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Appropriate surgical prophylaxis in transurethral genitourinary surgery and potential reduction in nosocomial infections
APPROPRIATE
SURGICAL
TRANSURETHRAL POTENTIAL
GENITOURINARY
REDUCTION
STACY J. CHILDS,
PROPHYLAXIS
IN
SURGERY AND
IN NOSOCOMIAL
INFECTIONS
M.D.
From the Shelby and Brookwood Birmingham, Alabama
Medical
Centers,
ABSTRACT-Despite the high rate of urinary tract infectionsseen in hospitals, until recently many surgeons did not advise antibiotic prophylaxis for transurethral genitourinary surgery. This situation has changed with the realization that older trials with questionable results were poorly designed. Several recent well-controlled clinical studies show that appropriate antibiotic prophylaxis greatly reduces the high incidence of infections following transurethral genitourinary surgery. Effective antibiotic prophylaxis for transurethral operations may be a major route to substantial reduction in nosocomial urinary tract infections and bacteremia. To achieve effective prophylaxis, the surgeon must choose a correct antibiotic and use it according to proved principles.
Considerable evidence supports the principle that preoperative antibiotics, appropriately administered, reduce infections in many types of surgery. The role of antibiotic prophylaxis in transurethral genitourinary surgery, however, has been particularly difficult to clarify. Since the first clinical study in 1938,’ surgeons have debated whether or not surgical antibiotic prophylaxis reduces infections following transurethral procedures. Initial rejection of prophylaxis in genitourinary surgery rested on the classification of this surgery as “clean contaminated,” as well as on clinical trials in which antibiotic prophylaxis prior to genitourinary procedures did not reduce the long-range incidence of subsequent infections. More recently, the true “contaminated” nature of this surgery has been better appreciated. In addition, well-controlled trials performed in the last five years have convincingly demonstrated that antibiotic prophylaxis, administered according to established guidelines, greatlv decreases the incidence of postoperative infection after transurethral genitourinary surgery.
UROLOGY
i
MAY
1986
i
VOLUME
XXVII,
NUMBER
5
Problem
of Nosocomial Tract Infections
Urinary
Of all patients admitted to hospitals in the United States, in 3 to 4 of every 100 an infection will develop that was not present on admission.2 About half of these nosocomial infections will be in the urinary tract.2 These hospital-acquired infections are severe and dangerous. Among persons with nosocomial infections, the rate of secondary bacteremia tripled during the 1970s.3 And about 40 per cent of secondary bacteremias arise from the urinary tract.3 Patients in whom a bacteremia develops from a nosocomial urinary tract infection stand a 10 per cent chance of dyinga One of the primary reasons for this high fatality rate is the changing pattern of hospital pathogens. In addition to the standard urinary tract organisms, primarily Escherichia coli, we are seeing an increasing number of other, more refractory, gram-negative pathogens, such as Serratia, Pseudomonas, Enterobacter, and Klebsiella5 (Table I). (Note that enterococcal isolates are also common.) In fact, the frequency of gram-negative bacteremia in all sites
415
TABLE I.
Most frequently isolated pathogens (12) and percentage distribution for each site of infection, 1980-1982 Total UT1
Pathogen
SW
BACT
Per Cent 19.7
E. coli
31.9
13.0
12.8
S. aureus Enterococci P aeruginosa Klebsiella spp. Proteus spp. Enterobacter spp. Coagulase-negative staphylococci Candida spp. Serratia spp. Bacteroides spp. Group B Streptococcus
1.9 13.6 11.7 8.7
16.9 11.3 7.4 5.3
13.1 6.8 5.7 9.3
7.5 4.3 3.5 4.6
5.8 6.0 5.9 1.3
1.7 6.8 10.3 4.7 3.8 4.0 3.0 18.0 6,843
All others*
1.6 0.0 1.2
1.8 6.5 2.3 16.5 25,858
9.5
Number of isolates
49,261
KEY: UT1 = urinary tract infection, SW1 = surgical wound infection, mial Infection Surveillance, 1980-1982.2 ‘No other pathogen accounted for more than 3 per cent of the isolates
of infection has increased dramatically in many institutions over the last twenty or thirty years and is now one of the most frequent types of lethal infections in the United States (Table II). This evolution m.ay be due in part to selective pressure exerted by the use or misuse of newer and more potent antimicrobials. A large majority of urinary tract infections and resulting bacteremias, in turn, result from urologic manipulation, such as cystoscopy, catheterization, or urethral dilatation.6 In fact, urologic instrumentation ranks among the top three causes of hospital-acquired bacteremia, along with vascular catheters and mechanical ventilation.7 Together these three types of intervention account for 75 per cent of nosocomial bacteremias.’ Given this association between urinary tract procedures and the overall serious problem of hospital-originated infections, one might expect unanimous recommendation of antibiotic prophylaxis prior to transurethral genitourinary surgery. But it has been only recently that sufficient evidence has accumulated to support this recommendation.
BACT =
primary
bacteremia.
Adapted
10.8 10.1
9.9 8.0 6.1 5.6 4.7 4.5 2.3 2.1 1.7 14.7 100.0 from
National
Nosoco-
at any site.
TABLE II. Relative frequency of pathogenic infections leading to secondary bacteremias, 1984
Pathogen S. aureus E. coli P aeruginosa Coagulase-negative Klebsiella spp. Enterobacter spp. Other for
*Personal Disease
Per Cent 23.4 14.4 11.1 8.9 7.6 4.7 29.9
Staphylococcus
communication, Control, Atlanta,
Hospital Georgia,
Infections Branch, Centers September, 1984.
