Infection, Antimicrobial Drugs, and Anesthesia




Abstract


Prevention of surgical site infection (SSI) remains a high priority, particularly as the number of surgical procedures performed continues to increase. Surgical antibiotic prophylaxis is cost-effective in reducing SSI. The ideal prophylactic agent should prevent SSI, prevent SSI-related morbidity and mortality, be cost-effective, avoid adverse effects, and have no adverse consequences on the microbial flora of the patient or the hospital. Cefazolin remains the drug of choice for prophylaxis in most procedures because it is safe and has proven efficacy. Anesthesiologists play a major role in preventing SSI and should contribute to the development of local guidelines based on national guidelines, local patterns of resistance, cost, and surgeon preference.




Keywords

surgical antibiotic prophylaxis, infection control, antibiotics, surgical site infection

 





Historical Perspective


After antibiotics came into widespread use in the 1940s and 1950s, the possibility that giving antibiotics perioperatively might prevent surgical site infection (SSI) became a matter of debate. Miles and colleagues used a guinea pig model to demonstrate that appropriate antibiotics were effective in preventing invasive infection and necrosis only when given within 2 hours before or after intradermal injection. This gave rise to the concept of a “decisive period” during which antibiotics are effective, which remains a guiding principle of antibiotic prophylaxis. Miles and colleagues also established the crucial role of local perfusion in delivering antibiotics when they showed that intradermal injection of epinephrine prior to antibiotic administration led to antibiotic failure.


Knighton and colleagues, using the same model, demonstrated that increased inspired oxygen was equally as effective as antibiotics in preventing infection by Escherichia coli and that the two effects were additive. He also concluded that the decisive period for oxygen is considerably longer (up to 6 hours) than that of antibiotics.


The first controlled clinical trial of the efficacy of antibiotic prophylaxis in 1964 demonstrated a benefit in abdominal operations. Thereafter, numerous clinical trials were performed with somewhat variable results, likely due to the wide range of approaches to antibiotic prophylaxis in terms of dosage, antibiotic selection, and timing of administration, among other factors. Eventually, in terms of timing, the use of antibiotic prophylaxis immediately prior to incision was demonstrated to be most effective.


By the 1970s, antibiotic prophylaxis for high-risk surgery—meaning clean contaminated and contaminated cases—was becoming well accepted and widely used. In 1985, DiPiro and colleagues showed that higher serum and tissue cephalosporin concentrations were better achieved when the drugs were given at the time of anesthesia induction compared with administration later in the operating room. Classen and colleagues published a prospective series of 2,847 patients in 1992 and introduced the 0- to 60-minute interval that subsequently became the clinical standard. While the decisive period for human (as opposed to guinea pig) SSI extends about 60 minutes both before and after incision, dosing before incision was chosen as the standard. Resident bacteria become enmeshed in fibrin clot that forms after incision, while antibiotics generally do not penetrate the fibrin clot. Thus, it is important that antibiotics are present at adequate levels in the wound at the time of incision so that they are incorporated into the fibrin clot as it forms.




Introduction


Between 2006 and 2009, SSIs complicated approximately 1.9% of surgical procedures in the United States. Rates vary widely, however, depending on site of surgery, surgical technique, patient comorbidities, and other factors. Moreover, the number of SSIs is likely underestimated given that approximately 50% of SSIs become evident after discharge from the hospital.


The United States Centers for Disease Control and Prevention (CDC) define SSI as an infection related to operative procedures that occurs near or at the surgical incision (incisional or organ/space) within 30 days of the procedure or within 90 days if a prosthetic implant was left after surgery.


The prevention of SSI remains a national priority, particularly as the number of surgical procedures performed in the United States continues to increase. SSIs are a major cause of morbidity, mortality, patient suffering, intensive care unit admissions, prolonged length of stay, hospital readmission, and increased health care cost. It has been estimated that approximately half of SSIs are preventable by application of evidence-based strategies.


National quality-improvement initiatives have been established as joint efforts by professional organizations and government agencies to further improve the safety and outcomes of surgery and health care. These efforts have identified antibiotic prophylaxis before surgery as the standard of care and a keystone for the prevention of SSI.




