Pathogenicity of the Enterococcus in Surgical Infections
PHILIP S. BARIE, M.D.,* NICOLAS V. CHRISTOU, M.D.,t E. PATCHEN DELLINGER, M.D.,4 W. ROBERT ROUT, M.D.,§ H. HARLAN STONE, M.D.,11 and J. PAUL WAYMACK, M.D.¶
From the Scientific Studies Committee, Surgical Infection Society, and Departments of Surgery, Cornell University,* New York, New York; McGill University,t Montreal, Canada; University of Washington, t Seattle, Washington; University of Florida,§ Gainesville, Florida; Fairview General Hospital,"' Cleveland, Ohio; and the U. S. Army Institute of Surgical Research,¶ Fort Sam Houston, Texas
The enterococcus has been relegated to a position of unimportance in the pathogenesis of surgical infections. However the increasing prevalence and virulence of these bacteria prompt reconsideration of this view, particularly because the surgical patient has become increasingly vulnerable to infectious morbidity due to debility, immunosuppression, and therapy with increasingly potent antibiotics. The enterococcus is a versatile opportunistic nosocomial pathogen, causing such diverse infections as wound, intra-abdominal, and urinary tract infections; catheterassociated infection; suppurative thrombophlebitis; endocarditis; and pneumonia. Although surgical drainage remains the cornerstone of therapy for enterococcal infections involving a discrete focus, in the circumstances typified by the compromised surgical patient, specific antibacterial therapy directed against the enterococcus is warranted. Recent evidence indicates that parenteral antibiotic therapy for enterococcal bacteremia is mandatory and that appropriate therapy clearly reduces the number of deaths.
T n HE PATHOGENIC ROLE of enterococci in surgical infections has long been debated. The prevailing wisdom has been to discount the importance of enterococci in the pathogenesis of these infections. However these bacteria are increasingly prevalent in nosocomial infections arising from many sources, including surgical wounds and intra-abdominal abscesses, leading to reconsideration of the virulence of these organisms. The probable reasons for the increased frequency of the enterococci in nosocomial infections are many. These reasons include increasingly ill hospital inpatients, the increased need for invasive monitoring and therapy for these seriously ill patients, and the increasing use of extremely potent broad-spectrum antibiotics. Furthermore increasing numbers of immunosuppressed patients, such as organ
transplant recipients, patients with active autoimmune Address reprint requests to Philip S. Barie, M.D., Department of Surgery, F-1926, The New York Hospital-Cornell Medical Center, 525 East 68th St., New York, NY 10021.
Accepted for publication December 27, 1989.
155
diseases requiring glucocorticoid therapy, and HIV-infected patients also require surgical therapy. There is also evidence that the enterococci are versatile in their development of new mechanisms of resistance to antimicrobial agents. There is renewed debate regarding the need to use antibiotic therapy active against enterococci in patients with intra-abdominal and other surgical infections. Whether the immunosuppressed patient or the patient previously treated with broad-spectrum antibiotics represents a special circumstance with respect to prophylaxis or empiric therapy for presumed enterococcal infection is also at issue.
Clinical and Experimental Observations The incidence of enterococcal infections is clearly increasing. 1-5 Enterococci account for more than 9% of isolates from nosocomial infections,6 making these organisms collectively the third most commonly encountered nosocomial isolate.7 The overall incidence of isolation of enterococci from blood cultures is also increasing, and currently is about 5%.8 9 However enterococci have been reported in 8.4% of positive blood cultures taken because of a suspected infection from a series of general and thoracic surgical patients.'" A large series of enterococcal bacteremias complicating burn wound sepsis also has been reported.5 A longitudinal study of enterococcal bacteremia in the University of Wisconsin Hospitals showed a striking
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annual increase in the number of enterococcal bacteremias beginning in 1975.4 Forty-eight per cent (74 of 153) of those patients had undergone recent surgery or sustained major burns or multiple injuries. Four enterococcal species can cause human disease. Enterococcus faecalis accounts for 85% to 90% of isolates, E. faecium accounts for 5% to 15% of strains, while E. durans and E. casselifavius are rarely identified clinically.' The genus Enterococcus has recently gained formal taxonomic status based on DNA homology." Enterococci traditionally have been considered nonpathogenic other than in their well-recognized role as causative agents in urinary and biliary tract infections. There has been reluctance to consider them pathogenic elsewhere, even if isolated in pure culture. Enterococci isolated in pure culture from surgical wounds are rarely associated with signs of wound infection such as fever, wound erythema or tenderness, or leukocytosis. 