Preventing Surgical Site Infections after Bariatric Surgery: Value of Perioperative Antibiotic Regimens

Teena Chopra; Jing J Zhao; George Alangaden; Michael H Wood; Keith S Kaye

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2010;10(3):317-328. 

In This Article

Antimicrobial Prophylaxis: Overview

The benefits of perioperative antimicrobial prophylaxis in preventing SSIs have been clearly demonstrated through numerous trials and endorsed in various guidelines.[13,40,43–48] The goal of perioperative antimicrobial prophylaxis is to ensure that adequate antibiotic levels are maintained above the minimum inhibitory concentration (MIC) from the time of incision and throughout the procedure. The selection of appropriate prophylactic antibiotic regimens requires consideration of the expected microbial flora at the surgical site, patient-specific factors such as allergy and exposure to resistant bacteria, institution-specific factors such as local antibiograms and antibiotic formulary availability and drugs. Drug considerations include bactericidal activity, pharmacokinetic and pharmacodynamic parameters to ensure the adequate delivery of antibiotics in relation to surgical incision and the maintenance of optimal drug levels throughout the procedure. The bariatric surgery population presents challenges related to optimal drug dosage, infusion time and drug disposition. Unfortunately, there are only limited data describing the pharmacokinetic properties of antimicrobials in the obese patient population.

Antimicrobial Prophylaxis: Agent Selection for Bariatric Surgery The goal of surgical antimicrobial prophylaxis is not to sterilize tissues, but to decrease bacterial burden to a level that can be controlled by host defenses. Numerous microbial species have been implicated as SSI pathogens. In bariatric surgical procedures, the predominant organisms include Gram-positive bacteria such as staphylococci, streptococci and enterococci, and Gram-negative pathogens such as Enterobacteriaceae including Proteus mirabilis, Serratia marcescens, Enterobacter and Escherichia coli, and anaerobes including Bacteroides fragilis.[18,19]

Regimens for Patients not Allergic toβ-lactams Antimicrobial prophylaxis is delivered by the intravenous route. Historically, cephalosporins have been the dominant class of antimicrobials for surgical prophylaxis. They are well tolerated and have a low incidence of allergy. The rates of cross-reactivity with penicillin are low enough to justify the use of a cephalosporin in patients who do not have a history of IgE-mediated reaction to a penicillin.[49] The most advocated prophylactic agent for gastroduodenal procedures is cefazolin.[40] For bariatric surgeries above or including the duodenum, cefazolin is the drug of choice. For bariatric procedures below the duodenum, agent(s) with anaerobic activity are preferred, such as the cephamycins or cefazolin in combination with metronidazole. The cephamycins are a unique group of cephalosporins with good activity against anaerobic organisms and they are frequently used as prophylactic agents in bariatric surgery.[40] Available cephamycins in the USA are cefoxitin a and cefotetan. Cephamycin activity against the B. fragilisgroup varies significantly by agent and species. The percentage susceptibility of B. fragilisand the B. fragilis group against cefotetan re 81 and 56%, respectively.[50] Activity for cefoxitin against B. fragilisand the B. fragilisgroup are 94.8 and 92.6%, respectively.[50] Therefore, cefoxitin is the preferred cephamycin as it provides adequate coverage of the pathogens that are most commonly identified as causing SSI following bariatric surgery. Based on the Gram-negative susceptibility data from local surgical surveillance, nonantipseudomonal third-generation cephalosporins (such as cefotaxime or ceftriaxone) may provide excellent activity against E. coli and are an alternative to cefazolin. Enterococci are questionable pathogens in polymicrobial surgical settings;[51–55] hence, they are not routinely covered by surgical antimicrobial prophylaxis.