Surgical Antibiotic Prophylaxis


Ideally, the antimicrobial of choice for prophylaxis should prevent SSI, prevent SSI-related morbidity and mortality, be cost-effective, avoid adverse effects, and have no adverse consequences on the microbial flora of the patient or the hospital. The agent for antibiotic prophylaxis must therefore cover the most likely spectrum of bacteria present in the surgical field, and ensure adequate serum and tissue concentrations during the period of potential contamination when the surgical site is open. See Fig. 39.1 for antibiotic choice by site of surgery.




Fig. 39.1


Common surgical microbial organisms and antibiotic prophylaxis. Alternatives may be used when there is a patient history of hypersensitivity, contraindications, or resistance, as outlined in reference 21; note that use of alternatives should be avoided when possible, as alternatives are often less effective.

(Information incorporated from Bratzler DW, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect (Larchmt) . 2013;14:73. Antimicrobial prophylaxis for surgery. Med Lett Drugs Ther 2016; 58:63)


Wounds are divided into four classes according to the degree of expected microbial contamination during surgery ( Table 39.1 ). The most common surgical-site pathogens in clean procedures are skin flora, including Staphylococcus aureus and coagulase-negative staphylococci (e.g., Staphylococcus epidermidis ). In clean-contaminated procedures, the most common pathogens include gram-negative rods and enterococci in addition to skin flora. Data from the National Nosocomial Infections Surveillance (NNIS) system for 2006 to 2007 indicated that the proportion of SSI caused by S. aureus has increased to 30%, with about half of those caused by methicillin-resistant S. aureus (MRSA), although there is considerable local variability. Colonization with S. aureus , primarily in the nares, occurs in roughly 1 in 4 persons and increases the risk of SSI by 2- to 14-fold. MRSA infections are associated with higher mortality rates, longer hospital stays, and higher hospital costs compared with other infections.



TABLE 39.1

Classification of Surgical Wounds According to Bacterial Contamination



















Classification Description


  • 1.

    Clean (Class I)

Uninfected operative wounds in which no inflammation is encountered and the wound is closed primarily. A systemic tract (respiratory, alimentary, genital, or urinary tract) is not entered.


  • 2.

    Clean-Contaminated (Class II):

Operative wounds in which any of the systemic tracts (respiratory, alimentary, genital, or urinary tract) is entered under controlled conditions and without unusual contamination.


  • 3.

    Contaminated (Class III):

Open, fresh, traumatic wounds.
Operations with major breaks in sterile technique (open cardiac massage, spillage from the gastrointestinal tract, and so on)
Incisions with acute, nonpurulent inflammation (dry gangrene)


  • 4.

    Dirty or Infected (Class IV):

Old infected/traumatic wounds with retained devitalized tissue, foreign bodies, or perforated viscera, or abscesses.

Adapted from Ortega G et al. An evaluation of surgical site infections by wound classification system using the ACS-NSQIP. J Surg Res . 2012;174(1):33–38.


Effective antibiotic prophylaxis requires therapeutic drug concentrations to be delivered to the operative site before contamination and to remain adequate until the end of surgery. Timing of prophylactic antibiotic administration for surgical procedures depends on the pharmacology and half-life of the drug. The preoperative dose timing recommended by the American Society of Health-System Pharmacists (ASHP) involves administering doses within 60 minutes (120 minutes for vancomycin and fluoroquinolones) before surgical incision. Timing is challenging, because both early and late antibiotic administration increase SSI rates. The importance of having a standardized approach to antimicrobial prophylaxis involves institution-specific guidelines that emphasize timing and choice of appropriate agents according to the type of procedure, local sensitivity patterns, and allergy ( Table 39.2 ).



TABLE 39.2

General Recommendations for Antibiotic Prophylaxis








  • Administer preoperative, prophylactic antimicrobial agents only when indicated based on published clinical practice guidelines and timed such that an effective concentration of the agent is established in the serum and tissues at the time of surgical incision.



  • Antibiotic prophylaxis choice, dose, and timing should be determined by a hospital committee based on national guidelines, local patterns of antibiotic sensitivity, and other considerations.



  • Always confirm the antibiotic selection with surgeons at the time-out or earlier.




    • The surgeon may wish to delay antibiotics until after culture.



    • Antibiotics may not be indicated (e.g., low risk, elective procedures such as laparoscopic cholecystectomy or breast biopsy in which implants will not be used).