2 Experimental inoculation of enterococci into the peritoneal cavity of rats did not cause death from sepsis or subsequent abscess formation,'3 although a synergistic relationship between enterococci and anaerobic gram-negative bacilli for the production of abscesses was identified. '4" 5 Although enterococci in pure culture are sometimes associated with infection outside the biliary or urinary tract,14 most surgical infections are mixed infections. Virulence has generally been attributed either to aerobic gram-negative or to anaerobic flora when enterococci have been isolated with other bacteria. There is ample experimental'6"17 and clinical evidence that mixed intra-abdominal infections that contain enterococci can be treated successfully with appropriate surgical drainage and an antibiotic regimen that is not active against enterococci.16,18 9 Furthermore enterococcal bacteremia has been considered rare as a consequence of surgical infection,1220 even in the absence of specific antienterococcal therapy. The partial efficacy of gentamicin, commonly used in intra-abdominal sepsis, against the enterococcus may explain this observation.2' In addition results of treatment of pure enterococcal infections have been variable, prompting questions about the pathogenicity of enterococcal infestations.'0 The historical disregard for the pathogenicity of the enterococcus also requires re-examination because the nosocomial nature of these infections is increasingly clear.4'2226 Maki and Agger4 considered 77% of their 153 cases to be nosocomial in origin. Furthermore the 37 nosocomial intra-abdominal or surgical wound infections constituted the largest patient subgroup reported with enterococcal bacteremia in that series, suggesting that surgical patients may be at particular risk. An indwelling urinary catheter, one or more intravascular catheters, or both were present in all but one of these cases. Twentyfour of the cases consisted of catheter-associated entero-
Ann. Surg. * August 1990
coccal bacteremia.4 There are many other reports of enterococcal infection related to indwelling urinary or vascular catheters as well. Enterococci represent about 15% of all urinary tract isolates.22'27 Enterococcal bacteriuria is strongly associated with manipulation of the urinary tract22 and with previous antibiotic therapy,28'29 and clearly can lead to bacteremia.30 Enterococcal contamination of intravascular devices is less common but clearly occurs.26'31'32 This can lead not only to bacteremia from contaminated central venous catheters31'32 but also to the dangerous complication of suppurative thrombophlebitis.26 The association between enterococcal infection and previous antibiotic therapy has been made at sites other than the urinary tract. For example enterococcal pneumonia has been reported after cefamandole therapy in patients also receiving enteral hyperalimentation through a nasoenteric tube.33 Enterococci are resistant to most antibiotics, including most beta-lactam antibiotics.34 Even antibiotics with activity against enterococci (such as ampicillin and vancomycin) are not bactericidal against most strains.35'36 Combinations of these agents with an aminoglycoside (usually gentamicin) may produce a synergistic effect when aminoglycoside penetration is promoted by damage to the bacterial cell wall by the other antibiotic in combination,37 although the clinical benefit of in vitro antibacterial synergy is difficult to quantitate. The increase in enterococcal urinary tract infections in the past 10 years has paralleled the striking increase in the use of cephalosporin antibiotics during that period,29 and a similar pattern is emerging for intra-abdominal infections.2' None of the currently available cephalosporin antibiotics are therapeutically beneficial against enterococci.36 38 Many reports of secondary enterococcal infection after treatment of intra-abdominal infections with these agents have also appeared,41-43 particularly as a cause of treatment failure after therapy with moxalactam.44-9 Furthermore these infections have emerged after short-course presumptive therapy for penetrating abdominal trauma with both moxalactam and other cephalosporin agents,43 in which a majority of specimens from postoperative wound and intra-abdominal infections included enterococci. Enterococcal intra-abdominal abscesses have been reported after major hepatic resection for trauma or tumor, even in the setting of appropriate (piperacillin/gentamicin) antibacterial prophylaxis.50
Epidemiology of Enterococcal Infection The source of the enterococci in these infections has been thought to be endogenous,22 particularly in the case of urinary tract infection. Enterococci are present in feces in concentrations of 106 organisms per gram.5' They are also indigenous to the human oral cavity,52 gallbladder,
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female genital tract and perineum,53 and male and female urethra.54 Seriously ill patients frequently have perineal fecal contamination, and there has been scant epidemiologic documentation of epidemic enterococcal infections.55 Even if the flora are endogenous, the hospital environment may render endogenous flora more invasive. Treatment with imipenem-cilastatin resulted in enterococcal overgrowth in fecal flora.56 Overgrowth was observed despite the fact that E. faecalis is sensitive to imipenem-cilastatin in vitro, although E. faecium is resistant. Bacterial overgrowth may lead to intestinal bacterial translocation. It is possible that broad-spectrum antibiotic therapy may render the already compromised host susceptible to sepsis from endogenous sources, even without catheterization or other manipulation, although the pathogenicity of the translocation phenomenon in humans is still being defined. Enterococci are capable of translocation, although not to the extent of Escherichia co/i, for example.57 Enterococcal translocation has been reported to be facilitated in mice treated with parenteral metronidazole.58 59 However the assumption that enterococci arise solely from endogenous sources also requires re-examination. Zervos and colleagues59 60 noted a large increase in nosocomial enterococcal surgical infections caused by highly gentamicin-resistant strains at the University of Michigan, and determined in epidemiologic studies that those strains were extrinsically acquired and had been transmitted by direct contact with medical personal. Two outbreaks of extrinsically acquired neonatal enterococcal sepsis also have been reported recently.6'62 The recent exogenously