The initial classification of genitourinary surgery as “clean contaminated” arose from the view that this type of surgery did not involve gross contamination of the wound. But the overriding admission is that transurethral procedures do entail a break in sterile technique.
The entry of the endoscope abrades the surface of the urinary tract. The potential for manipulation or abrasion of the urinary tract to inoculate pathogenic organisms is great. The normal flora of the prostate includes potentially pathogenic bacterias; about 5 per cent of males carry enterobacteria in the distal urethrag; and up to 30 per cent of catheterized males have enterococcus in the meatus. lo In addition, transurethral procedures are performed in a cystoscopy room, which is definitely a contaminated environment. Contact between the cystoscope lens and the eye provides an additional opportunity for transfer of potentially pathogenic bacteria to the prostate or urethra. Finally, transurethral surgery is performed just centimeters away from the rectum. Organisms that are a normal part of the bowel
416
UROLOGY
Is Genitourinary
Surgery
“Contaminated”?
/
MAY
1986
/
VOLUME
XXVII,
NUMBER
5
TABLE: III.
Incidence of postoperative urinary tract infection in prospective controlled trials in patients undergoing transurethral surgery Placebo ( % )
Series Korbel and Maher”
37 26 28
Nielsen, et aZ.12 Shah 2 et al.‘”
19, 30 29 35 17
Childs, et al. *I* Childs, et aZ.15 Prokocimer, et al. Ifi Frimodt-Moller and MadsenI *Included
some cases of non-transurethral
genitourinary
for genitourinary
surgery
However, many clinicians have stated that antibiotic prophylaxis is not necessary for transurethral genitourinary surgery. 18-23They based this opinion largely on the failure of clinical trials consistently to demonstrate a clear effect of antibiotic prophylaxis. In 1979 Chodak and Plautz4 analyzed published studies of genitourinary prophylaxis. They concluded that poor design features were responsible for the failure of these trials, rather than lack of effectiveness of prophylactic antibiotics. They identified these shortcomings: Many older studies did not No cutoff date. establish a cutoff date for judgiiid the rate of postoperative infections. Infections occurring even at several weeks after surgery were counted as failures of antibiotic prophylaxis, It is unreasonable to assume that perioperative antibiotics will affect urinary tract infections at day 14. Our current practice is to set day 5 following surgery as the cutoff for postoperative infections (and even this may be too long). Inappropriate drugs. Prophylaxis for genitourinary surgery requires bactericidal levels of
UROLOGY
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MAY
1986
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VOLUME
XXVII,
NUMBER
Cephalexin Amoxicillin Cefoxitin Cephalexin TrimethoprimSulfaurethoxazole Ceftriaxone Aztreonam Cefotaxime Cefoperazone
1 0 4 16 8 0, 5 6 3 0
surgery.
flora may well be pathogenic in the urinary tract. Given these considerations, it is not surprising that placebo-controlled trials have demonstrated an incidence of infection between 20 per cent and 40 per cent in control groups following transurethral surgery 11-17(Table III). Although the incidence of sepsis has been much lower, between 2 per cent and 8 per cent, that is still too high for this more serious consequence of surgery. Therefore, efforts to reduce these infections via prophylaxis are certainly justified. Early view of prophylaxis
Incidence of Infection Active Drug (%)
5
drug in the bladder, urethra, or prostate. But older studies tested drugs such as ampicillin and nitrofurantoin, which do not achieve adequate levels in the prostate. Znappropriate dosing schedules. Adequate tissue levels must be achieved at the time of surgery. Yet according to older studies dosing often began too late. In some, prophylaxis was defined as an antibiotic injecton in the recovery room. Furthermore, antibiotics were sometimes administered for as long as ten days after surgery. Currently, we know that prophylaxis requires twenty-four-hour dosing at most. Longer treatment can select for resistant organisms. Lack of appreciation of ongoing infection. A patient with an existing infection requires therapy, not prophylaxis. Yet it has been only recently that we have appreciated that colony counts as low as lo3 may be significant at an operative site25 and urinary counts below lo5 may indicate infection in a catheterized patientz6 Moreover, we are finding that up to 20 per cent of specimens that do not yield organisms on an agar plate may be positive in broth culture. We now follow the principle that the detection of any bacteria in an operative site, regardless of the colony count, moves the patient from a prophylactic category to a therapeutic one. In addition, many of these early trials were retrospective and uncontrolled and contained small numbers of patients and heterogeneous, unrandomized surgical procedures. Contemporary prophylactic genitourinary trials In contrast, virtually every well-designed study of antibiotic prophylaxis done in the last
417
five years has found at least a 50 per cent reduction in postoperative infection rates following transurethral surgery II-l7 (Table III). (Note that only one of these publications predates 1981.) Nielsen and colleagues12 published one of the first well-controlled studies of antibiotic prophylaxis in transurethral surgery. They found a decrease in postoperative infections from 26 per cent in the placebo group to 4 per cent among patients treated with a second-generation cephalosporin. However, even in this study “prophylaxis” was extended as long as a catheter was indwelling. The result was an increase in urinary tract infections with time after surgery in the antibiotic-treated group. Even more ominous, two antibiotic-resistant organisms were isolated. Subsequent trials were able to avoid this problem. Looking at all the studies together, most antibiotic-treated groups show an incidence of postoperative infection in the range of 0 to 6 per cent, truly a substantial decrease from the 20 per cent to 40 per cent range in the placebo groups. The need for an adequate comparison group in antibiotic prophylaxis trials is underscored by our own work with one antibiotic. In the five studies, the frequency of postoperative infections with the same drug ranged from 0 to 13 per cent. 27-2g Guidelines
for Effective Antibiotic Prophylaxis in Transurethral Surgery
Studies showed that substantial reductions in postoperative infections in transurethral surgery followed similar principles: Correct dosing suchedule Prophylaxis begins with one dose of the antibiotic at a time sufficient to provide adequate tissue levels at the time of surgery, Newer drugs such as cefotaxime and cefoperazone, which have effective half-lives of two to three hours, can easily be given thirty to sixty minutes before surgery. No more than perioperative dosingthe immediate twenty-four hours following surgery-is necessary. However, with the newer drugs we have found no advantage to perioperative dosing relative to a single preoperative dose.