    • Make sure to record the reason for not giving antibiotics on the record.




  • Beta-Lactam Allergies




    • Penicillin allergy is almost never a contraindication to cefazolin or other cephalosporin administration. A documented history of anaphylaxis or other serious reaction (angioedema, bronchospasm, Stevens-Johnson syndrome, or toxic epidermal necrolysis) is the exception. Determine the severity of a patient’s beta-lactam allergy prior to choosing an alternative antimicrobial.



    • Lack of understanding of a true allergic reaction can lead to choosing an antimicrobial with reduced efficacy, increased cost, and greater risk of side effects.




  • Ideally, an antibiotic infusion should be completed before incision, but Centers for Medicare and Medicaid guidelines consider starting the infusion before incision adequate. When possible, for drugs requiring slow (> 30 minutes) infusion, the infusion should be initiated in the preoperative holding area.



  • Administer the appropriate parenteral prophylactic antimicrobial agents before skin incision for cesarean section, as this reduces the risk of SSI compared to the previous practice of administering the antibiotic after delivery of the baby and clamping of the umbilical cord.



  • When a tourniquet is used, the dose should be completed at least 5 minutes before the tourniquet is inflated.



  • Dosing schedules for prophylactic antibiotics are more frequent than for therapeutic use to maintain wound tissue levels throughout surgery and ongoing contamination; usually, re-dosing is recommended after 2 half-lives. For cefazolin, 1 g is the recommended re-dose, regardless of initial dose. Renal insufficiency may delay re-dosing, although the initial dose is usually not affected.



  • Additional intraoperative doses should be given when there is significant blood loss (~half to 1 blood volume). Use the recommended second dose for this purpose.



  • In clean and clean-contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain. The duration of antimicrobial prophylaxis should be less than 24 hours for most procedures



  • When therapeutic antibiotics are given preoperatively for an infection or presumed infection (e.g., acute appendicitis), prophylactic antibiotics are not required. Each situation should be examined individually. In some cases, coverage of skin flora may be appropriate prior to skin incision; often, however, continuation of the therapeutic antibiotics is all that is required.



  • Patients should be treated on a case-by-case basis. While local guidelines are the starting point, other factors, such as colonization with resistant organisms, should inform the decision.


Modified with permission from University of Utah Health.




Clinical Pharmacology of Common Perioperative Antimicrobial Agents


Beta-Lactam Antibiotics


Beta-lactam antibiotics, defined by their shared structural β-lactam ring, are among the most common perioperatively prescribed drugs, including penicillin, cephalosporins, carbapenems, monobactams, and β-lactamase inhibitors. Beta-lactam antibiotics inhibit the transpeptidation reaction in sensitive bacteria and inactivate several enzymes known as penicillin-binding proteins (PBPs) that are involved in cross-linking cell wall peptidoglycans. This interferes with osmotic stability of the bacteria. Different β-lactam antibiotics inhibit different PBPs and have varying efficacies in inhibiting bacterial growth or killing the organism. Apart from a few agents, all are excreted renally and require dose adjustment in renal insufficiency.


Resistance to penicillins and other β-lactams can be caused by inactivation of the antibiotic, altered target PBPs, or impaired penetration/efflux. Hydrolysis of the β-lactam ring by certain bacterial β-lactamases yields penicilloic acid, which lacks antibacterial activity. Beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) resemble β-lactam molecules and extend the spectrum of other β-lactams when combined. Altered target PBPs are the basis of MRSA and the use of an efflux pump or altered drug entry are exhibited by gram-negative species.


Penicillins


Penicillins can be assigned to 1 of 3 groups: penicillins, antistaphylococcal penicillins, or extended-spectrum penicillins. These groups have varying activity against gram-positive organisms and gram-negative organisms.


Serum concentrations of penicillins after intravenous administration is determined by protein binding. Penicillins are widely distributed in body fluids and tissues with the exception of a few formulated to delay absorption, resulting in prolonged blood and tissue concentrations. Doses must be adjusted according to renal function except with nafcillin, oxacillin, and dicloxacillin, which are cleared by biliary excretion as well.


Penicillins are generally well tolerated. The serious adverse effects are due to hypersensitivity or autoimmune reactions to a penicillin–protein complex. Patients with true allergy to penicillins can be treated with alternative drugs, although, as discussed earlier, this increases the risk of SSI and thus should be avoided when the risk of cross-reaction is low, as with a history of rash.


