JAC Advance Access originally published online on May 15, 2007
Journal of Antimicrobial Chemotherapy 2007 60(1):166-169; doi:10.1093/jac/dkm128
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Inadequate antimicrobial prophylaxis during surgery: a study of ß-lactam levels during burn debridement
1 Burns Trauma and Critical Care Research Centre, University of Queensland, Brisbane, Queensland, Australia 2 Therapeutics Research Unit, School of Medicine, University of Queensland, Brisbane, Queensland, Australia 3 Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia 4 Department of Intensive Care Medicine, Princess Alexandra and Wesley Hospitals, Brisbane, Queensland, Australia 5 Department of Surgery, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
* Correspondence address. Therapeutics Research Unit, School of Medicine, University of Queensland, Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, Queensland 4102, Australia. Tel: +61-7-3240-5364; Fax: +61-7-3240-5806; E-mail: s.cross{at}uq.edu.au
Received 13 February 2007; returned 11 March 2007; revised 28 March 2007; accepted 5 April 2007
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Abstract |
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Objectives: To determine how long single-dose prophylactic antibiotic regimens for burns surgery maintained plasma concentrations above the MICs for target organisms during surgery.
Patients and methods: We monitored antibiotic plasma concentrations in 12 patients (mean ± SD 43 ± 12% total burn surface area) throughout debridement surgery after administration of the standard prophylactic antibiotic dosing regimens of either 1 g of intravenous cefalotin or 4.5 g of intravenous piperacillin/tazobactam.
Results: The eschar debridement and grafting procedures ranged in duration from 2.25 to over 8.5 h. The duration of total plasma cefalotin concentration above an MIC of 0.2 mg/L for Staphylococcus aureus was 6.49 ± 2.85 h, whereas the mean duration of total plasma piperacillin concentration above an MIC of 64 mg/L for Pseudomonas aeruginosa was only 1.15 ± 0.59 h. None of the patients dosed with piperacillin/tazobactam was adequately protected for the duration of their surgery and adequate prophylaxis was only evident in four of the nine patients administered cefalotin.
Conclusions: These results suggest a need to review antibiotic prophylaxis dosage regimens for burns surgery and the adoption of regimens that will minimize the risk of infection in this high-risk patient group. It is suggested that the antibiotic prophylaxis guideline for burn debridement surgery be modified to include re-dosing or a continuous infusion of ß-lactam antibiotics.
Keywords: antibiotic prophylaxis , intraoperative period , drug administration schedule , adult burns
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Introduction |
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The purpose of prophylactic antibiotic dosing is to ensure adequate drug concentrations are present to inhibit infection during the time that sites are at risk of bacterial contamination.1 Current guidelines vary, with some recommending a single prophylactic dose.2,3 The incidence of post-operative bacteraemia increases with burn area over 40%4 and with the length and intensity of surgery,5 however antibiotic prophylaxis during surgical debridement in such patients is still a contentious issue.
The Surgical Infection Prevention Project recommended that administration should be repeated intraoperatively if the operation is still continuing two half-lives after the first dose to ensure adequate antimicrobial levels until wound closure.1,6 In burns surgery where ß-lactam antibiotics are preferred, a single dose of perioperative antibiotic for prophylaxis is normally given.2 Burn surgery presents a continuous risk of bacterial contamination, so the question remains that if prophylaxis is used, does a single antibiotic dose provide adequate protection for the duration of bacterial exposure risk during prolonged burn debridement and grafting procedures?
The aim of the current study was to evaluate whether the antimicrobial prophylactic regimens used for burns surgery were adequate. We therefore determined serial plasma concentrations of cefalotin or piperacillin on 12 occasions of burn debridement surgery (mean ± SD patient body surface area of burn 43 ± 12%) after recommended intravenous dosing (1 g of cefalotin or 4.5 g of piperacillin/tazobactam).
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Study design
The protocol received approval from Hospital and University of Queensland Human Research Ethics Committees. Written informed consent was obtained from the legal guardians of enrolled patients. Patients younger than 18 years were excluded from participation.
Studies were conducted during debridement and grafting procedures within 4 days of trauma. Established protocol was followed, substituting piperacillin/tazobactam for cefalotin where co-morbidity or prior antibiotic issues necessitated a broader spectrum of antimicrobial cover. Patients received either 1 g of cefalotin over 5 min or 4.5 g of piperacillin/tazobactam over 30 min through a dedicated lumen of a central venous catheter. Blood sampling into heparinized vacutainers from an indwelling arterial cannula at stipulated time intervals continued for 8 h. Samples were kept on ice, centrifuged and plasma fractions stored at –20°C.
Plasma was analysed within 1 week by HPLC with UV detection using 150 mm x 4.6 mm Gemini C18 columns (Phenomenex, Australia).