though aminoglycosides are very effective against many organisms that cause urinary tract infections and are appropriate therapy for established infections with gram-negative pathogens, these drugs have a high risk of nephrotoxicity (about 10 % ) . However, aminoglycoside nephrotoxicity rarely develops prior to seven days of full-dosage therapy in nonazotemic patients. When used for prophylaxis (24-28 hours), aminoglycoside antibiotics should not lead to nephrotoxicity in patients who are not severely azotemic. Most men undergoing TURP do not have significant azotemia and particularly do not have azotemia secondary to upper tract obstruction. Those who have the latter condition should initially be managed by bladder catheter drainage prior to surgery until the azotemia is resolved. However, there are conditions at the time of surgery that theoretically could place the patient at greater risk of nephrotoxicity. For instance, patients in surgery may have a decrease in renal blood flow due to dehydration, spinal anesthesia, or bleeding. This leaves the aminoglycoside at the proximal tubule for a prolonged period. Many surgical patients are elderly, and already have lost 50 per cent to 60 per cent of their functioning nephrons. Often they are taking or may be given furosemide, which potentiates aminoglycoside toxicity. Patients undergoing transurethral surgery are also likely to have an enlarged prostate, which can obstruct the ureters and further concentrate the aminoglycoside in the kidney. An additional consideration would be not to use an antibiotic that is associated with a bleeding side effect, e.g., moxalactam, because there may be a substantial blood loss associated with the surgical procedure itself. Choice of an effective
antibiotic
Choice of a safe antibiotic When giving an antibiotic for a potential infection, one must balance the side effects of the drug versus the probability of infection. Al-
The antibiotic must be matched to the known prevalence of gram-negative opportunistic bacteria in urinary tract infections. Trimethoprim-sulfamethoxazole, ampicillin, and first-generation cephalosporins may not cover for Pseudomonas or Klebsiella, for example. More important, there is a substantial increase in strains resistant to older antibiotics, i.e., cefazolin.30 The newer broad-spectrum antibiotics are excellent choices for transurethral prophylaxis. These include the thirdgeneration cephalosporins (cefoperazone, cefotaxime, ceftazidime, and ceftriaxone) and the fourth-generation penicillins (piperacillin and
418
UROLOGY
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mezlocillin) , Recent data suggest especially good potency of cefoperazone and piperacillin against Pseudomonas isolates (Table IV). Special consideration We have found that the aforementioned suggestions for antibiotic selection must be modified in one special group of patients: elderly males with enlarged prostates who have been in a hospital or nursing home for a long time and have an indwelling Foley catheter. In our experience these patients have a high rate of carriage or infection with enterococcus,31 an organism that is not adequately covered by third-generation cephalosporins. In this case we tend to use a fourth-generation penicillin. Enterococcus bacteremia can have a fatality rate as high as 50 per cent ,31 cost
The newer beta-lactam antibiotics are substantially more expensive than previous agents. However, we believe that there are three reasons why this should not be a major factor in selecting an antibiotic for prophylaxis. First, the cost of the drug itself is only a minor part of the cost of administering an antibiotic. Nursing and pharmacy time and the cost of an IV administration set contribute much more to the price of prophylaxis. Second, newer drugs are effective in a single preoperative dose,14.2s whereas older cephalosporins should be used perioperatively. Thus, the total cost of using cefazolin, for example, actually can be twice that of using a third-generation cephalosporin. Third, the cost of using an ineffective drug can be $4,000 to $5,000 for long-term hospitalization to treat an episode of sepsis. Opportunity to Reduce Nosocomial by Appropriate Prophylaxis Transurethral Surgery
Infections for
Use of effective antibiotics according to established principles is able to decrease greatly the incidence of infections following transurethral surgery. Since urinary tract infections account for a major share of hospital-acquired infections, both directly and by seeding other sites, especially the blood, reducing the incidence of urinary tract infections after transurethral surgery should lead to a substantial decrease in nosocomial infections. Appropriate transurethral prophylaxis also may contribute to a reduction in nosocomial infections by restraining the increase in antibiotic-resistant organisms. Administration of
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419
antibiotics beyond the immediate perioperative period is associated with an increase in the incidence of infections. 1g,21In addition, resistant organisms begin to arise. l2 On the other hand, we are not aware of any evidence that short-term antibiotic use leads to an increase in resistance. Rather, in vitro evidence suggests that resistance arises from repeated exposures to an antibiotic, especially sub-therapeutic doses.32 It is interesting that the most recent National Nosocomial Infections Study already registered a high incidence of resistant Pseudomonas to newly introduced antibiotics in the first year in which figures were available (1982) ,2 Resistance to moxalactam, for example, was found in 24 per cent to 41 per cent of all P aeruginosa isolates. Occasionally one hears the recommendation to save an especially potent antibiotic for special situations so that resistance will not develop so quickly. I have given this advice.33 If we were to follow proper, short-term surgical prophylactic technique, resistance to antibiotics would probably not arise nearly as fast as we have witnessed in the past decade.