Cephalosporins


Cephalosporins have a broader spectrum of activity than penicillins but are not active against Listeria monocytogenes and strains of E. coli and Klebsiella species expressing extended-spectrum β-lactamases. They are classified into 4 generations according to their spectrum of antimicrobial activity.




  • First-generation cephalosporins (cephalexin, cefazolin). Cefazolin (half-life, 1.5 hours) is the drug of choice for surgical prophylaxis and many streptococcal and staphylococcal infections.



  • Second-generation cephalosporins (cefaclor, cefuroxime, cefprozil, and the cephamycins cefoxitin and cefotetan). Members of this group have differences in pharmacokinetics: protein binding and toxicity. In addition to inhibiting organisms covered by first-generation drugs, they have extended gram-negative coverage against organisms such as Haemophilus influenzae and Bacteroides fragilis . Cefoxitin has an approximate 4-hour half-life and must be re-dosed every 2 hours intraoperatively. While cefoxitin is effective for antibiotic prophylaxis for clean-contaminated abdominal colorectal surgery, cefazolin and metronidazole are recommended because cefazolin only requires re-dosing every 4 hours.



  • Third-generation cephalosporins (including cefotaxime, ceftazidime, and ceftriaxone). Cephalosporins of this group also have extended gram-negative coverage and achieve therapeutic levels in the cerebrospinal fluid when given intravenously. Ceftazidime is the only agent with useful activity against Pseudomonas aeruginosa . Ceftriaxone requires no dose adjustment in renal insufficiency because it is excreted through the biliary tract.



  • Fourth-generation cephalosporins (cefepime). Cefepime is active against P. aeruginosa , Enterobacteriaceae , methicillin-susceptible S. aureus (MSSA), S. pneumoniae , and Haemophilus and Neisseria sp . It penetrates well into cerebrospinal fluid. It has a half-life of only 2 hours, however.



  • Cephalosporins active against methicillin-resistant staphylococci. Ceftaroline is a distinct cephalosporin with increased binding to penicillin-binding protein 2a, which mediates methicillin resistance in staphylococci. It is therefore active against methicillin-resistant staphylococci, and gram-negative organisms, excluding P. aeruginosa .

Despite an increased risk of hypersensitivity in patients with documented penicillin anaphylaxis, the frequency of cross-allergenicity between the two drugs is low. Cephalosporins that contain a methylthiotetrazole group, such as cefotetan, may cause hypoprothrombinemia and bleeding disorders as well as disulfiram-like reactions. Administration of vitamin K and the avoidance of alcohol-containing medications is required in patients with such sensitivity.


Monobactams (Aztreonam)


Aztreonam is active against aerobic gram-negative organisms but not gram-positive bacteria or anaerobes. It penetrates well into the cerebrospinal fluid. It should be used with caution in patients with documented allergies to ceftazidime owing to structural similarity.


Carbapenems (Doripenem, Ertapenem, Imipenem, and Meropenem)


Carbapenems have a wide spectrum of activity against most gram-negative rods and gram-positive organisms. All but ertapenem penetrate body tissues and fluids well. Enterococcus faecium , methicillin-resistant strains of staphylococci, and C. difficile are resistant to the carbopenems. Imipenem, unlike doripenem and meropenem, is administered together with cilastatin, an inhibitor of renal dehydropeptidase, to prevent inactivation. Excessive levels of imipenem in patients with renal failure may lead to seizures.


Aminoglycosides (Including Streptomycin, Neomycin, Kanamycin, Amikacin, Gentamicin, and Tobramycin)


Aminoglycosides diffuse across the bacterial cell membrane and irreversibly inhibit protein synthesis by binding to the 30S ribosomal protein subunits. In combination with β-lactam antibiotics and vancomycin, they exhibit synergistic killing against drug-resistant gram-positive and gram-negative bacteria. They are water soluble and more active at alkaline than at acid pH.


Mechanisms of resistance to aminoglycosides include inactivation of the drug by adenylylation, acetylation, or phosphorylation as well as impaired entry or deleted/altered target receptors. Aminoglycosides (half-life ~ 2–3 hours) exhibit concentration-dependent killing (higher concentrations kill a larger proportion of bacteria faster) and have a significant postantibiotic effect through which their antibacterial activity persists beyond the time during which measurable drug is present.