acquired epidemics of enterococcal infection were caused by strains that are highly resistant to gentamicin.59,60 Although the incidence of high-level streptomycin resistance increased throughout the 1960s and 1970s,63 64high-level gentamicin resistance is a relatively new phenomenon. Unknown as recently as 1977 at the Massachusetts General Hospital,65 widespread reports of high-level gentamicin resistance appeared between 1979 and 1984.6648 These gentamicin-resistant strains are generally resistant to all other aminoglycosides by a transferable plasmid-mediated mechanism that may have been originally acquired from Staphylococcus aureus.69 Beta-lactamase production by gentamicin-resistant strains of E. faecalis has also been described.70'7' Gentamicin and beta-lactamase resistance may occur in tandem because the beta-lactamase gene is present on the same plasmid as that for gentamicin resistance in staphylococci.67 This association is of concern because of the rapid proliferation of gentamicin-resistant strains. Similar proliferation of beta-lactamase-producing enterococci may make treatment of serious enterococcal infections all the more difficult. Even more worrisome are the recent reports of vancomycin-resistant enterococci, including both E. faecalis
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and E. faecium.72 These highly resistant strains were isolated from blood, peritoneal fluid or collections, urine, pleural fluid, or bile from 22 critically ill patients with multiple-organ failure. Beginning 3 months before the outbreak, vancomycin and ceftazidime had been used empirically for sepsis before diagnosis, further documenting the enormous capability of the enterococci to develop resistance to commonly used antimicrobial agents. The emergence of these resistant strains may be of enormous clinical significance. Many hospitalized patients are found to have gentamicin-resistant strains when the organisms are initially isolated, and other patients will acquire these resistant strains. One third ofthe deaths due to enterococcal infections reported by Zervos and coworkers60 were caused by gentamicin-resistant strains.
Recommendations for Therapy
Surgical drainage or removal of infected vascular catheters or prostheses remains the cornerstone of therapy for enterococcal infections involving discrete foci-abscesses, infected wounds or burns, or ureteral or biliary obstruction. Yet the enterococci are more likely to become pathogenic or cause bacteremia in the compromised patient. In the selected circumstances typified by many surgical patients, specific adjunctive antibacterial therapy directed against enterococci is now warranted. The sick surgical patient seems almost ideally compromised from the standpoint of the enterococcus as an opportunistic pathogen, particularly after trauma, shock, major burns, organ transplantation, or persistent sepsis. Empiric therapy for the enterococcus in intra-abdominal, nonbiliary/urinary infection in the good risk patient does not appear necessary (except possibly for patients with valvular heart disease),4 nor is the addition of anti-enterococcal coverage (ampicillin, piperacillin, or vancomycin) necessary if initial intraperitoneal cultures yield enterococci but the patient is doing well. However, if the patient has had enterococci cultured previously during the hospitalization or if the infection is nosocomial, particularly with previous gastrointestinal or genitourinary surgery or previous antibiotic therapy, a drug effective against enterococci should be included in the regimen for both proved and presumptive abdominal/pelvic infections, burn or surgical wound infections, urosepsis, postoperative/acalculous cholecystitis, and catheter-related infection. This is especially true in patients with valvular heart disease or a prosthetic heart valve. Enterococcal bacteremia requires parenteral antibiotic therapy.4 Appropriate therapy for enterococcal bacteremia without endocarditis should use a bactericidal antibiotic such as ampicillin, an acylureido penicillin (piperacillin, mezlocillin, or azlocillin), or vancomycin for 10 to 14 days.4 Because enterococcal bacteremia is often polymi-
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crobial, appropriate antibiotic therapy also should be directed against any additional isolates. Synergistic therapy with an aminoglycoside can also be used but may not be necessary. Although some reports suggest that antibiotic therapy did not influence the outcome of intra-abdominal sepsis caused by enterococci,73 recent evidence suggests that adjunctive antibiotic therapy with appropriate agents clearly reduces mortality.44' All patients with enterococcal bacteremia must be closely monitored for signs of endocarditis. Enterococcal endocarditis should be suspected in the presence of embolic lesions or echocardiographic findings,74 and treated with an appropriate bactericidal combination for 4 to 6 weeks.475 Penicillin, ampicillin, or vancomycin combined with an aminoglycoside (gentamicin, or streptomycin if high-level enterococcal gentamicin resistance is identified) may be administered with dosage predicated on the serum bactericidal titer of the organism.76 Patients with prosthetic valve endocarditis may require 6 weeks of therapy.75 The overall cure rate for enterococcal endocarditis is approximately 75%.76 Therapy for patients in whom an extracardiac source of enterococcal bacteremia cannot be identified remains a matter of debate. Patients with valvular heart disease should be presumed to have endocarditis and should be treated accordingly.4 Similar recommendations recently have been made for patients without valvular heart disease.4 Fortunately endocarditis rarely develops after nosocoinial enterococcal bacteremia4,8' 4'473 and is exceedingly unusual if the enterococcal bacteremia is polymicrobial.4
10. 11.