1. Gaudin HJ, Zide HA, and Thompson GJ: Use of sulfanilamide after transurethral prostatectomy, JAMA 110: 1938 (1938). 2. Hughes JM, et al: Nbsocomial infection surveillance, 19&l1982. CDC Surveillance Summaries 1983. 32 (4SS): lSS-16SS (1983). 3. Center for Disease Control: National Nosocomial Infections Study Report 1979; Nov. 2-14, 1979. 4. Platt R, Polk B, Murdock B, and Rosner B: Mortality associated with nosocomial urinary tract infection, N Engl J Med 307: 637 (1982). 5. Madsen P, and Nielsen 0: Microflora of urinary tract infections in hospitalized male patients, in Neu H, and Percival A (Eds): Antibiotic Prophylaxis in Surgery: Current Concept, Merck Sharp & Dohme International, 1980, p 20. 6. Goldwasser B, et al: Urinary infections following transurethral resection of bladder tumors. Rate and source, J Urol 129: 1123 (1983). 7. Kreger B, et nl: Gram-negative bacteremia. III. Reassessment of etiology, epidemiology and ecology in 612 patients, Am J Med 68: 332 (1980). 8. Morris M, et al: The value of prophylactic antibiotics in transurethral prostatic resection: a controlled trial with observations on the origin of postoperative infection, J Urol 48: 479 (1976). 9. Stamey T: Pathogenesis and Treatment of Urinary Tract Infections, Baltimore, Williams and Wilkins, 1980. 10. Garibaldi T, et al: Meatal colonization and catheter-associated bacteriuria, N Engl J Med 303: 316 (1980).
11. Korbel E, and Maher P: Use of prophylactic antibiotics in urethral instrumentation, J Urol 116: 744 (1976). 12. Nielsen 0, Maigaard S, Frimodt-Moller N, and Madsen P: Prophylactic antibiotics in transurethral prostatectomy. ihid 126: 60 (1981). 13. Shah P, Williams G, and Chaudary M: Short-term antibiotic prophylaxis and prostatectomy, Br J Urol 53: 339 (1981). 14. Childs S, Wells W, and Mirelman S: Antibiotic prophylaxis for genitourinary surgery in community hospitals, J Uroll30: 305 (1983). 15. Childs S, Mirelman S, Wells W, and Hurst A: A comparison of aztreonam and placebo for genitourinary surgery prophylaxis, Abstract 524, ICACC, 1983. 16. Prokocimer P et al: A prophylaxis by 2 doses of cefotaxime is useful in prostatic surgery, Abstract #122, ibid, 1983. 17. Frimodt-Moller PC, and Madsen PO: Perioperative antibiotic prophylaxis with cefoperazone in transurethral surgery: a prospective randomized placebo-controlled study. Presented at 13th International Congress of Chemotherapy, Vienna, Austria, August 28-September 2: 1983, pp 33/15-33119. 18. Turck M. and Petersdorf RG: The role of antibiotics in the prevention of urinary tract infection, J Chronic Dis 15: 683 (1962). 19. Madsen PO, Chaney MH, and Lapinski EM: Neg-Gram and Furadantin in the treatment of infection following transurethral prostatectomy, Acta Chir Stand 129: 656 (1965). 20. Wear JB Jr, and Haley P: ‘Bansurethral prostatectomy without antibiotics, J Urol 110: 436 (1973). 21. Gibbons RP, et al: The prophylactic use-or misuse-of antibiotics in transurethral prostatectomy, ibid 119: 381 (1978). 22. Osius TG, Tavel FR, and Hinman F Jr: Tetracycline used prophylactically in transurethral procedures, Maryland State Med J 14: 37 (1965). 23. Dellinger P: Perioperative antibiotics in urologic surgery, Urol Clin North Am 3: 23 (1976). 24. Chodak GW, and Plaut ME: Systemic antibiotics for prophylaxis in urologic surgery: a critical review, J Urol 121: 695 (1979). 25. Gordon DL, et al: Diagnostic criteria and natural history of catheter-associated urinary tract infections after prostatectomy, Lancet 2: 1269 (1983). 26. Starr RP, and Make DC: Bacteriuria in the catheterized patient: what quantitative level of bacteriuria is relevant? N Engl J Med 311: 560 (1984). 27. Childs SJ, Wood PD, and Kosola JW: Antibiotic prophylaxis in genitourinary surgery, Clin Therapeutics 4(Suppl A): 111 (1981). 28. Childs SJ, Wood PD, and Kosola JW: Antibiotic prophylaxis in genitourinary surgery: a comparison of cefotaxime and cefazolin, Clin Ther S(Supp1 A): 48 (1982). 29. Childs SJ, Wells SE, and Mirelman S: Role of penicillins in the prophylaxis of gram-negative genitourinary infections. Presented at 13th International Congress of Chemotherapy, Vienna, Austria, August 28-September 2, 1983. 30. Matsuo K, et al: Comparison of in vitro activity against first, second, and third-generation cephem antibiotics against various pathogens isolated from clinical materials in 1983, Jpn J Antibiot 37: 1040 (1984). 31. Childs S: Enterococcus in urologic infections, Infect Surg 1984: April Suppl: 12-14 (1984). 32. Clewell DB, and Yagi Y: Amplification of the tetracycline resistance determinant on plasmid pAm 1 in StreptococcusfaecaIi. DNA Insertion Elements, Plasmids, and Episomes, 1977, p 235-246. 33. Childs SJ: Perioperative prevention of infection in genitourinary surgery, in Antibiotics in Chemotherapy: The Perioperative Prevention of Infections, Basel, Karger, 1985, ~0133, pp 1-29.
