., S e r r a t i a m a r c e s c e n s or spp. 3 T h e aim of this study was to determine if any conclusion as to the relative efficacy of amoxycillin-clavulanic acid v s . other antibiotic regimens could be drawn from the literature.
Pseudomonas
Methods
Meta-analysis followed the m e t h o d of L ' A b b + e t a l . 2 T h e criteria for inclusion of studies in the review were that they were randomized comparative trials of the efficacy of anaoxycillin-clavulanic acid v s . other antibiotic regimens in the prevention of surgical w o u n d infection. Randomization had to be performed in a m a n n e r that precluded knowledge of the next treatment assignment. Antibiotic prophylaxis had to be administered prior to skin incision. Studies were rejected on the basis of methods not results. Relevant studies were identified by a c o m p u t e r search on 'Medline' from 1983 to 1991, by reviewing the references in the trials found and in other reviews. 3 T o find studies that were only partially published, the records of the m a n u f a c t u r e r were consulted. Data extraction was performed i n d e p e n d e n t l y by two of the authors. Inter-observer agreement was recorded and any differences resolved by discussion. Assessment of quality was similarly performed by two of the authors using a published method. 4 Differences in efficacy were expressed by the odds ratio (OR) and results were pooled by the m e t h o d of Mantel-Haenszel. 2's T h e pooled OR gave an estimate of the relative risk of w o u n d infection in patients given amoxycillin-clavulanic acid or a comparator antibiotic in groups of trials covering, for example, a surgical speciality. Heterogeneity was tested graphically 2 and by the m e t h o d of W o o l f using an adjustment for small subsets, s Confidence intervals were calculated for the individual trials and for the combined data, using the m e t h o d of Cornfield. 6 T h e effect of inclusion of the quality index 4 was examined by the m e t h o d of Klein et al. 7 Where possible, efficacy was examined for specific surgical specialities: colorectal, gynaecological and biliary surgery. Comparison was made with regimens containing cephalosporins or aminoglycosides. One study showed a significant difference between amoxycillin-clavulanic acid and metronidazole in gynaecological surgery as a result of infections caused by aerobic Gram-negative bacteria. 8 T h e effects of exclusion of this trial were examined. Results Literature
review
T h e literature search identified 30 studies. ~ 37 Nine trials were excluded, including two duplicate publications (references 14 and 29, and references
Meta-analysis of surgical prophylaxis
11
19 and 30) and one that did not indicate in which antibiotic group infections occurred. 31 One study was excluded because it gave no indication of patient randomization. 32 It claimed a significant i m p r o v e m e n t in the rate of sepsis after amputation in patients given amoxycillin-clavulanic acid (three of 31 patients), compared to those given penicillin (9 of 13 patients) ( P < 0"001). Three trials were placebo-controlled 33'34'3: and two compared different regimens of amoxycillin-clavulanic acid. 3S'36 For the remaining 21 trials, the characteristics of the patients, and the dosage and duration of the test and control regimens are shown in "Fable I. T h e criteria for w o u n d infection and results are shown in Table II. All except two studies used control regimens effective against G r a m - n e g a t i v e bacteria. ~'16 Control regimens for contaminated surgery usually included metronidazole or clindamycin but, with one exception, 25 amoxycillinclavulanic acid was given as a 'single' agent. T w o studies were double-blind, three observer-blind and two patient-blind. T h e r e were 20 (7%) points of disagreement between the two authors in Tables I and II. These were all resolved by discussion. Statistically significant differences in favour of amoxycillin-clavulanic acid vs. comparator regimens were present in two trials. In one the excess of infections was caused by Gram-negative aerobes as the comparator was metronidazole alone (2% vs. 11%, difference in proportions 95% C1 0.03-0"15). s T h e other study compared amoxycillin-clavulanic acid with metronidazole plus gentamicin in paediatric surgery (5% vs. 25%, difference in proportions 95% confidence limits 0"08-0-33). 