Do Changes in Antimicrobial Resistance Necessitate Reconsideration of Surgical Antimicrobial Prophylaxis Strategies?

Abstract

Background:

The potential need for re-evaluation of guidelines on surgical antimicrobial prophylaxis (AMP) in an era of advancing antimicrobial resistance is a matter of a considerable controversy.

Method:

Review of the pertinent literature.

Results:

Over the last decade, the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has increased significantly, as illustrated by several surveillance studies. The blending of community acquisition and long-term carriage may increase the probability of unrecognized MRSA carriers being admitted to the hospital. Thus, MRSA is considered a major epidemiological threat in most parts of the world, exerting pressure for reconsideration of the guidelines for surgical AMP. The use of a glycopeptide as first-choice prophylaxis in major procedures such as cardiac surgery generally is not recommended but is not ruled out. Current recommendations are based on trials performed almost a decade ago at the latest and do not reflect the contemporary epidemiology of resistance. A few recent studies suggested that vancomycin in combination with gentamicin and rifampicin reduces the incidence of surgical site infections significantly in high-risk patients. These developments led some surgeons and infectious diseases clinicians to consider advanced antimicrobial coverage in surgical AMP. On the other hand, other clinicians are rightfully skeptical about extensive administration of glycopeptides or other agents beyond first- or second-generation cephalosporins because of the risk of further emergence and dissemination of antimicrobial resistance.

Conclusion:

Properly designed randomized trials are needed urgently to determine whether standard perioperative AMP should be reconsidered in settings with changing etiology of surgical infections.

Surgical site infections (SSIs) are among the most common nosocomial infections [1]. The incidence of SSIs is as high as 5% in patients undergoing clean extra-abdominal operations, whereas almost 20% of patients undergoing intra-abdominal operations develop SSIs [2]. Choosing the appropriate antimicrobial prophylaxis (AMP) is an important consideration for surgeons, particularly for major operations such as cardiac or prosthesis surgery having high rates of postoperative infections and longer hospitalization.

Established knowledge tells us that the use of first- and second-generation cephalosporins is preferable, not only in delaying the emergence of antimicrobial resistance, but also with regard to costs and safety. However, in many settings, the epidemiological patterns of multi-drug-resistant (MDR) bacteria and the severity of infections caused by such pathogens force surgeons to consider the use of more advanced antimicrobial drugs. In the surgical setting, the most important threat is posed by methicillin-resistant Staphylococcus aureus (MRSA), a common health care-associated pathogen [3], contributing to prolonged hospital stays and deaths [4,5].

The changing bacterial ecology necessitates frequent updating of preventive and therapeutic antimicrobial strategies. Nowadays, the clinical effectiveness of AMP with β-lactam drugs is questioned by many surgeons and infectious diseases experts. Should we consider more aggressive AMP strategies for some patients undergoing certain types of surgery or in specific settings with a higher incidence of infections caused by pathogens resistant to β-lactam antibiotics? We reviewed the current literature and evaluated the available recommendations.

Changing Epidemiology and Increased Prevalence of MRSA Infections

The first reports of MRSA were published in the 1960s, and the infection was rapidly documented worldwide; in the 1980s, MRSA became a major problem in U.S. hospitals [6]. Over the last decade, the prevalence of MRSA has increased significantly, as illustrated by several surveillance studies. In the U.K., during the period 1997–2002, almost 50% of the isolated causal pathogens for SSIs were staphylococci: 81% of them were S. aureus, and 63% proved to be methicillin-resistant [7]. In addition, data from the Surveillance and Control of Pathogens of Epidemic Importance (SCOPE) project during the period 1995–2002 showed that almost 45% of nosocomial blood stream infections were caused by staphylococci resistant to several relevant antibiotics [8].

The National Nosocomial Infections Surveillance system (NNIS) in the U.S. reported in 2004 that the overall rate of methicillin resistance among S. aureus strains isolated from patients in intensive care units (ICUs) was 59.5% [9]: 11% higher than the rate for 1998–2002. A two-fold increase in the proportion of methicillin resistance was observed from 1995 to 2001 in a hospitalized pediatric population [10].