Alternative prophylactic regimens include the β-lactam/β-lactamase inhibitor combiniations such as ampicillin/sulbactam. However, there has been a significant increase in resistance of certain organisms such as E. coli to ampicillin/sulbactam.[56–58] Ertapenem, a type 1 carbapenem, and tigecycline, a novel glycylcycline, have good activity against flora that are commonly encounterd during bariatric surgery. However, these agents have a broad spectrum of activity and should be reserved for the treatment of documented resistant pathogens rather than for routine prophylaxis. Other β-lactams used alone or in combination are also options, although they are not recommended for routine antimicrobial prophylaxis use. These agents include ceftazidime (an antipseudomonal third-generation cephalosporin), cefepime, type 2 carbapenems (such as meropenem, imipenem-cilastatin or doripenem) and other β-lactam/β-lactamase inhibitor combinations such as piperacillin/tazobactam and ticarcillin/clavulanic acid. Use of these agents should be restricted owing to their broad spectrum of activity against pathogens that do not commonly cause SSIs such as Pseudomonas aeruginosa.

Regimens for Patients Allergic toβ-lactams Although no formal guidelines exist for choosing a prophylaxis agent for patients with a history of IgE-mediated allergy to penicillins or cephalosporins, several potential agents are available. For example, non-β-lactam agents such as clindamycin plus ciprofloxacin, levofloxacin, or clindamycin plus an aminoglycloside (such as gentamicin, tobramycin or amikacin depending on local Gram-negative susceptibility) are options for bariatric surgeries, particularly if the ileum is not involved. If the ileum is involved in the procedure, additional anaerobic coverage can be provided by combining levofloxacin with metronidazole, or by administering moxifloxacin as a single agent. Aztreonam is a β-lactam with Gram-negative activity that does not cross-react with other β-lactams, except for ceftazidime. Hence, it may also be considered as an option in combination with agents that have activity against Gram-positive and anaerobic organisms.

Table 1 summarizes the antimicrobial recommendations for bariatric surgical prophylaxis.

Increasingly, the emergence of more resistant pathogens, such as methicillin-resistant S. aureus(MRSA), has complicated decisions regarding preoperative antimicrobial prophylaxis. Vancomycin has been advocated for surgical prophylaxis in certain types of surgeries for patients with severe allergies to β-lactams. Vancomycin has been increasingly considered for prophylaxis at institutions with a high rate of infections caused by MRSA or methicillin-resistant coagulase-negative staphylococci. However, there is no consensus regarding what constitutes high levels of methicillin resistance. One guideline defines a high rate of infection caused by MRSA as over 20%, based on expert panel consensus.[40] Christou et al. examined 269 patients undergoing isolated RYGB surgery and cultured S. aureusfrom 39% of infected wounds. However, the frequency of methicillin resistance was not reported.[18] At our institution, among 91 SSIs, S. aureus was isolated in only four cases, and two of these were MRSA.[19] Thus, MRSA does not appear to be a common SSI pathogen following bariatric surgery; therefore, in most cases, antimicrobial prophylaxis to target MRSA is unnecessary. However, decisions regarding the need to provide antimicrobial prophylaxis against MRSA should be based on local SSI surveillance data and the frequency of MRSA SSIs.

Antimicrobial Prophylaxis: Route of Administration Most antimicrobial agents do not achieve optimal serum levels when administered orally. Although certain oral antimicrobials have comparable bioavailability with their intravenous formulation, the time to achieve maximum serum concentration is slower due to the need for absorption through the gastrointestinal tract. Intravenous antimicrobial prophylaxis is the most extensively studied route and remains the preferred route of administration.