13 C u l t u r e of wound exudate usually produced a mixed growth and the n u m b e r of patients with positive cultures in each group was not given. However, there were eight isolates of S. a u r e u s and four of E n t e r o c o c c u s spp. after the comparator regimen compared with none after amoxycillin-clavulanic acid. T h e likelihood of a T y p e II error (i.e. of failing to detect a significant difference) was discussed in three trials but, in two, the n u m b e r s needed were t h o u g h t impractical. 24'27 T h e third designed the trial to recruit sufficient numbers to detect a 50% reduction in the rate of sepsis with a power of 0"8. 2~ T w o other trials were of sufficient size to detect a 50-60% reduction but recruited patients in a 2:1 ratio. 2s'26 Bacterial isolates were c o m m o n l y mixed and the n u m b e r of isolates, rather than patients, were given, making statistical differentiation of antibacterial efficacy difficult. Quality
assessment
Quality scores varied from 25% to 89% and the difference between the assessors was largely d e p e n d e n t on the interpretation of the criteria. F u r t h e r criteria for the answering of these questions were decided as previously reported. 3s T h e resulting mean difference in score was 0.01 with a range of - 0'05 0"06. These differences were resolved by discussion. I n f o r m a t i o n on the outcome of patients withdrawn from study was given in only one study. 2s
12
A. P. R. W i l s o n e t a L
"Fable I. Characteristics of comparative trials of amoxycillin-clavulanic acid (ACA) in the
prevention of surgical wound prevention Trial/ indication
Blind
Exclusions
Quality
Age (years) ACA/comparator
Sex
Abri '~ Colon
NB
NK
0-40
NK
NK
Ashall '~ General
NB
NK
0.46
NK
NK
Bernard ~' Colorectal
PB
NK
0.51
65+2 67 4- 1-5
Beytout ~2 Abdominal
NB
NK
0.34
NK
Brereton ~3 paediatric, Abdominal
NB
M i n o r surgery, recent antibiotics, sepsis, allergy, C S F shunts, < 10% risk of w o u n d infection
0'69
0-13 0-13
33M 22M
18F 16F
0 9
20M
13F
18M 12M
14F 17F
NK
Brown* Hysterectomy
NB
Allergy, recent antibiotics, renal failure, infection, diabetes, steroids, a u t o i m m u n e disease
0"77
26 74 25 80
Dieterich TM Vascular
NB
Liver disease, allergy, recent antibiotics
0.46
24-86 23-78
D o m b r o v i c h 's Hysterectomy
NB
NK
0.25
NK
NK
D r u m m u' OB Appendicectomy (a) n o n gangrenous (b) g a n g r e n o u s
< 12 years, recent antibiotics, allergy
076
(a) N K NK (b) N K NK
NK
E1 M u f t i ' : NB Cholecystectomy
Allergy
0"54
22 75 16-67
4M 2M
El M u f t i TM Biliary
NB
Allergy
0"41
18-73 18-72
IlM 13M
Friese t'' Gynaecological
NB
Allergy, < 16 years, recent antibiotics, malignancy, pregnancy
0.71
Allergy, < lg years, lactation, pregnancy, renal failure, infection, inflammatory bowel disease, e m e r g e n c y
0.70
Hall > Colorectal
NB
394- 15 to 62 + 14 38• to 5 9 • 13 18 90 18-92
138F 142F
57M 56M
15f: 13F
NK
46t: 48F 89F 87F
199F 196t; 59M 46M
1231," 131F
Meta-analysis of surgical prophylaxis Table I. Trial/ indication
Blind
13
(continued)
Exclusions
Quality
Age (years) ACA/comparator
Sex
Menzies 21 PB Abdominal (a) clean (b) c o n t a m i n a t e d
< 14 years, allergy, renal or liver failure, pregnancy, recent antibiotics
0"74
(a) 19-81 20-88 (b) 18-88 20-88
27M 25M 32M 38M
35F 42F 31F 28F
M e u n i e r 22 Abdominal (carcinoma)
NB
Neutropenia
0'35
24-84 40-80
10M
16F
13M
14F
Mosimann > Colorectal
NB
NK
0.45
NK
Palmer 24 Abdominal
OB
< 12 years, allergy, o t h e r antibiotics, infection, pregnancy, renal or hepatic failure, previous entry
0"78
12-96 13--96
103M l15M
127F ll0F
Playforth 2s Abdominal
DB
< 1 2 years, allergy, hernias, mistaken administration
0.85
>12<89
173M
180F
>12<89
95M
NK
91F
Tehan > General and gynaecological
DB
Allergy, recent antibiotics, hepatic or renal failure, pregnancy, lactation, emergency
0.79
16-89 18-92
156M 84M
553F 264F
Weersink 27 Abdominal
OB
< 18 years, infection, other antibiotics, allergy, pregnancy
0.74
26-86
26M
33F
22-85
19M
24F
NK
0.25
Wenzel 2s Colorectal
NB
NK
NK
NK = not known; I)B = double-blind; OB = observer blind; I'B = patient blind; NB = not blinded.