In Europe also, MRSA is a problem of increasing importance. The 2006 annual report of the European Antimicrobial Resistance Surveillance System (EARSS) categorized participating countries according to the MRSA endemic prevalence [13]. Almost half of the countries (n = 15) reported rates of MRSA higher than 25% [14]. Even in the developing world, MRSA is a growing problem [15]. Worldwide, the annual increase in the proportion of MRSA among S. aureus isolates in ICUs is almost 3%. This rise has been stable during the last two decades, contributing to increasing morbidity and a higher mortality rate [6,9]. Thus, it comes as no surprise that MRSA is considered a major epidemiological threat throughout the world [11,12].

Emergence of Community-Acquired MRSA

In 1993, in Western Australia, MRSA strains were retrieved from indigenous patients who did not have the typical risk factors for acquisition, such as previous hospitalization [16]. Since that time, the reported prevalence of community-acquired (CA)-MRSA has risen, and the organism is now considered an emerging epidemiological threat [19 –22], even in the pediatric population [17,18]. The combination of community acquisition, long-term carriage, and absence of previously recognized risk factors may increase the probability that unrecognized MRSA carriers will be admitted to a hospital.

Vancomycin-Resistant Strains

In 1997, the first strain of S. aureus with reduced susceptibility to vancomycin (VRSA) was isolated [23]. Eight more cases of VRSA were reported between 1997 and 2003 [24 –27]. All patients had previously been exposed to vancomycin for a long time. However, in 2004, a case of VRSA infection without previous vancomycin exposure was reported [28]. Many observers predict this organism will become the “MRSA of the future.”

Current Guidelines on Perioperative AMP with Glycopeptides

Guidelines regarding the perioperative use of AMP and management of the high prevalence of MDR bacteria are far from established and accepted in the international scientific community. For example, the guidelines of the Health Care Infection Control Practices Advisory Committee (HICPAC) [29] and the Society for Healthcare Epidemiology of America (SHEA) [30] do not agree on an evidence-based practice of active surveillance for nosocomial transmission of MDR pathogens. In addition, the use of vancomycin as first-choice prophylaxis in major procedures such as cardiac surgery generally is not recommended although it has not been disregarded conclusively.

The American Society of Thoracic Surgeons, in recently issued guidelines [31], supported the use of first-generation cephalosporins as the standard for AMP in adult cardiac surgery. According to the Society, prophylaxis with vancomycin in combination with an aminoglycoside for gram-negative coverage should be considered only in patients with β-lactam allergy or as an adjuvant to a β-lactam drug in high-risk patients. Similarly, the guidelines from the U.S. Centers for Disease Control and Prevention (CDC) recommend prudent use of glycopeptides.

The summary of the Surgical Infection Prevention Guideline Writers Workgroup consensus document also illustrates the need for limiting the use of vancomycin to β-lactam-allergic patients undergoing hip or knee arthroplasty or cardiothoracic or vascular surgery, and patients with known MRSA colonization [32]. The authors of this consensus document agree with the current policy adopted by the Society for Healthcare Epidemiology of America [30], according to which routine surveillance cultures should be acquired from patients at high risk for MRSA carriage at the time of admission. The risk is considered greater for patients who have spent more than five days in a hospital. However, even in clinical settings with a higher incidence of MRSA infections, there is no evidence that routine vancomycin administration would reduce the rate of SSIs compared with antibiotics such as cefazolin. This is illustrated by the findings of a large trial in which patients who underwent cardiac surgery in a hospital with perceived high rates of MRSA were randomized to vancomycin or cefazolin for preoperative prophylaxis [33]. The group that received cefazolin was more likely to be infected with MRSA when the postoperative complication was SSI, but in general, there were no differences in the SSI rates in the two groups. These results are similar to those of another trial in which the only postoperative factors associated with a higher rate of MRSA SSIs were postoperative antibiotic treatment for more than one day and discharge to a long-term facility [34].

The Joint Working Party of the British Society for Antimicrobial Chemotherapy (BSAC) in 2006 [35] recommended the limited use of vancomycin for perioperative AMP in patients with MRSA carriage, a history of MRSA colonization, or patients undergoing surgery for prosthetic implants during MRSA infection outbreaks. Glycopeptides combined with other antibiotics may be considered if it is probable that MRSA carriage has occurred or if the patient is being transferred from facilities with a high prevalence of MRSA.