12. 13. 14. 15.
16. 17. 18.
19.
20.
21. 22. 23.
24.
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35. Kaye D. Enterococci: biologic and epidemiologic characteristics and in-vitro susceptibility. Arch Intern Med 1982; 142:20069. 36. Toala P, McDonald A, Wilcox C, Finland M. Susceptibility of group D streptococcus (enterococcus) to 21 antibiotics in vitro, with special reference to species differences. Am J Med Sci 1969; 258: 416-430. 37. Moellering RC Jr, Wennersten CBG, Weinberg AN. Studies on antibiotic synergism against enterococci: II. Effect of various antibiotics on the uptake of 14C-labelled streptomycin by enterococci. J Clin Invest 1971; 50:2580-2584. 38. Barry AL, Schoenknect FD, Shadomy S, et al. In-vitro activities of cefamandole and cephalothin against 1,881 clinical isolates. Am J Clin Pathol 1979; 72:858-860. 39. Kim MJ, Weiser M, Gottschall S, Randall EL. Identification of Streptococcus faecalis and Streptococcus faecium and susceptibility studies with newly developed antimicrobial agents. J Clin Microbiol 1987; 25:787-790. 40. Thornsberry C. Review of in-vitro activity of third-generation cephalosporin and other newer beta-lactam antibiotics against clinically important bacteria. Am J Med 1985; 79:14-20. 41. Dougherty SH, Flohr AB, Simmons RL. "Breakthrough" enterococcal septicemia in surgical patients. Arch Surg 1983; 118:232237. 42. Maslow MJ, Levine JF, Pollock AA, et al. Efficacy of a twelve-hour ceftriaxone regimen in the treatment of serious bacterial infections. Antimicrob Agents Chemother 1982; 22:103-107. 43. Feliciano DV, Gentry LO, Bitondo CG, et al. Single agent cephalosporin prophylaxis for penetrating abdominal trauma. Results and comments on the emergence ofthe enterococcus. Am J Surg 1986; 152:674-681. 44. Busuttil RW, McGrattan MA, Winston DJ. Moxalactam in the treatment of intraabdominal sepsis and other surgical infections. Rev Infect Dis 1982; 4:676-682(Suppl). 45. Chempakanallore TT, Berk S, Eapen T. Enterococcal liver abscess associated with moxalactam therapy. Arch Intern Med 1983; 143: 1780-1781. 46. Mathisen GE, Meyer RD, Thompson JM, Finegold SM. Clinical evaluation of moxalactam. Antimicrob Agents Chemother 1982; 21:780-786. 47. Moellering RC Jr. Enterococcal infections in patients treated with moxalactam. Rev Infect Dis 1982; 4:708-711. 48. Salzer W, Pegram PS Jr, McCall CE. Clinical evaluation of moxalactam: evidence of decreased efficacy in gram-positive aerobic infections. Antimicrob Agents Chemother 1983; 23:565-570. 49. Yu VL. Enterococcal superinfection and colonization after therapy with moxalactam, a new broad-spectrum antibiotic. Ann Intern Med 1981; 94:784. 50. Pace RF, Blenkharn JI, Edwards WJ. Intra-abdominal sepsis after hepatic resection. Ann Surg 1989; 209:302-306. 51. Levison ME, Kaye D. Fecal flora in man: effect of cathartic. J Infect Dis 1969; 119:591-596. 52. Nord CE, Wadstrom T. Characterization of hemolytic enterococci isolated from oral infections. Acta Odontol Scand 1973; 31:387392. 53. Adhami Z. The beta-lactamase activity of the vaginal flora of asymptomatic pregnant women. J Antimicrob Chemother 1982; 10:303-309. 54. Koenig GM, Kaye D. Enterococccal endocarditis: report of 19 cases with long-term follow-up data. N Engl J Med 1961; 264:257264. 55. Stamm WE, Weinstein RA, Dixon RE. Comparison of endemic and epidemic nosocomial infection. Am J Med 1981; 70:393397. 56. Welkon CJ, Long SS, Gilligan PH. Effect of imipenem-cilastatin