The application of topical and subcutaneous antimicrobials to the bariatric surgical site has also been studied. Alexander et al. examined the infusion of kanamycin 0.1% solution (1000 µg/ml), at the time of incision closure, into the subcutaneous space of 837 morbidly obese patients undergoing open, primary or revisional bariatric procedures, in addition to standard systemic antimicrobial prophylaxis (e.g., intravenous cefazolin).[59] Kanamycin was allowed to dwell for 2 h. Overall, SSIs developed in the subcutaneous tissues of 0.72% of patients, and superficial infections developed in 2.5% of patients. Unfortunately, no control group was included in this study. A finding of concern related to this route of administration is the absorption of kanamycin into the serum of patients, as reported in another study by the same investigators.[60] Christou et al. supplemented parenteral prophylactic antibiotic with 500 mg of cefazolin powder, which was placed directly in the wound before incision closure in patients undergoing an open RYGB.[18] No difference in the rate of wound infection was observed among patients receiving cefazolin powder compared with patients who did not (20 with, 17% without local antibiotic). Although the role of topical and incisional antimicrobials in prevention of SSI is intriguing, currently, they are not the standard of care for the prevention of SSI following bariatric surgery.

Mechanical bowel preparation, which includes the preoperative administration of laxatives, enemas and sometimes oral antimicrobial agents, has not been studied for use in bariatric surgery, and should not be routinely used as prophylaxis for SSIs.

Hence, intravenous administration is preferred over topical, subcutaneous or mechanical bowel preparation as the route of delivery for bariatric antimicrobial surgical prophylaxis.

Antimicrobial Prophylaxis: Dosage in the Bariatric Population Many factors affect antimicrobial concentrations in the surgical patient. Patient-specific factors include age, weight, body composition, renal function and volume status and surgery-specific factors include blood loss and fluid or blood replacement during surgery. Antimicrobial-specific factors include dosage, half-life, frequency of administration and the degree of protein binding. Furthermore, the effectiveness of the antibiotic is also influenced by the MICs of pathogens targeted. These various patient, surgical and antimicrobial factors influence the total versus free concentration of the antimicrobial in the blood and tissues. One of the most important determinants of antimicrobial levels in the serum and tissues at the time of surgical incision is antimicrobial dosing.

Limited pharmacokinetic studies have been conducted in obese patients, in whom multiple physiologic alterations can influence drug disposition. In many ways, pharmacokinetics are similar for obese and nonobese patients. For example, the absorption of drugs does not appear to be significantly altered by the weight of a patient,[61] and in general, the fat mass should not significantly influence the distribution of hydrophilic drugs. Albumin-bound drugs are unlikely to have significantly altered protein-binding characteristics in obese versus nonobese individuals.[62] However, there are some notable differences in obese individuals; for example, the distribution of lipophilic drugs is generally increased, and obese individuals generally have an increased glomerular planar surface area and altered renal elimination.[61] Both of these factors might affect serum and tissue antimicrobial levels. The optimal dosing of prophylactic antimicrobials before bariatric surgery remains undetermined, although some experts believe that 'more is better' and that high antimicrobial doses are warranted. Study findings in obese patients are often drug specific and utilize different classifications to define obesity.

Studies examining the cephalosporins have reported that drug clearance (Cl) and volume of distribution (Vd) for cefotaxime and cefotiam (a third- and second-generation cephalosporin, respectively) were increased in obese patients, and both Cl and Vd were correlated with body surface area.[63,64] These findings support increasing the dose of cephalosporins when they are used for prophylaxis.

A case describing the administration of piperacillin/tazobactam dosed at 3.375 g every 4 h in an obese patient (BMI: 50) noted an increased Vd and a decreased peak serum concentration of the antibiotic.[65] The authors concluded that altered dosing regimens may be required to optimize antimicrobial activity in morbidly obese patients.