Cefalotin assay: the isocratic mobile phase was 22% acetonitrile in 10 mM phosphate buffer, pH 3.5; flow rate 1.2 mL/min; 5 µm column; detection at 238 nm 
. Cefalotin sample preparation: 500 µL of plasma, 20 µL of 2.5 mg/mL cefazolin (internal standard) and 500 µL of acetonitrile were mixed, then 0.2 g of sodium chloride and 45 µL of 85% phosphoric acid were added. After centrifugation (18 000 g, 12 min), 100 µL of upper phase was diluted with 100 µL of water and analysed. Linearity was demonstrated to 200 µg/mL. Validation with pooled human plasma gave a limit of quantification (LOQ) (signal to noise ratio 10) of 45 ng/mL, an intraday coefficient of variation (CV) (for 10 µg/mL) of 1% and an interday CV (for 5 µg/mL) of 6.3% over 4 months.
Piperacillin assay: a gradient of acetonitrile in 10 mM phosphate buffer, pH 2.7, was increased linearly from 21.8% to 35.9% over 15 min then decreased to 21.8% by 27 min. Flow rate 0.8 mL/min; 3 µm column; detection at 218 nm . Piperacillin sample preparation: 500 µL of plasma, 50 µL of 5 mg/mL penicillin G (internal standard) and 1500 µL of acetonitrile were centrifuged (13 000 g, 5 min). Two millilitres of supernatant and 2 mL of dichloromethane were mixed and centrifuged (1500 g, 10 min), analysing the top layer. Linearity was demonstrated to 500 µg/mL. Assay validation gave a LOQ of 2.5 µg/mL, an intraday CV (for 50 µg/mL) of 2.2% and an interday CV (for 50 µg/mL) of 6.4% over 5 months.
Microsoft® Excel 2003 (Microsoft Corporation, USA) and Graphpad Prism Version 4.03 for Windows (Graphpad Software Inc., USA) were used for non-linear regression and statistical analysis. Biexponential fits (C = Ae–
t + Be–ßt) were plotted, applying 1/y2 weighting to account for assay heteroscedasticity. Values of time above MIC (t> MIC) were calculated from non-linear regressions using published MIC90 data.
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Results |
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Post-infusion antibiotic concentration–time profiles for burn patients receiving surgery were established on 12 occasions (3 piperacillin/tazobactam and 9 cefalotin). The study cohort was predominantly male (two female) and Caucasian, ranged in age from 23 to 54, had burns (full and partial thickness) to 43 ± 12% of their bodies and received eschar debridement and grafting procedures ranging in duration from 2.25 h to over 8.5 h (mean 5.9 ± 1.8 h).
Figure 1 depicts graphically the total plasma concentration–time profiles resulting from the 8-hourly dosing of (a) cefalotin and (b) piperacillin. The levels of established MIC concentrations for Staphylococcus aureus (0.2 mg/L7), as the principal target for prophylaxis with cefalotin, and Pseudomonas aeruginosa (64 mg/L8), the target organism of piperacillin, are shown to provide an indication of theoretical antibacterial efficacy.
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On average, plasma concentrations of cefalotin were above the MIC for S. aureus for 6.5 h (6.49 ± 2.85 h), equating to 81% of the 8 h dose interval. Cefalotin concentrations fell below MIC levels before completion of surgery in five out of nine cases. Mean piperacillin concentrations were above the MIC for P. aeruginosa for just the first hour of debridement surgery (1.15 ± 0.59 h); 14% of an 8 h dose interval. Piperacillin concentrations fell below MIC levels before surgery completion in every case. Plasma piperacillin concentrations did not exceed 5 x MIC for P. aeruginosa, and cefalotin levels in excess of 5 x MIC for S. aureus were maintained for only 2.75 h (2.79 ± 1.65 h); 35% of an 8 h dose interval.
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Discussion |
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Burn debridement procedures can be time consuming with risk of bacterial contamination present throughout, calling for sustained antibiotic concentrations to achieve effective prophylaxis. The current study is the first to document plasma levels of ß-lactams in burn patients during eschar debridement surgery. We believe it raises questions as to the adequacy of single dose antibiotic regimes for perioperative prophylaxis of bacteraemia in patients with >40% body surface area burns.
The Surgical Infection Prevention Project proposes trauma patient surgery as potentially warranting dosage adjustment over its current guidance.6 Infection prophylaxis in burn patients requires greater consideration than would normally be the case for elective procedures, with transient bacteraemia being of little consequence in healthy patients but potentially deleterious in burn patients.4
Currently, repeat prophylactic dosing is recommended to provide antimicrobial cover during prolonged surgery.1,9 Appropriate repeat dosing of cefazolin is associated with lower surgical site infection (SSI) rates in lengthy cardiac surgery,9 and the relationship between suboptimal antibiotic concentrations during surgery and SSI has been established for aminoglycosides,10 but not specifically for ß-lactams. In the current study, we document potentially ineffectual plasma levels of ß-lactams during eschar debridement, which are often prolonged procedures with an ever-present infection risk.