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therapy on fecal flora. Antimicrob Agents Chemother 1986; 29: 741-743. Wells CL, Jechorek RP, Maddaus MA, Simmons RL. Effects of clindamycin and metronidazole on the intestinal colonization and translocation of enterococci in mice. Antimicrob Agents Chemother 1988; 32:1769-1775. Wells CL, Maddaus MA, Reynolds CM, et al. Role of anaerobic flora in the translocation of aerobic and facultatively anaerobic intestinal bacteria. Infect Immun 1987; 55:2689-2694. Zervos MJ, Dembinski S, Mikesell T, Schaberg DR. High-level resistance to gentamicin in Streptococcus faecalis: risk factors and evidence for exogenous acquisition of infection. J Infect Dis 1986; 153:1075-1083. Zervos MJ, Kauffamn CA, Therasse PM, et al. Nosocomial infection by gentamicin-resistant Streptococcus faecalis. Ann Intern Med 1987; 106:687-691. Courdron PE, Mayhall CG, Facklam RR, et al. Streptococcus faecium outbreak in a neonatal intensive care environment. J Clin Microbiol 1984; 20:1044-1048. Luginbuhl LM, Rotbart HA, Facklam RR, et al. Neonatal enterococcal sepsis. Case control study and description of an outbreak. Pediatr Infect Dis 1987; 6:1022-1030. Mandell GL, Kaye D, Levison ME, et al. Enterococcal endocarditis: an analysis of 38 patients observed at The New York HospitalCornell Medical Center. Arch Intern Med 1970; 125:258-264. Roberts R. Discussion of enterococcal endocarditis: duration and mode of treatment. Trans Am Clin Climatol Assoc 1977; 89:5657. Calderwood SB, Wennersten C, Moellering RC Jr, et al. Resistance to six aminoglycosidic aminocyclitol antibiotics among enterococci: prevalence, evolution, and relationship to synergism with penicillin. Antimicrob Agents Chemother 1977; 1:401-405. Horodniceanu T, Bougueleret L, El-Solh N, et al. High-level, plasmidborne resistance to gentamicin in Streptococcus fecalis subsp. zymogenes. Antimicrob Agents Chemother 1979; 16:686-689. McDonnell RW, Sweeney HM, Cohen S. Conjugational transfer of gentamicin reesistance plasmids intra- and interspecifically in Staphylococcus aureus and Staphylococcus epidermidis. Antimicrob Agents Chemother 1983; 23:15 1-160. Chen HY, Williams JD. Transferable resistance and aminoglycosidemodifying enzymes in enterococci. J Med Microbiol 1985; 20: 1870-1896. Murray BE, Mederski-Samoraj B, Foster SK, et al. In vitro studies of plasmid-mediated penicillinase from Streptococcus faecalis suggest a Staphylococcal origin. J Clin Invest 1986; 77:289-293. Murray BE, Church DA, Wagner A, et al. Comparison of two betalactamase producing strains of Streptococcus faecalis. Antimicrob Agents Chemother 1986; 30:861-864. Patterson JE, Zervos MJ. Susceptibility and bactericidal activity studies of four beta-lactamase-producing enterococci. Antimicrob Agents Chemother 1989; 33:251-253. Uttley AHC, Collins CH, Naidoo J, George RC. Vancomycin-resistant enterococci. Lancet 1988; ii:57-58. Garrison RN, Fry DE, Berberich S, Polk HC. Enterococcal bacteremia: clinical implications and determinants of death. Ann Surg 1982; 196:43-47. O'Brien JT, Geiser EA. Infective endocarditis and echocardiography. Am Heart J 1984; 108:386-394. Bisno AL, Dismukes WE, Durack DT, et al. Antimicrobial treatment of infective endocarditis due to viridans stretococci, enterococci, and staphylococci. JAMA 1989; 261:1471-1477. Weinstein MP, Stratton CW, Ackley A, et al. Multicenter collaborative evaluation of a standradizeed serum bactericidal test as a prognostic indicator in infective endocarditis. Am J Med 1985; 78:262-268.