420
UROLOGY
Suite 203 1006 First Street North Alabaster, Alabama 35007 References
\
I
/
MAY
1986
/
VOLUME
XXVII,
NUMBER
5
SURGICAL
TRANSURETHRAL POTENTIAL
GENITOURINARY
REDUCTION
STACY J. CHILDS,
PROPHYLAXIS
IN
SURGERY AND
IN NOSOCOMIAL
INFECTIONS
M.D.
From the Shelby and Brookwood Birmingham, Alabama
Medical
Centers,
ABSTRACT-Despite the high rate of urinary tract infectionsseen in hospitals, until recently many surgeons did not advise antibiotic prophylaxis for transurethral genitourinary surgery. This situation has changed with the realization that older trials with questionable results were poorly designed. Several recent well-controlled clinical studies show that appropriate antibiotic prophylaxis greatly reduces the high incidence of infections following transurethral genitourinary surgery. Effective antibiotic prophylaxis for transurethral operations may be a major route to substantial reduction in nosocomial urinary tract infections and bacteremia. To achieve effective prophylaxis, the surgeon must choose a correct antibiotic and use it according to proved principles.
Considerable evidence supports the principle that preoperative antibiotics, appropriately administered, reduce infections in many types of surgery. The role of antibiotic prophylaxis in transurethral genitourinary surgery, however, has been particularly difficult to clarify. Since the first clinical study in 1938,’ surgeons have debated whether or not surgical antibiotic prophylaxis reduces infections following transurethral procedures. Initial rejection of prophylaxis in genitourinary surgery rested on the classification of this surgery as “clean contaminated,” as well as on clinical trials in which antibiotic prophylaxis prior to genitourinary procedures did not reduce the long-range incidence of subsequent infections. More recently, the true “contaminated” nature of this surgery has been better appreciated. In addition, well-controlled trials performed in the last five years have convincingly demonstrated that antibiotic prophylaxis, administered according to established guidelines, greatlv decreases the incidence of postoperative infection after transurethral genitourinary surgery.
UROLOGY
i
MAY
1986
i
VOLUME
XXVII,
NUMBER
5
Problem
of Nosocomial Tract Infections
Urinary
Of all patients admitted to hospitals in the United States, in 3 to 4 of every 100 an infection will develop that was not present on admission.2 About half of these nosocomial infections will be in the urinary tract.2 These hospital-acquired infections are severe and dangerous. Among persons with nosocomial infections, the rate of secondary bacteremia tripled during the 1970s.3 And about 40 per cent of secondary bacteremias arise from the urinary tract.3 Patients in whom a bacteremia develops from a nosocomial urinary tract infection stand a 10 per cent chance of dyinga One of the primary reasons for this high fatality rate is the changing pattern of hospital pathogens. In addition to the standard urinary tract organisms, primarily Escherichia coli, we are seeing an increasing number of other, more refractory, gram-negative pathogens, such as Serratia, Pseudomonas, Enterobacter, and Klebsiella5 (Table I). (Note that enterococcal isolates are also common.) In fact, the frequency of gram-negative bacteremia in all sites
415
TABLE I.
Most frequently isolated pathogens (12) and percentage distribution for each site of infection, 1980-1982 Total UT1
Pathogen
SW
BACT
Per Cent 19.7
E. coli
31.9
13.0
12.8
S. aureus Enterococci P aeruginosa Klebsiella spp. Proteus spp. Enterobacter spp. Coagulase-negative staphylococci Candida spp. Serratia spp. Bacteroides spp. Group B Streptococcus
1.9 13.6 11.7 8.7
16.9 11.3 7.4 5.3
13.1 6.8 5.7 9.3
7.5 4.3 3.5 4.6
5.8 6.0 5.9 1.3
1.7 6.8 10.3 4.7 3.8 4.0 3.0 18.0 6,843
All others*
1.6 0.0 1.2
1.8 6.5 2.3 16.5 25,858
9.5
Number of isolates
49,261
KEY: UT1 = urinary tract infection, SW1 = surgical wound infection, mial Infection Surveillance, 1980-1982.2 ‘No other pathogen accounted for more than 3 per cent of the isolates
of infection has increased dramatically in many institutions over the last twenty or thirty years and is now one of the most frequent types of lethal infections in the United States (Table II). This evolution m.ay be due in part to selective pressure exerted by the use or misuse of newer and more potent antimicrobials. A large majority of urinary tract infections and resulting bacteremias, in turn, result from urologic manipulation, such as cystoscopy, catheterization, or urethral dilatation.6 In fact, urologic instrumentation ranks among the top three causes of hospital-acquired bacteremia, along with vascular catheters and mechanical ventilation.7 Together these three types of intervention account for 75 per cent of nosocomial bacteremias.’ Given this association between urinary tract procedures and the overall serious problem of hospital-originated infections, one might expect unanimous recommendation of antibiotic prophylaxis prior to transurethral genitourinary surgery. But it has been only recently that sufficient evidence has accumulated to support this recommendation.
BACT =
primary
bacteremia.
Adapted
10.8 10.1
9.9 8.0 6.1 5.6 4.7 4.5 2.3 2.1 1.7 14.7 100.0 from
National
Nosoco-
at any site.
TABLE II. Relative frequency of pathogenic infections leading to secondary bacteremias, 1984
Pathogen S. aureus E. coli P aeruginosa Coagulase-negative Klebsiella spp. Enterobacter spp. Other for
*Personal Disease
Per Cent 23.4 14.4 11.1 8.9 7.6 4.7 29.9
Staphylococcus
communication, Control, Atlanta,
Hospital Georgia,
Infections Branch, Centers September, 1984.