Aminoglycosides are ototoxic and nephrotoxic. Slow administration, over 30 to 60 minutes, reduces the risk of toxicity. Toxicity increases with concurrent administration of loop diuretics (e.g., furosemide or ethacrynic acid) or other nephrotoxic antimicrobial agents (e.g., vancomycin or amphotericin). The administration of high doses with nondepolarizing neuromuscular blocking agents can result in prolonged neuromuscular blockade, which is usually reversible with calcium gluconate or neostigmine.


Fluoroquinolones


The clinically administered fluoroquinolones are active against a variety of gram-positive and gram-negative bacteria, including P. aeruginosa and Enterobacter . They act by inhibiting bacterial DNA synthesis and replication. Resistance is through alteration in drug permeability and target enzymes.


Most fluoroquinolones require dose adjustment in renal insufficiency, except for moxifloxacin, which is metabolized in the liver and should be used with caution in patients with hepatic dysfunction.


Fluoroquinolones are generally well tolerated. Use of fluoroquinolones is associated with a higher risk of C. difficile infection. Photosensitivity has been reported with lomefloxacin and pefloxacin. Gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin should be avoided or used with caution in patients with known QTc interval prolongation or uncorrected hypokalemia. Fluoroquinolones are not recommended as first-line agents for patients under 18 years of age owing to risks of growing cartilage damage and arthropathy. Fluoroquinolones also present a risk of tendinopathy. Fluoroquinolones should be reserved for patients in whom there are not equally effective alternative options.


Vancomycin


Vancomycin is a glycopeptide antibiotic primarily active against gram-positive bacteria. It also inhibits cell wall synthesis by binding to the bacterial d-Ala-d-Ala peptidoglycan binding site, preventing cross-linking and causing lysis. Resistance is through the modification and replacement of the d-Ala-d-Ala terminus by d-lactate. Vancomycin is effective against methicillin-resistant staphylococci and is widely distributed in the body. However, penicillins are still more effective against methicillin-susceptible strains.


The administration of vancomycin with other aminoglycosides increases the risk of ototoxicity and nephrotoxicity associated with the drug. Dose adjustment is required in renal insufficiency. Infusion-related flushing, known as “red man” syndrome, is also a common reaction attributed to the release of histamine. These adverse effects, along with hypotension, can be prevented by prolonging the infusion period (1–2 hours) or pretreating with an antihistamine, such as diphenhydramine.


Clindamycin


Clindamycin inhibits protein synthesis by binding to the 50S bacterial ribosomal subunit and interfering with aminoacyl translocation reactions. It is active against streptococci, staphylococci, pneumococci, bacteroides species, and other anaerobes. Enterococci and gram-negative aerobic organisms are resistant because of poor permeability. Clindamycin is recommended for prophylaxis in patients with true penicillin allergies, although it is not as effective. It should be administered over 15 to 30 minutes to prevent hypotension.


Resistance to clindamycin, which generally confers cross-resistance to macrolides, is through enzymatic inactivation or altered target receptor protein. Clindamycin penetrates well into abscesses (half-life ~ 2.5 hours) and is metabolized by the liver. No dosage adjustment is required for renal insufficiency. Impaired liver function can sometimes occur with the administration of clindamycin as well as increased risk for diarrhea and colitis due to C. difficile .


Metronidazole


Metronidazole is an antiprotozoal drug with potent antibacterial activity against anaerobes, including bacteroides and clostridium species. It forms toxic metabolites intracellularly through absorption by anaerobic bacteria and sensitive protozoa. Metronidazole is widely distributed in tissues and is metabolized in the liver. Patients taking metronidazole should be instructed to avoid alcohol because of a disulfiram-like effect.


Amphotericin B


Amphotericin B is a macrolide antifungal with the broadest spectrum of action, yet quite toxic. It is insoluble in water; therefore, it is administered either as a colloidal suspension with sodium deoxycholate or packaged in liposomal preparations to reduce toxicity.


Amphotericin B binds to ergosterol in fungal cell membranes and alters permeability through the formation of pores, leading to cell death. Resistance occurs through impaired binding or altered target sterols.