For infection treatment, time of ß-lactam concentrations above the MIC for the organism (t > MIC) must be more than 40% to 60% of the dose interval to ensure standard efficiency, t > MIC of 100% of the dose interval is suggested for immunocompromised patients, but improved efficiency of time-dependent antimicrobials is seen when concentrations of 4- to 5-fold MIC are achieved.11
If t > MIC for the target organism is used as the criteria for adequacy in this patient population, based on a reported MIC of cefalotin acting on penicillin- and methicillin-susceptible S. aureus strains of 0.2 mg/L,7 we found that, on average, patients were at risk of Gram-positive bacteraemia for 20% of the dose interval, potential prophylactic failure occurring in five out of nine studies. Prophylaxis against Gram-negative infections with 4.5 g of piperacillin/tazobactam was ostensibly ineffective in every case, with patients at risk of P. aeruginosa (MIC = 64 mg/L8) infection for the majority (over 80%) of the 8 h dose interval.
During burn surgery, the risk of bacterial contamination is high throughout the entire procedure and our demonstration of inadequate prophylaxis highlights a significant clinical problem in the under-dosing of burn patients during surgical procedures and the need for adoption of more suitable dosing regimens for this high-risk population. Since up to 75% of post-resuscitation phase burn patient mortality is linked to infection, more proficient antibiotic therapy could significantly improve patient survival.
In the absence of definitive data on dosages needed to prevent bacteraemia or burn site infection, or definitive data on prophylactic dosing for burn surgery, 4- to 5-fold MIC therapeutic targets are the most attractive in this high-risk population. To obviate the problem of inadequate prophylaxis, we suggest either repeat dosing or, even better, a continuous infusion as the latter has been shown to provide longer t > MIC.11
In conclusion, we have shown that conventional pre-operative prophylaxis with single doses of cefalotin and piperacillin did not provide adequate plasma concentrations above established MICs during lengthy debridement surgery. In keeping with other recent literature,1,6,9,10 it is suggested that the guidelines for dosage regimens for prophylactic peri-operative burn surgery be reviewed. Our data provide the impetus for more frequent or even continuous infusion administration of ß-lactams for effective burn surgery prophylaxis.
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Transparency declarations |
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None to declare.
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Acknowledgements |
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We acknowledge the financial support of the National Health and Medical Research Council of Australia together with Ms Renae Deans without the help of whom patient sample collection could not have been so effectively achieved and Ms Melissa Rutt for her technical laboratory assistance.
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References |
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1 Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Am J Surg (2005) 189:395–404.[CrossRef][Web of Science][Medline]
2 Victorian Drug Usage Advisory Committee. In: Therapeutic Guidelines—Thirteenth Edition: Antibiotic (2006.) Melbourne, Australia: VMPF Therapeutics Committee.
3 Scottish Intercollegiate Guidelines Network. In: SIGN publication Number 45: Antibiotic Prophylaxis in Surgery (2000.) Edinburgh, UK: SIGN Council.
4 Mozingo DW, McManus AT, Kim SH, et al. Incidence of bacteremia after burn wound manipulation in the early postburn period. J Trauma (1997) 42:1006–10.[Web of Science][Medline]
5 Sasaki TM, Welch GW, Herndon DN, et al. Burn wound manipulation-induced bacteremia. J Trauma (1979) 19:46–8.[Web of Science][Medline]
6 Fry DE. The surgical infection prevention project: processes, outcomes, and future impact. Surg Infect (2006) 7(Suppl 3):s17–s26.
7 Williams JD, Moosdeen F. In vitro antibacterial effects of cephalosporins. Drugs (1987) 34:44–63.
8 Bryson HM, Brogden RN. Piperacillin/tazobactam—a review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs (1994) 47:506–35.[Web of Science][Medline]
9 Zanetti G, Giardina R, Platt R. Intraoperative redosing of cefazolin and risk for surgical site infection in cardiac surgery. Emerg Infect Dis (2001) 7:828–31.[Web of Science][Medline]
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Zelenitsky SA, Ariano RE, Harding GKM, et al. Antibiotic pharmacodynamics in surgical prophylaxis: an association between intraoperative antibiotic concentrations and efficacy. Antimicrob Agents Chemother (2002) 46:3026–30.
11 Roberts J, Lipman J. Antibacterial dosing in intensive care: pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet (2006) 45:755–73.[CrossRef][Web of Science][Medline]
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