Pooling of trial results The 21 trials covered 2685 patients given amoxycillin-clavulanic acid and 2220 patients given comparator regimens with median rates of postoperative wound infection of 6 and 10% respectively (Table III). The pooled OR for wound infection in the 21 trials was 0-84 (95% confidence limits 0.68 1.03) by Mantel-Haenszel, not significantly different from 1"0 but with a trend in favour of amoxycillin-clavulanic acid (Table I I I; Figure 1). By including the quality index, this trend was lost and the pooled OR became 0"89 (95% confidence limits 0'7-1"2). Excluding the two trials in which the comparator was metronidazole alone, s'16 the pooled odds ratio
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was 0-93 (95% confidence limits 0"7-1"2) (Z x= 0"4, P > 0"5), becoming 1"00 (95% confidence limits 0"8-1"3) when quality was included. With the exception of gynaecological surgery, the pooled results did not suggest any difference in efficacy between amoxycillin-clavulanic acid and comparator antibiotics. Nine studies gave separate results for colorectal surgery, including 705 patients given amoxycillin-clavulanic acid and 628 given comparator regimens. 9'2~ T h e rates of post-operative w o u n d infection were similar and the pooled O R was not significantly different from 1"0 (Table III). Pooling the four studies reporting biliary surgery 17dS'24,2s gave a similar result (3 % v s . 4% infection). T h e pooled ratio of the four studies of gynaecological surgery 8'1s,19'26 was distorted by the inclusion of the trial of Brown e t a l . 8 and was not significantly different from 1-0 when trial quality was included. Nine trials c o m p a r e d w o u n d infections in a total of 1685 patients given amoxycillin-clavulanic acid with 1232 given a cephalosporin with/without metronidazole.m,11,14,17 19,24-26 T h e r e was no significant difference in efficacy in the pooled results (odds ratio 1"0), the median rate of infection being 6% in both cases (Table III). Six trials included gentamicin in the comparator regimen but again efficacy was similar (odds ratio 0"98). 12'13'20'22'23'27 T h e r e was a significant heterogeneity amongst these trials ()r 13, P < 0 " 0 2 5 ) but this was lost when the quality index was included (X2= 7"6, P > 0 " I ) . Fourteen trials compared amoxycillin-clavulanic acid as m o n o t h e r a p y with a combination of two or more antibiotics. T h e pooled odds ratio was very close to 1"0, despite inclusion of 2053 v s . 1581 patients (Table III). 9'1~176 Eight trials used a single agent as comparator and again there was no evidence of any difference in efficacy (odds ratio 0.94, Table Ill). 8'11'14'16 t8,21,25 Bacteriological efficacy was not interpretable in many trials as the n u m b e r of w o u n d s from which isolates derived was not given. In nine trials, covering 1438 test patients and 985 controls, the odds ratio was 0"83 (95% confidence limits 0"5-1'2) (Z 2= 0-8, P > 0"3). Six studies reported adverse events following amoxycillin clavulanic acid or comparator. 8'1~ 9/128 v s . 3/126, 2/47 v s . 2/36, 2/138 v s . 0/142, 2/72 v s . 3/69, 10/521 v s . 2/251 and 2/59 v s . 2/43. T h e pooled odds ratio was 1"87 (95% confidence limits 0"9-4) (Z2=2"6, P > 0 " I ) with or without the quality index. T h e r e was no significant heterogeneity. Discussion
T h e meta-analysis suggests that there is no statistically significant difference in efficacy between amoxycillin clavulanic acid and comparator regimens of similar antimicrobial s p e c t r u m in the prevention of w o u n d infection. Both single and combination comparator regimens showed similar efficacy to amoxycillin clavulanic acid. T h e incidence of adverse events following amoxycillin-clavulanic acid was not significantly different from that of other regimens.