PHILIP S. BARIE, M.D.,* NICOLAS V. CHRISTOU, M.D.,t E. PATCHEN DELLINGER, M.D.,4 W. ROBERT ROUT, M.D.,§ H. HARLAN STONE, M.D.,11 and J. PAUL WAYMACK, M.D.¶
From the Scientific Studies Committee, Surgical Infection Society, and Departments of Surgery, Cornell University,* New York, New York; McGill University,t Montreal, Canada; University of Washington, t Seattle, Washington; University of Florida,§ Gainesville, Florida; Fairview General Hospital,"' Cleveland, Ohio; and the U. S. Army Institute of Surgical Research,¶ Fort Sam Houston, Texas
The enterococcus has been relegated to a position of unimportance in the pathogenesis of surgical infections. However the increasing prevalence and virulence of these bacteria prompt reconsideration of this view, particularly because the surgical patient has become increasingly vulnerable to infectious morbidity due to debility, immunosuppression, and therapy with increasingly potent antibiotics. The enterococcus is a versatile opportunistic nosocomial pathogen, causing such diverse infections as wound, intra-abdominal, and urinary tract infections; catheterassociated infection; suppurative thrombophlebitis; endocarditis; and pneumonia. Although surgical drainage remains the cornerstone of therapy for enterococcal infections involving a discrete focus, in the circumstances typified by the compromised surgical patient, specific antibacterial therapy directed against the enterococcus is warranted. Recent evidence indicates that parenteral antibiotic therapy for enterococcal bacteremia is mandatory and that appropriate therapy clearly reduces the number of deaths.
T n HE PATHOGENIC ROLE of enterococci in surgical infections has long been debated. The prevailing wisdom has been to discount the importance of enterococci in the pathogenesis of these infections. However these bacteria are increasingly prevalent in nosocomial infections arising from many sources, including surgical wounds and intra-abdominal abscesses, leading to reconsideration of the virulence of these organisms. The probable reasons for the increased frequency of the enterococci in nosocomial infections are many. These reasons include increasingly ill hospital inpatients, the increased need for invasive monitoring and therapy for these seriously ill patients, and the increasing use of extremely potent broad-spectrum antibiotics. Furthermore increasing numbers of immunosuppressed patients, such as organ
transplant recipients, patients with active autoimmune Address reprint requests to Philip S. Barie, M.D., Department of Surgery, F-1926, The New York Hospital-Cornell Medical Center, 525 East 68th St., New York, NY 10021.
Accepted for publication December 27, 1989.
155
diseases requiring glucocorticoid therapy, and HIV-infected patients also require surgical therapy. There is also evidence that the enterococci are versatile in their development of new mechanisms of resistance to antimicrobial agents. There is renewed debate regarding the need to use antibiotic therapy active against enterococci in patients with intra-abdominal and other surgical infections. Whether the immunosuppressed patient or the patient previously treated with broad-spectrum antibiotics represents a special circumstance with respect to prophylaxis or empiric therapy for presumed enterococcal infection is also at issue.
Clinical and Experimental Observations The incidence of enterococcal infections is clearly increasing. 1-5 Enterococci account for more than 9% of isolates from nosocomial infections,6 making these organisms collectively the third most commonly encountered nosocomial isolate.7 The overall incidence of isolation of enterococci from blood cultures is also increasing, and currently is about 5%.8 9 However enterococci have been reported in 8.4% of positive blood cultures taken because of a suspected infection from a series of general and thoracic surgical patients.'" A large series of enterococcal bacteremias complicating burn wound sepsis also has been reported.5 A longitudinal study of enterococcal bacteremia in the University of Wisconsin Hospitals showed a striking
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annual increase in the number of enterococcal bacteremias beginning in 1975.4 Forty-eight per cent (74 of 153) of those patients had undergone recent surgery or sustained major burns or multiple injuries. Four enterococcal species can cause human disease. Enterococcus faecalis accounts for 85% to 90% of isolates, E. faecium accounts for 5% to 15% of strains, while E. durans and E. casselifavius are rarely identified clinically.' The genus Enterococcus has recently gained formal taxonomic status based on DNA homology." Enterococci traditionally have been considered nonpathogenic other than in their well-recognized role as causative agents in urinary and biliary tract infections. There has been reluctance to consider them pathogenic elsewhere, even if isolated in pure culture. Enterococci isolated in pure culture from surgical wounds are rarely associated with signs of wound infection such as fever, wound erythema or tenderness, or leukocytosis. 