The initial classification of genitourinary surgery as “clean contaminated” arose from the view that this type of surgery did not involve gross contamination of the wound. But the overriding admission is that transurethral procedures do entail a break in sterile technique.
The entry of the endoscope abrades the surface of the urinary tract. The potential for manipulation or abrasion of the urinary tract to inoculate pathogenic organisms is great. The normal flora of the prostate includes potentially pathogenic bacterias; about 5 per cent of males carry enterobacteria in the distal urethrag; and up to 30 per cent of catheterized males have enterococcus in the meatus. lo In addition, transurethral procedures are performed in a cystoscopy room, which is definitely a contaminated environment. Contact between the cystoscope lens and the eye provides an additional opportunity for transfer of potentially pathogenic bacteria to the prostate or urethra. Finally, transurethral surgery is performed just centimeters away from the rectum. Organisms that are a normal part of the bowel
416
UROLOGY
Is Genitourinary
Surgery
“Contaminated”?
/
MAY
1986
/
VOLUME
XXVII,
NUMBER
5
TABLE: III.
Incidence of postoperative urinary tract infection in prospective controlled trials in patients undergoing transurethral surgery Placebo ( % )
Series Korbel and Maher”
37 26 28
Nielsen, et aZ.12 Shah 2 et al.‘”
19, 30 29 35 17
Childs, et al. *I* Childs, et aZ.15 Prokocimer, et al. Ifi Frimodt-Moller and MadsenI *Included
some cases of non-transurethral
genitourinary
for genitourinary
surgery
However, many clinicians have stated that antibiotic prophylaxis is not necessary for transurethral genitourinary surgery. 18-23They based this opinion largely on the failure of clinical trials consistently to demonstrate a clear effect of antibiotic prophylaxis. In 1979 Chodak and Plautz4 analyzed published studies of genitourinary prophylaxis. They concluded that poor design features were responsible for the failure of these trials, rather than lack of effectiveness of prophylactic antibiotics. They identified these shortcomings: Many older studies did not No cutoff date. establish a cutoff date for judgiiid the rate of postoperative infections. Infections occurring even at several weeks after surgery were counted as failures of antibiotic prophylaxis, It is unreasonable to assume that perioperative antibiotics will affect urinary tract infections at day 14. Our current practice is to set day 5 following surgery as the cutoff for postoperative infections (and even this may be too long). Inappropriate drugs. Prophylaxis for genitourinary surgery requires bactericidal levels of
UROLOGY
i
MAY
1986
i
VOLUME
XXVII,
NUMBER
Cephalexin Amoxicillin Cefoxitin Cephalexin TrimethoprimSulfaurethoxazole Ceftriaxone Aztreonam Cefotaxime Cefoperazone
1 0 4 16 8 0, 5 6 3 0
surgery.
flora may well be pathogenic in the urinary tract. Given these considerations, it is not surprising that placebo-controlled trials have demonstrated an incidence of infection between 20 per cent and 40 per cent in control groups following transurethral surgery 11-17(Table III). Although the incidence of sepsis has been much lower, between 2 per cent and 8 per cent, that is still too high for this more serious consequence of surgery. Therefore, efforts to reduce these infections via prophylaxis are certainly justified. Early view of prophylaxis
Incidence of Infection Active Drug (%)
5
drug in the bladder, urethra, or prostate. But older studies tested drugs such as ampicillin and nitrofurantoin, which do not achieve adequate levels in the prostate. Znappropriate dosing schedules. Adequate tissue levels must be achieved at the time of surgery. Yet according to older studies dosing often began too late. In some, prophylaxis was defined as an antibiotic injecton in the recovery room. Furthermore, antibiotics were sometimes administered for as long as ten days after surgery. Currently, we know that prophylaxis requires twenty-four-hour dosing at most. Longer treatment can select for resistant organisms. Lack of appreciation of ongoing infection. A patient with an existing infection requires therapy, not prophylaxis. Yet it has been only recently that we have appreciated that colony counts as low as lo3 may be significant at an operative site25 and urinary counts below lo5 may indicate infection in a catheterized patientz6 Moreover, we are finding that up to 20 per cent of specimens that do not yield organisms on an agar plate may be positive in broth culture. We now follow the principle that the detection of any bacteria in an operative site, regardless of the colony count, moves the patient from a prophylactic category to a therapeutic one. In addition, many of these early trials were retrospective and uncontrolled and contained small numbers of patients and heterogeneous, unrandomized surgical procedures. Contemporary prophylactic genitourinary trials In contrast, virtually every well-designed study of antibiotic prophylaxis done in the last
417
five years has found at least a 50 per cent reduction in postoperative infection rates following transurethral surgery II-l7 (Table III). (Note that only one of these publications predates 1981.) Nielsen and colleagues12 published one of the first well-controlled studies of antibiotic prophylaxis in transurethral surgery. They found a decrease in postoperative infections from 26 per cent in the placebo group to 4 per cent among patients treated with a second-generation cephalosporin. However, even in this study “prophylaxis” was extended as long as a catheter was indwelling. The result was an increase in urinary tract infections with time after surgery in the antibiotic-treated group. Even more ominous, two antibiotic-resistant organisms were isolated. Subsequent trials were able to avoid this problem. Looking at all the studies together, most antibiotic-treated groups show an incidence of postoperative infection in the range of 0 to 6 per cent, truly a substantial decrease from the 20 per cent to 40 per cent range in the placebo groups. The need for an adequate comparison group in antibiotic prophylaxis trials is underscored by our own work with one antibiotic. In the five studies, the frequency of postoperative infections with the same drug ranged from 0 to 13 per cent. 27-2g Guidelines
for Effective Antibiotic Prophylaxis in Transurethral Surgery
Studies showed that substantial reductions in postoperative infections in transurethral surgery followed similar principles: Correct dosing suchedule Prophylaxis begins with one dose of the antibiotic at a time sufficient to provide adequate tissue levels at the time of surgery, Newer drugs such as cefotaxime and cefoperazone, which have effective half-lives of two to three hours, can easily be given thirty to sixty minutes before surgery. No more than perioperative dosingthe immediate twenty-four hours following surgery-is necessary. However, with the newer drugs we have found no advantage to perioperative dosing relative to a single preoperative dose.