Although not advocated as first-line prophylactic agents, the carbapenems have been well studied in obese patients. Chen et al. compared the pharmacokinetic and pharmacodynamic parameters of ertapenem in normal-weight patients and obese patients.[66] They found that after adjusting for body surface area or total body weight, the Vd increased with increasing weight, while Cl decreased. Total drug exposure also decreased with weight. Pharmacodynamic modeling suggested that obesity decreased the probability of attaining the desired time above the MIC for the drug, suggesting the need for higher doses.[66] By contrast, for meropenem, no weight-based dose changes were needed because the drug's short half-life minimized the impact of increased Vd and Cl.[67]

For the aminoglycosides, both the Vd and Cl are increased in obesity, and appear to offset one another.[68–73] Since the aminoglycosides exhibit a concentration-dependent mechanism of action, achieving appropriate peak concentrations is most important. Hence, adjusted body weight (commonly accounts for 40% of excess body weight) should be used to derive doses to correct for the excess mass in obese patients. However, increased dosing must be weighted against the potential for toxicity, particularly among patients with renal insufficiency. Since less toxic agents are available for prophylaxis, aminoglycosides are not the preferred agents for use in patients with renal insufficiency.

Studies with ciprofloxacin have reported varying results. The study by Allard et al. described an increase in Vd and Cl in obese patients[74] and this was supported by a case report by Caldwell et al.[75] By contrast, Hollenstein et al. administered a single intravenous dose of ciprofloxacin 2.85 mg/kg (based on total body weight) to 12 obese (mean BMI: 41; mean weight: 122 kg) and normal-weight patients (mean BMI: 19.8) and found that the Vd and Cl were lower in the obese subjects.[76] Although peak serum concentrations were higher in the obese subjects, tissue penetration was lower. Hence, the study suggested that higher doses should be given to improve tissue concentrations in obese patients.

Investigators have also analyzed the dose and pharmacokinetics of prophylactic antimicrobials in patients undergoing bariatric surgery. All of these studies involved a cephalosporin. In a study by Mann et al., the Vd and Cl of cefamandole increased in obese patients undergoing Roux-en-Y gastrojejunostomy when compared with historical nonobese controls.[77] When the dose was doubled, improved therapeutic tissue concentrations were attained. Forse et al. observed that in obese patients undergoing vertical banded gastroplasty, serum and adipose cefazolin concentrations at the time of incision and closure were similar between obese patients who received a 2-g prophylactic dose versus nonobese patients who were given a 1-g prophylactic dose.[78] Furthermore, obese patients who received a 2-g prophylactic dose of cefazolin were found to have decreased postoperative infections compared with obese patients who received cefazolin 1-g (16.5 vs 5.6% for 1 and 2 g of prophylactic cefazolin, respectively; p = 0.03). Edmiston et al. examined patients undergoing open or laparoscopic RYGB who received cefazolin 2 g intravenously 30–60 min before incision.[28] They reported decreasing concentrations of cefazolin in the serum, skin, adipose tissue and omental tissue with increasing BMI. Overall, therapeutic cefazolin tissue concentrations were achieved in only 48.1, 28.6 and 10.2% of the BMI categories of 40–50, 50–60, and 60 or higher, respectively. Before the second dose (cefazolin 2 g delivered in the third hour of operation), serum concentrations were above the cefazolin breakpoint of 32 µg/ml in 41.1, 18.2 and 0% of patients in the three BMI groups, respectively.

In bariatric surgical patients who require prophylaxis against MRSA, vancomycin can be used. There have been several reports regarding vancomycin pharmacokinetics in obesity, although they are not specific to bariatric surgery.[73,79–82] Vancomycin Cl appears to increase uniformly with obesity across studies.[61] However, the magnitude of increase in Vd is more variable.[61] Currently, the recommendation is to dose vancomycin using total body weight.[83] However, the maximum vancomycin dose that can be safely used in patients of extreme body weight is unknown. Although routine therapeutic drug monitoring does not appear to be necessary given the limited duration of vancomycin administration for surgical prophylaxis, caution must be exercised in patients who have decreased renal function, as large doses may result in unnecessarily prolonged exposure (see Table 2 for details).