2 Experimental inoculation of enterococci into the peritoneal cavity of rats did not cause death from sepsis or subsequent abscess formation,'3 although a synergistic relationship between enterococci and anaerobic gram-negative bacilli for the production of abscesses was identified. '4" 5 Although enterococci in pure culture are sometimes associated with infection outside the biliary or urinary tract,14 most surgical infections are mixed infections. Virulence has generally been attributed either to aerobic gram-negative or to anaerobic flora when enterococci have been isolated with other bacteria. There is ample experimental'6"17 and clinical evidence that mixed intra-abdominal infections that contain enterococci can be treated successfully with appropriate surgical drainage and an antibiotic regimen that is not active against enterococci.16,18 9 Furthermore enterococcal bacteremia has been considered rare as a consequence of surgical infection,1220 even in the absence of specific antienterococcal therapy. The partial efficacy of gentamicin, commonly used in intra-abdominal sepsis, against the enterococcus may explain this observation.2' In addition results of treatment of pure enterococcal infections have been variable, prompting questions about the pathogenicity of enterococcal infestations.'0 The historical disregard for the pathogenicity of the enterococcus also requires re-examination because the nosocomial nature of these infections is increasingly clear.4'2226 Maki and Agger4 considered 77% of their 153 cases to be nosocomial in origin. Furthermore the 37 nosocomial intra-abdominal or surgical wound infections constituted the largest patient subgroup reported with enterococcal bacteremia in that series, suggesting that surgical patients may be at particular risk. An indwelling urinary catheter, one or more intravascular catheters, or both were present in all but one of these cases. Twentyfour of the cases consisted of catheter-associated entero-
Ann. Surg. * August 1990
coccal bacteremia.4 There are many other reports of enterococcal infection related to indwelling urinary or vascular catheters as well. Enterococci represent about 15% of all urinary tract isolates.22'27 Enterococcal bacteriuria is strongly associated with manipulation of the urinary tract22 and with previous antibiotic therapy,28'29 and clearly can lead to bacteremia.30 Enterococcal contamination of intravascular devices is less common but clearly occurs.26'31'32 This can lead not only to bacteremia from contaminated central venous catheters31'32 but also to the dangerous complication of suppurative thrombophlebitis.26 The association between enterococcal infection and previous antibiotic therapy has been made at sites other than the urinary tract. For example enterococcal pneumonia has been reported after cefamandole therapy in patients also receiving enteral hyperalimentation through a nasoenteric tube.33 Enterococci are resistant to most antibiotics, including most beta-lactam antibiotics.34 Even antibiotics with activity against enterococci (such as ampicillin and vancomycin) are not bactericidal against most strains.35'36 Combinations of these agents with an aminoglycoside (usually gentamicin) may produce a synergistic effect when aminoglycoside penetration is promoted by damage to the bacterial cell wall by the other antibiotic in combination,37 although the clinical benefit of in vitro antibacterial synergy is difficult to quantitate. The increase in enterococcal urinary tract infections in the past 10 years has paralleled the striking increase in the use of cephalosporin antibiotics during that period,29 and a similar pattern is emerging for intra-abdominal infections.2' None of the currently available cephalosporin antibiotics are therapeutically beneficial against enterococci.36 38 Many reports of secondary enterococcal infection after treatment of intra-abdominal infections with these agents have also appeared,41-43 particularly as a cause of treatment failure after therapy with moxalactam.44-9 Furthermore these infections have emerged after short-course presumptive therapy for penetrating abdominal trauma with both moxalactam and other cephalosporin agents,43 in which a majority of specimens from postoperative wound and intra-abdominal infections included enterococci. Enterococcal intra-abdominal abscesses have been reported after major hepatic resection for trauma or tumor, even in the setting of appropriate (piperacillin/gentamicin) antibacterial prophylaxis.50
Epidemiology of Enterococcal Infection The source of the enterococci in these infections has been thought to be endogenous,22 particularly in the case of urinary tract infection. Enterococci are present in feces in concentrations of 106 organisms per gram.5' They are also indigenous to the human oral cavity,52 gallbladder,
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female genital tract and perineum,53 and male and female urethra.54 Seriously ill patients frequently have perineal fecal contamination, and there has been scant epidemiologic documentation of epidemic enterococcal infections.55 Even if the flora are endogenous, the hospital environment may render endogenous flora more invasive. Treatment with imipenem-cilastatin resulted in enterococcal overgrowth in fecal flora.56 Overgrowth was observed despite the fact that E. faecalis is sensitive to imipenem-cilastatin in vitro, although E. faecium is resistant. Bacterial overgrowth may lead to intestinal bacterial translocation. It is possible that broad-spectrum antibiotic therapy may render the already compromised host susceptible to sepsis from endogenous sources, even without catheterization or other manipulation, although the pathogenicity of the translocation phenomenon in humans is still being defined. Enterococci are capable of translocation, although not to the extent of Escherichia co/i, for example.57 Enterococcal translocation has been reported to be facilitated in mice treated with parenteral metronidazole.58 59 However the assumption that enterococci arise solely from endogenous sources also requires re-examination. Zervos and colleagues59 60 noted a large increase in nosocomial enterococcal surgical infections caused by highly gentamicin-resistant strains at the University of Michigan, and determined in epidemiologic studies that those strains were extrinsically acquired and had been transmitted by direct contact with medical personal. Two outbreaks of extrinsically acquired neonatal enterococcal sepsis also have been reported recently.6'62 The recent exogenously acquired epidemics of enterococcal infection were caused by strains that are highly resistant