though aminoglycosides are very effective against many organisms that cause urinary tract infections and are appropriate therapy for established infections with gram-negative pathogens, these drugs have a high risk of nephrotoxicity (about 10 % ) . However, aminoglycoside nephrotoxicity rarely develops prior to seven days of full-dosage therapy in nonazotemic patients. When used for prophylaxis (24-28 hours), aminoglycoside antibiotics should not lead to nephrotoxicity in patients who are not severely azotemic. Most men undergoing TURP do not have significant azotemia and particularly do not have azotemia secondary to upper tract obstruction. Those who have the latter condition should initially be managed by bladder catheter drainage prior to surgery until the azotemia is resolved. However, there are conditions at the time of surgery that theoretically could place the patient at greater risk of nephrotoxicity. For instance, patients in surgery may have a decrease in renal blood flow due to dehydration, spinal anesthesia, or bleeding. This leaves the aminoglycoside at the proximal tubule for a prolonged period. Many surgical patients are elderly, and already have lost 50 per cent to 60 per cent of their functioning nephrons. Often they are taking or may be given furosemide, which potentiates aminoglycoside toxicity. Patients undergoing transurethral surgery are also likely to have an enlarged prostate, which can obstruct the ureters and further concentrate the aminoglycoside in the kidney. An additional consideration would be not to use an antibiotic that is associated with a bleeding side effect, e.g., moxalactam, because there may be a substantial blood loss associated with the surgical procedure itself. Choice of an effective
antibiotic
Choice of a safe antibiotic When giving an antibiotic for a potential infection, one must balance the side effects of the drug versus the probability of infection. Al-
The antibiotic must be matched to the known prevalence of gram-negative opportunistic bacteria in urinary tract infections. Trimethoprim-sulfamethoxazole, ampicillin, and first-generation cephalosporins may not cover for Pseudomonas or Klebsiella, for example. More important, there is a substantial increase in strains resistant to older antibiotics, i.e., cefazolin.30 The newer broad-spectrum antibiotics are excellent choices for transurethral prophylaxis. These include the thirdgeneration cephalosporins (cefoperazone, cefotaxime, ceftazidime, and ceftriaxone) and the fourth-generation penicillins (piperacillin and
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mezlocillin) , Recent data suggest especially good potency of cefoperazone and piperacillin against Pseudomonas isolates (Table IV). Special consideration We have found that the aforementioned suggestions for antibiotic selection must be modified in one special group of patients: elderly males with enlarged prostates who have been in a hospital or nursing home for a long time and have an indwelling Foley catheter. In our experience these patients have a high rate of carriage or infection with enterococcus,31 an organism that is not adequately covered by third-generation cephalosporins. In this case we tend to use a fourth-generation penicillin. Enterococcus bacteremia can have a fatality rate as high as 50 per cent ,31 cost
The newer beta-lactam antibiotics are substantially more expensive than previous agents. However, we believe that there are three reasons why this should not be a major factor in selecting an antibiotic for prophylaxis. First, the cost of the drug itself is only a minor part of the cost of administering an antibiotic. Nursing and pharmacy time and the cost of an IV administration set contribute much more to the price of prophylaxis. Second, newer drugs are effective in a single preoperative dose,14.2s whereas older cephalosporins should be used perioperatively. Thus, the total cost of using cefazolin, for example, actually can be twice that of using a third-generation cephalosporin. Third, the cost of using an ineffective drug can be $4,000 to $5,000 for long-term hospitalization to treat an episode of sepsis. Opportunity to Reduce Nosocomial by Appropriate Prophylaxis Transurethral Surgery
Infections for
Use of effective antibiotics according to established principles is able to decrease greatly the incidence of infections following transurethral surgery. Since urinary tract infections account for a major share of hospital-acquired infections, both directly and by seeding other sites, especially the blood, reducing the incidence of urinary tract infections after transurethral surgery should lead to a substantial decrease in nosocomial infections. Appropriate transurethral prophylaxis also may contribute to a reduction in nosocomial infections by restraining the increase in antibiotic-resistant organisms. Administration of
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antibiotics beyond the immediate perioperative period is associated with an increase in the incidence of infections. 1g,21In addition, resistant organisms begin to arise. l2 On the other hand, we are not aware of any evidence that short-term antibiotic use leads to an increase in resistance. Rather, in vitro evidence suggests that resistance arises from repeated exposures to an antibiotic, especially sub-therapeutic doses.32 It is interesting that the most recent National Nosocomial Infections Study already registered a high incidence of resistant Pseudomonas to newly introduced antibiotics in the first year in which figures were available (1982) ,2 Resistance to moxalactam, for example, was found in 24 per cent to 41 per cent of all P aeruginosa isolates. Occasionally one hears the recommendation to save an especially potent antibiotic for special situations so that resistance will not develop so quickly. I have given this advice.33 If we were to follow proper, short-term surgical prophylactic technique, resistance to antibiotics would probably not arise nearly as fast as we have witnessed in the past decade.