In summary, although data are limited, it appears that standard doses of antimicrobial agents, particularly the cephalosporins, result in low serum and tissue levels in obese patients. Pending additional studies, we recommend that the highest dose of prophylactic antimicrobial agent that can be safely administered, after being adjusted for renal function, be used for surgical prophylaxis. Proposed doses for different antimicrobial agents that are commonly used for bariatric surgical prophylaxis are listed in Table 2 .[48]

Antimicrobial Prophylaxis: Timing of Administration Current guidelines based on published literature suggest that infusion of the first dose of most prophylactic antimicrobial sshould begin within 30 min to 1 h before incision.[13,40,84,85] Antimicrobials such as fluoroquinolones or vancomycin require longer infusion times and thus, infusion should begin within 1–2 h prior to incision. This slower infusion can help to prevent infusion-related arrhythmias (with fluoroquinolones) or Red-man syndrome (with vancomycin). Obese patients often require higher doses of antimicrobials to achieve similar concentrations of the drug in their serum and tissues. Depending on the antimicrobial agent, higher doses may require a longer infusion time. Owing to the ability to rapidly infuse cephalosporins, increasing the prophylactic dose of this type of agent should not significantly impact the timing of administration. By contrast, current guidelines recommend extending the vancomycin infusion time to 1.5–2 h for doses of 1.5 and 2 g.[83] Unfortunately, these prolonged infusion times can greatly complicate preoperative planning. For example, surgical prophylaxis using higher doses of vancomycin that would necessitate infusion for longer than 2 h would not meet the performance measure set forth by the Centers for Medicare & Medicaid Services and the CDC under the Surgical Infection Prevention Project.[84] Situations where optimal dosing conflicts with regulatory requirements need to be re-evaluated by clinicians and regulatory agencies.

The β-lactams exhibit time-dependent killing properties. Doubling the dose of a β-lactam drug in obese patients achieves similar concentrations to those obtained in normal-weight patients with standard doses.[62,77,78] Thus, adequate levels of these drugs can be achieved in the serum and tissues of bariatric surgical patients by administering higher doses or shortening the time to redosing.

Repeating administration of the dose of prophylactic antimicrobials is necessary for prolonged procedures in which the concentration of the antimicrobial is anticipated to fall below the MIC of target pathogens. The need for redosing depends on the duration of surgery, the serum and tissue levels obtained from the initial prophylactic dose, the half-life of the drug and the MIC of the target organisms. Redosing of prophylactics is recommended if the procedure exceeds two half-lives of the drug from the time that the first dose was administered or if the operation extends beyond 3 h in duration.[40,84] Excessive bleeding[86] or fluid replacement during surgery may expedite the need to redose, while renal insufficiency would prolong the half-life of most drugs, and thus, prolong the time period before redosing is necessary. Currently, guidelines do not recommend a standardized redosing approach based on fluid loss or replacement. In general, for cefazolin-based prophylactic regimens, cefazolin should be redosed if the procedure exceeds 2–5 h, or if the procedure exceeds 2–3 h for cefoxitin, 3–5 h for aztreonam, 4–10 h for ciprofloxacin or 6–8 h for metronidazole.[84]

Computerized dosing prompts can enhance adherence to prophylactic antimicrobial administration times, particularly pertaining to redosing. In a study by St Jacques et al., a timer notified the clinician of an approaching antibiotic redose time and prompted the clinician to redose the agent.[87] The use of such a system increased the rate of appropriate redosing of antimicrobials from 20 to 58%.

In summary, for bariatric procedures, the first dose of most prophylactic antimicrobials should be infused within 30 min to 1 h before incision. For fluoroquinolones, the infusion should begin within 1–2 h prior to incision. For vancomycin, the infusion time should generally be 1 h per gram of drug prior to the operation. Redosing of antimicrobials during surgery should occur if the procedure exceeds two half-lives of the drug (see Table 2 for details).

Antimicrobial Prophylaxis: Duration The initial prophylactic dose, administered 1–2 h before incision, is the most important dose in terms of SSI prevention. As is the case for most procedures, the duration of antimicrobial prophylaxis for bariatric surgery should not exceed 24 h after surgery is completed.[13,84]

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