to gentamicin.59,60 Although the incidence of high-level streptomycin resistance increased throughout the 1960s and 1970s,63 64high-level gentamicin resistance is a relatively new phenomenon. Unknown as recently as 1977 at the Massachusetts General Hospital,65 widespread reports of high-level gentamicin resistance appeared between 1979 and 1984.6648 These gentamicin-resistant strains are generally resistant to all other aminoglycosides by a transferable plasmid-mediated mechanism that may have been originally acquired from Staphylococcus aureus.69 Beta-lactamase production by gentamicin-resistant strains of E. faecalis has also been described.70'7' Gentamicin and beta-lactamase resistance may occur in tandem because the beta-lactamase gene is present on the same plasmid as that for gentamicin resistance in staphylococci.67 This association is of concern because of the rapid proliferation of gentamicin-resistant strains. Similar proliferation of beta-lactamase-producing enterococci may make treatment of serious enterococcal infections all the more difficult. Even more worrisome are the recent reports of vancomycin-resistant enterococci, including both E. faecalis
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and E. faecium.72 These highly resistant strains were isolated from blood, peritoneal fluid or collections, urine, pleural fluid, or bile from 22 critically ill patients with multiple-organ failure. Beginning 3 months before the outbreak, vancomycin and ceftazidime had been used empirically for sepsis before diagnosis, further documenting the enormous capability of the enterococci to develop resistance to commonly used antimicrobial agents. The emergence of these resistant strains may be of enormous clinical significance. Many hospitalized patients are found to have gentamicin-resistant strains when the organisms are initially isolated, and other patients will acquire these resistant strains. One third ofthe deaths due to enterococcal infections reported by Zervos and coworkers60 were caused by gentamicin-resistant strains.
Recommendations for Therapy
Surgical drainage or removal of infected vascular catheters or prostheses remains the cornerstone of therapy for enterococcal infections involving discrete foci-abscesses, infected wounds or burns, or ureteral or biliary obstruction. Yet the enterococci are more likely to become pathogenic or cause bacteremia in the compromised patient. In the selected circumstances typified by many surgical patients, specific adjunctive antibacterial therapy directed against enterococci is now warranted. The sick surgical patient seems almost ideally compromised from the standpoint of the enterococcus as an opportunistic pathogen, particularly after trauma, shock, major burns, organ transplantation, or persistent sepsis. Empiric therapy for the enterococcus in intra-abdominal, nonbiliary/urinary infection in the good risk patient does not appear necessary (except possibly for patients with valvular heart disease),4 nor is the addition of anti-enterococcal coverage (ampicillin, piperacillin, or vancomycin) necessary if initial intraperitoneal cultures yield enterococci but the patient is doing well. However, if the patient has had enterococci cultured previously during the hospitalization or if the infection is nosocomial, particularly with previous gastrointestinal or genitourinary surgery or previous antibiotic therapy, a drug effective against enterococci should be included in the regimen for both proved and presumptive abdominal/pelvic infections, burn or surgical wound infections, urosepsis, postoperative/acalculous cholecystitis, and catheter-related infection. This is especially true in patients with valvular heart disease or a prosthetic heart valve. Enterococcal bacteremia requires parenteral antibiotic therapy.4 Appropriate therapy for enterococcal bacteremia without endocarditis should use a bactericidal antibiotic such as ampicillin, an acylureido penicillin (piperacillin, mezlocillin, or azlocillin), or vancomycin for 10 to 14 days.4 Because enterococcal bacteremia is often polymi-
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crobial, appropriate antibiotic therapy also should be directed against any additional isolates. Synergistic therapy with an aminoglycoside can also be used but may not be necessary. Although some reports suggest that antibiotic therapy did not influence the outcome of intra-abdominal sepsis caused by enterococci,73 recent evidence suggests that adjunctive antibiotic therapy with appropriate agents clearly reduces mortality.44' All patients with enterococcal bacteremia must be closely monitored for signs of endocarditis. Enterococcal endocarditis should be suspected in the presence of embolic lesions or echocardiographic findings,74 and treated with an appropriate bactericidal combination for 4 to 6 weeks.475 Penicillin, ampicillin, or vancomycin combined with an aminoglycoside (gentamicin, or streptomycin if high-level enterococcal gentamicin resistance is identified) may be administered with dosage predicated on the serum bactericidal titer of the organism.76 Patients with prosthetic valve endocarditis may require 6 weeks of therapy.75 The overall cure rate for enterococcal endocarditis is approximately 75%.76 Therapy for patients in whom an extracardiac source of enterococcal bacteremia cannot be identified remains a matter of debate. Patients with valvular heart disease should be presumed to have endocarditis and should be treated accordingly.4 Similar recommendations recently have been made for patients without valvular heart disease.4 Fortunately endocarditis rarely develops after nosocoinial enterococcal bacteremia4,8' 4'473 and is exceedingly unusual if the enterococcal bacteremia is polymicrobial.4
10. 11.
12. 13. 14. 15.
16. 17. 18.
19.
20.
21. 22. 23.
24.
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