1. Gaudin HJ, Zide HA, and Thompson GJ: Use of sulfanilamide after transurethral prostatectomy, JAMA 110: 1938 (1938). 2. Hughes JM, et al: Nbsocomial infection surveillance, 19&l1982. CDC Surveillance Summaries 1983. 32 (4SS): lSS-16SS (1983). 3. Center for Disease Control: National Nosocomial Infections Study Report 1979; Nov. 2-14, 1979. 4. Platt R, Polk B, Murdock B, and Rosner B: Mortality associated with nosocomial urinary tract infection, N Engl J Med 307: 637 (1982). 5. Madsen P, and Nielsen 0: Microflora of urinary tract infections in hospitalized male patients, in Neu H, and Percival A (Eds): Antibiotic Prophylaxis in Surgery: Current Concept, Merck Sharp & Dohme International, 1980, p 20. 6. Goldwasser B, et al: Urinary infections following transurethral resection of bladder tumors. Rate and source, J Urol 129: 1123 (1983). 7. Kreger B, et nl: Gram-negative bacteremia. III. Reassessment of etiology, epidemiology and ecology in 612 patients, Am J Med 68: 332 (1980). 8. Morris M, et al: The value of prophylactic antibiotics in transurethral prostatic resection: a controlled trial with observations on the origin of postoperative infection, J Urol 48: 479 (1976). 9. Stamey T: Pathogenesis and Treatment of Urinary Tract Infections, Baltimore, Williams and Wilkins, 1980. 10. Garibaldi T, et al: Meatal colonization and catheter-associated bacteriuria, N Engl J Med 303: 316 (1980).
11. Korbel E, and Maher P: Use of prophylactic antibiotics in urethral instrumentation, J Urol 116: 744 (1976). 12. Nielsen 0, Maigaard S, Frimodt-Moller N, and Madsen P: Prophylactic antibiotics in transurethral prostatectomy. ihid 126: 60 (1981). 13. Shah P, Williams G, and Chaudary M: Short-term antibiotic prophylaxis and prostatectomy, Br J Urol 53: 339 (1981). 14. Childs S, Wells W, and Mirelman S: Antibiotic prophylaxis for genitourinary surgery in community hospitals, J Uroll30: 305 (1983). 15. Childs S, Mirelman S, Wells W, and Hurst A: A comparison of aztreonam and placebo for genitourinary surgery prophylaxis, Abstract 524, ICACC, 1983. 16. Prokocimer P et al: A prophylaxis by 2 doses of cefotaxime is useful in prostatic surgery, Abstract #122, ibid, 1983. 17. Frimodt-Moller PC, and Madsen PO: Perioperative antibiotic prophylaxis with cefoperazone in transurethral surgery: a prospective randomized placebo-controlled study. Presented at 13th International Congress of Chemotherapy, Vienna, Austria, August 28-September 2: 1983, pp 33/15-33119. 18. Turck M. and Petersdorf RG: The role of antibiotics in the prevention of urinary tract infection, J Chronic Dis 15: 683 (1962). 19. Madsen PO, Chaney MH, and Lapinski EM: Neg-Gram and Furadantin in the treatment of infection following transurethral prostatectomy, Acta Chir Stand 129: 656 (1965). 20. Wear JB Jr, and Haley P: ‘Bansurethral prostatectomy without antibiotics, J Urol 110: 436 (1973). 21. Gibbons RP, et al: The prophylactic use-or misuse-of antibiotics in transurethral prostatectomy, ibid 119: 381 (1978). 22. Osius TG, Tavel FR, and Hinman F Jr: Tetracycline used prophylactically in transurethral procedures, Maryland State Med J 14: 37 (1965). 23. Dellinger P: Perioperative antibiotics in urologic surgery, Urol Clin North Am 3: 23 (1976). 24. Chodak GW, and Plaut ME: Systemic antibiotics for prophylaxis in urologic surgery: a critical review, J Urol 121: 695 (1979). 25. Gordon DL, et al: Diagnostic criteria and natural history of catheter-associated urinary tract infections after prostatectomy, Lancet 2: 1269 (1983). 26. Starr RP, and Make DC: Bacteriuria in the catheterized patient: what quantitative level of bacteriuria is relevant? N Engl J Med 311: 560 (1984). 27. Childs SJ, Wood PD, and Kosola JW: Antibiotic prophylaxis in genitourinary surgery, Clin Therapeutics 4(Suppl A): 111 (1981). 28. Childs SJ, Wood PD, and Kosola JW: Antibiotic prophylaxis in genitourinary surgery: a comparison of cefotaxime and cefazolin, Clin Ther S(Supp1 A): 48 (1982). 29. Childs SJ, Wells SE, and Mirelman S: Role of penicillins in the prophylaxis of gram-negative genitourinary infections. Presented at 13th International Congress of Chemotherapy, Vienna, Austria, August 28-September 2, 1983. 30. Matsuo K, et al: Comparison of in vitro activity against first, second, and third-generation cephem antibiotics against various pathogens isolated from clinical materials in 1983, Jpn J Antibiot 37: 1040 (1984). 31. Childs S: Enterococcus in urologic infections, Infect Surg 1984: April Suppl: 12-14 (1984). 32. Clewell DB, and Yagi Y: Amplification of the tetracycline resistance determinant on plasmid pAm 1 in StreptococcusfaecaIi. DNA Insertion Elements, Plasmids, and Episomes, 1977, p 235-246. 33. Childs SJ: Perioperative prevention of infection in genitourinary surgery, in Antibiotics in Chemotherapy: The Perioperative Prevention of Infections, Basel, Karger, 1985, ~0133, pp 1-29.
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