Meta-analysis of surgical prophylaxis
19
Individual trials were usually of inadequate size to demonstrate differences of 50% in efficacy. T h e one exception was a trial of amoxycillin clavulanic acid v s . gentamicin plus metronidazole in paediatric surgery. 13 T h e study included a placebo group but the rate of withdrawal from the group was high. Detailed analysis was provided on only 122 of 171 operations but this did not appear to affect the significance of the result. Although statistical analysis of bacteriological efficacy was not possible, the excess of infections with the comparator regimen appeared to be due to S. a u r e u s and enterococci. T h e lack of a consistent trend in colorectal surgery despite the inclusion of 13 33 patients suggests that trials sufficient to show a significant difference would be too large to be practicable. T h e efficacy of regimens including a cephalosporin or an aminoglycoside appeared similar to those with amoxycillin-clavulanic acid, again including large n u m b e r s of patients. Metronidazole alone was inadequate in gynaecological surgery as w o u n d infections due to aerobic Gram-negative bacteria occurred in significant numbers, s Placebo-controlled trials demonstrate a significant reduction in surgical w o u n d infection in patients given amoxycillin-clavulanic acid. W o u n d infections after various procedures in a renal transplant unit were less frequent after 1"2 g amoxycillin-clavulanic acid (0/24 v s . 6/22, P = 0 - 0 1 , Fisher's test). 33 However, there were more transplant patients in the treated group. A double-blind placebo-controlled trial showed amoxycillinclavulanic acid to be effective in reducing clinical infection after animal bites when given between 9 and 24 h after injury but represents early t r e a t m e n t rather than prophylaxis. 34 An observer-blind study in head and neck surgery reported four infections in 16 patients given the antibiotic compared to 12 infections in 16 given placebo ( P = 0"01, Fisher's test). 37 T w o trials compared different regimens of amoxycillin clavulanic acid. One trial failed to show a significant difference in efficacy of a 5-day course and a short course of three doses in vascular surgery (9/56 v s . 12/52). 3s T h e other showed amoxycillin clavulanic acid given subcutaneously along the line of the proposed incision to be associated with fewer w o u n d infections than after the same dose given intravenously (25/296 v s . 52/328, P < 0-01, Z2 test). 36 Amoxycillin-clavulanic acid is effective in the prevention of w o u n d infection in operations where w o u n d infections are likely to develop with Gram-negative, anaerobic or mixed bacteria. This meta-analysis suggests that anaoxycillin-clavulanic acid m o n o t h e r a p y is as effective as single agent or combination regimens and it might be preferred to the latter by virtue of safety, convenience and lower cost. References
1. Guglielmo BJ, Hohn I)C, Koo PJ, Hunt TK, Sweet RI,, Conte JE. Antibiotic prophylaxis in surgical procedures. A r c h Surg 1983; 118:943 955. 2. L'Abb~ K, Detsky AS, O'Rourke K. Meta-analysis in clinical research. A n n Intern M e d 1987; 107: 224-233.
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A. P. R. W i l s o n e t a k
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