In July 2008, the Scottish Intercollegiate Guidelines Network (SIGN) published updated clinical guidelines on antimicrobial prophylaxis in surgery [36]. They advised preoperative eradication for MRSA carriers. Similarly, AMP against MRSA is considered good practice in carriers undergoing high-risk surgery. However, the above practices are not evidence-based. The use of a glycopeptide for antibiotic prophylaxis in MRSA-positive patients undergoing high-risk surgery is supported by level A evidence. Use of glycopeptides in settings with high prevalences of MRSA is not recommended if carriage is not identified. Finally, prophylactic use of intranasal mupirocin in known MRSA or other S. aureus carriers undergoing surgery with a high risk of morbidity is supported by level B evidence. However, although intranasal mupirocin has been associated with lower rates of S. aureus nasal carriage in various studies, the impact on the incidence of SSIs appears to be small, and perhaps the only benefit is a decrease in the rate of nosocomial S. aureus infections among carriers [37].

Regardless of the guidelines for AMP, one should consider the degree of physician adherence. Compliance with guidelines can be different among countries or even among hospitals in the same country. The degree of adherence may fluctuate substantially, affecting the quality of health care and infection control [36 –39]. The current strategies need to be re-evaluated to develop standardized guidelines for perioperative surgical prophylaxis. The Antibiotic Resistance Surveillance & Control in the Mediterranean Region (ARMed) Project in southern and eastern Mediterranean hospitals [40] and the AntiBiotic Strategies (ABS) Project, mostly in hospitals of central Europe [41], are two good examples of the way that common AMP strategies could be adapted, applied, and monitored.

Glycopeptides vs. Standard Regimens of β-Lactam Drugs for Perioperative AMP

Cardiac surgery

The emergence of and continuous increase in the prevalence of MDR bacteria prompted the use of glycopeptides such as vancomycin and teicoplanin for perioperative AMP in cardiac surgery. In 2004, a meta-analysis of seven randomized control trials (RCTs) compared the prophylactic use of glycopeptides with standard prophylaxis with cephalosporins; the findings did not support changes in the established recommendations [38]. However, it should be acknowledged that this meta-analysis had several limitations as a result of the heterogeneity of the trials, specifically, their definitions and protocols for surveillance of SSIs. Moreover, the epidemiology of MRSA has changed considerably in recent years. In addition, three original studies were performed after 2004. In an institution with a high prevalence of MRSA, AMP with a glycopeptide for cardiac surgery was believed to be effective in preventing postoperative SSIs [39]. Furthermore, a study of the serum concentration of glycopeptides administered for prophylaxis during cardiac surgery in a pediatric population at high risk of MRSA acquisition [40] demonstrated that glycopeptides are both safe and effective for AMP, as no postoperative SSIs were noted. Finally, a recent RCT [41] showed that vancomycin in combination with gentamicin and rifampicin reduced the likelihood of SSI significantly in high-risk patients undergoing cardiac surgery. This regimen is not only beneficial for infection control but also cost effective.

Orthopedic and vascular surgery and neurosurgery

The available evidence regarding the use of glycopeptides vs. cephalosporins for perioperative AMP in all types of clean and clean-contaminated surgery was recently subjected to meta-analysis [42]. Because of the heterogeneity of the studies and their small samples, the investigators failed to reach any definitive conclusions. It is important to note that the determination of a threshold MRSA prevalence—one that suggests when to switch from standard surgical prophylaxis to a glycopeptide—was not possible because of the paucity of data.

In a meta-analysis from our group [43], teicoplanin was compared with cephalosporins for perioperative prophylaxis in orthopedic and vascular surgery involving artificial prostheses. The outcomes did not favor the use of teicoplanin, especially for prosthetic implant surgery. However, the small sample size and the heterogeneity of the available trials, as well as the outdated epidemiology, indicate that until novel, well-designed, and properly performed trials are conducted, we cannot reach any definitive conclusions on this important clinical question.

General surgery

According to the British guidelines of 2006 [35], AMP in general surgery needs to be reassessed on the grounds of the increasing prevalence of MRSA. It is possible that cephalosporins will remain the standard of care for this type of procedures, but it is essential to provide evidence-based algorithms to define the patient groups that may benefit from a switch to glycopeptides.