The drug is widely distributed in most tissues (half-life ~15 days); no dose adjustment is required in hepatic or renal dysfunction. Toxicity ranges from infusion-related chills, muscle spasms, and hypotension to renal tubular acidosis with severe potassium and magnesium wasting. Premedication with antihistamines or corticosteroids can be helpful, as can slow infusion rates. It is because of this that amphotericin B is usually replaced with the newer azole drugs later during treatment when the fungal burden is reduced.




Selection of Antimicrobial Agents for SSI Prevention


A broad variety of agents are approved for use in surgical antimicrobial prophylaxis, including first- and second-generation cephalosporins, clindamycin, gentamicin, carbapenems, fluoroquinolones, and vancomycin. Cefazolin remains the drug of choice for prophylaxis in most procedures. It is the most widely studied antimicrobial agent with proven efficacy. It has a desirable duration of action, favorable spectrum of activity against organisms commonly encountered in surgery, reasonable safety, and low cost. The use of newer, broad-spectrum agents should be avoided to reduce the emergence of resistant bacterial strains.


Cephalosporins are also the antibiotics most commonly associated with allergic reactions. When a patient develops anaphylaxis intraoperatively, the offending agent is often difficult to identify and supportive care is indicated. In patients with a documented anaphylactic (immunoglobulin E [IgE]-mediated) or other serious reaction such as angioedema, bronchospasm, Stevens-Johnson syndrome, or toxic epidermal necrolysis to a given antibiotic, the antibiotic should be avoided and replaced with antibiotics with a similar spectrum of coverage in subsequent surgeries. Cephalosporins can, however, be used safely in patients with a history of non-IgE-mediated reactions, such as rash or nausea.


The most commonly reported antibiotic allergy is to penicillin. In patients with an anaphylactic reaction to penicillin, there is a less than 1% cross-reactivity to cephalosporins. While this risk is low, it is recommended that cephalosporins be avoided in such patients and replaced with appropriate alternatives, such as vancomycin or clindamycin. Most reactions to penicillin, however, are not IgE mediated, including the development of a rash or hives, nausea, or gastrointestinal distress. For patients who report a non-IgE-mediated reaction or who do not know what their reaction was, there is no contraindication to cephalosporins, including cefazolin. Alternatives to cefazolin have less efficacy, more side effects, and are usually more expensive. Vancomycin, while it kills most S. aureus (bactericidal), prevents the growth only of enterococcus (bacteriostatic), has poor bone penetration, and must be given slowly to prevent vasodilation and hypotension. Clindamycin can induce MRSA infections and cannot be administered as a bolus dose. Blumenthal et al., in a cohort of over 8000 patients who underwent surgery for which cefazolin is the recommended agent for antibiotic prophylaxis at Massachusetts General Hospital from 2010 to 2014, found a 50% increased risk of SSI in the 11% of patients who reported an allergy to penicillin, including those who report side effects, intolerance, and non-IgE-mediated hypersensitivity in addition to true allergy. The increased rate of SSI in these patients was completely attributable to the use of alternative antibiotics—including clindamycin, vancomycin, and gentamicin—for surgical antibiotic prophylaxis. Thus, it is important to use cefazolin whenever appropriate and to reserve the alternatives for patients in whom there is a true contraindication to cephalosporins.


In the context of known or suspected MRSA colonization, vancomycin is generally the prophylactic antibiotic of choice. Screening for MRSA carriage in the general population remains controversial, but there is some evidence for cost-effectiveness in certain subgroups of patients, such as joint replacement and cardiac surgery. Screening for S. aureus requires only a nasal swab, and decolonization is relatively easy and safe, requiring nasal mupirocin ointment and showering with chlorhexidine for 5 days. Administration of vancomycin is complex, as it must be given slowly and usually requires 1 to 2 hours to infuse completely. In general, it is considered acceptable if the infusion is started within 120 minutes before incision. Because the infusion must be started preoperatively, the timing can be difficult to estimate. Therefore, it is recommended to give a dose of cefazolin, as well, in the operating room as a way to ensure adequate antibiotic levels at the time of incision while providing coverage for MRSA with vancomycin.

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Apr 15, 2019 | Posted by in ANESTHESIA | Comments Off on Infection, Antimicrobial Drugs, and Anesthesia

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