Changing Epidemiology and Increased Prevalence of Infections with MDR Gram-Negative Bacteria

Gram-negative bacteria account for almost 40% of SSI pathogens [44]. Furthermore, critically ill patients, after extended surgical procedures, are at high risk of postoperative infections caused by such organisms [45]. Multidrug resistance is common and indeed increasing among gram-negative bacteria, and some strains exhibit resistance to most of the common antibiotics, including antipseudomonal penicillins, cephalosporins, aminoglycosides, tetracyclines, fluoroquinolones, co-trimoxazole, and carbapenems [46]. Few compounds target the aformentioned MDR gram-negative pathogens [47]; thus, effective AMP is crucial to prevent such difficult-to-treat infections. The changing patterns of the epidemiology of MDR gram-negative pathogens may indicate a need to reconsider current AMP regimens. The use of agents for AMP more active against MDR gram-negative pathogens agents, such as co-trimoxazole, ceftazidime, tygecycline, and quinolones, has not been evaluated by RCTs and thus is not suggested by any of the available guidelines for AMP in surgery.

Critical Evaluation of the Literature

The increasing prevalence of MDR bacteria, and particularly of MRSA, is an international epidemiological fact. However, there are major variations in regional prevalence rates, infection control policies, perioperative AMP strategies, and compliance of physicians with local and international guidelines [48], creating additional confusion that may lead to outdated and inappropriate practices.

Moreover, current recommendations regarding the use of glycopeptides for perioperative AMP are based on trials performed almost a decade ago and obviously do not reflect the contemporary bacterial epidemiology of surgical infections. Nowadays, considerable problems such as CA-MRSA and VRSA have emerged. Many surgeons and infectious disease specialists believe that advanced antimicrobial coverage should be considered for perioperative AMP. Conversely, other clinicians are skeptical about extensive administration of glycopeptides because of the risk of further development of resistance. It should be noted that although there is considerable debate on the issue, a single properly administered prophylactic dose of a glycopeptide may obviate extensive use of this class afterward for the treatment of infection.

So far, perioperative prophylaxis with vancomycin or teicoplanin has been applied in institutions with a high prevalence of MRSA or in high-risk patients. Current guidelines are re-considering this practice; however, there is no evidence to define a specific threshold of MRSA prevalence above which a glycopeptide instead of a cephalosporin should be administered for AMP. In addition, new and rapid molecular techniques such as the polymerase chain reaction can be as sensitive as the traditional selective MRSA agars. Their use could revolutionize the perioperative management of patients potentially colonized with MRSA [49]. Unfortunately, at present, these tests have a higher cost and thus, their application is limited; moreover, there are serious doubts regarding the value of universal rapid MRSA screening. A large crossover study compared two MRSA control policies—rapid screening on admission plus standard infection control vs. standard infection control alone—in terms of nosocomial MRSA infection rates. No significant differences were revealed [50].

Vancomycin is the glycopeptide most commonly used for clean and clean-contaminated surgical prophylaxis. However, there are concerns that vancomycin has relatively poor pharmacokinetic/pharmacodynamic characteristics: Poor tissue penetration, slow bactericidal activity, and a narrow antimicrobial spectrum that does not cover gram-negative pathogens [51,52]. Newer glycopeptides with better pharmacokinetics should be tested to define their potential for perioperative AMP in various MRSA prevalence settings [47,53]. Special consideration also should be given to other types of antibiotics such as tigecycline, a glycylcycline that provides coverage against most gram-positive and gram-negative pathogens. It would be wise to consider the other available antimicrobial drugs such as co-trimoxazole, clindamycin, and quinolones that may provide effective prophylaxis against MDR gram-positive bacteria and also, in the case of co-trimoxazole and quinolones, against an increasing trend to gram-negative infections. Certain combinations of antibiotics, such as glycopeptides with aminoglycosides, have been administered for prevention of perioperative infections with encouraging outcomes [41].

In conclusion, we believe that properly designed RCTs are required urgently to evaluate whether standard perioperative AMP should be reconsidered. The primary objectives of such trials should be to determine: (1) A threshold of MDR bacterial prevalence above which advanced AMP may be considered; (2) alternative agents or combinations of agents for various types of surgery; and (3) the cost-effectiveness of AMP. Finally, it should be emphasized that clinical guidelines throughout the world regarding surgical AMP need to be reassessed regularly and take into serious consideration the regional evolving epidemiology of implicated pathogens and their antimicrobial resistance.

Footnotes

Acknowledgments

We thank Doctor Victoria V. Wilmot for her kind effort to revise and edit this manuscript and for providing us with useful feedback. No funding was provided for this study. The authors have no conflicts of interest to disclose.

Author Disclosure Statement

No conflicting financial interests exist.

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