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Nosocomial urinary tract infections
NOSOCOMIAL URINARY TRACT INFECTIONS CLAIR E. COX, M.D. From the Department of Urology, University of Tennessee Center for the Health Sciences, Memphis, Tennessee
ABSTRACT-Hospital-acquired urinary tract infections, which account for approximately 40 percent of all nosocomial infections, often result in serious complications and ultimately lead to rising hospital costs. To combat the high incidence of nosocomial urinary tract infections, surveillance and control programs must be developed and carefully maintained by hospitals. When urinary tract infections cannot be prevented, empiric therapy with broad-spectrum antibiotics effective against beta-lactamase-producing bacteria should begin immediately.
Multihospital studies have indicated that nosocomial infections develop in 3 to 15 percent of all hospitalized patients in the United States. l Approximately 40 percent of these infections originate in the urinary tract2 It has been estimated that as many as one million patients a year suffer from hospital-acquired urinary tract infections (UTI) .3 It is ironic that modern medical technologies that have provided solutions for so many diseases should be so large a part of the problem in the spread of nosocomial urinary tract infections. Urinary catheterization, invasive diagnostic techniques, and the heavy use of antibiotic drugs are the primary sources for the overwhelming majority of nosocomial urinary tract infections. Genitourinary catheterization is responsible for as much as 80 percent of all hospital-acquired UTIs. l Resistance to antibiotic drugs, particularly the beta-lactam antibiotics, is increasing rapidly in the hospital environment and has been associated with the rise in hospital-acquired infections4 Many of the most commonly used beta-lactam antibiotics are no longer effective against the strains of beta-lactamase-producing organisms that are most often responsible for hospital-acquired UTIs. While many hospital-acquired urinary tract infections are asymptomatic, certain populations are at risk for developing serious complications. Among these groups at risk are patients
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with underlying diseases such as diabetes, or those elderly male patients who have undergone lengthy hospitalization. Potential complications may include chronic bacteriuria, renal disease, antibiotic toxicity, septicemia, bacteremia, and death. The acquisition of urinary tract infections associated with indwelling bladder catheterization has been linked to a threefold greater risk of mortality in hospitalized patients. 5 Unresolved nosocomial UTIs may account for as many as 56,000 deaths per year. 5 The number of serious complications due to nosocomial UTIs is significant, and the costs are rising rapidly. Due to the DRG system currently in use for Medicare patients, moreover, additional costs that accrue from the development of complicated nosocomial UTIs among the elderly population may have to be absorbed by the patients or the hospital. The costs for all nosocomial UTIs, both simple and complicated, are staggering. According to data analyzed in a study by Rutledge and McDonald,3 nosocomial UTIs prolong hospitalization by an average of 2.5 days. With the average total hospital cost running approximately $750/day, the additional total bill for a hospital-acquired urinary tract infection would be approximately $1,875. Using even the conservative estimate of one million nosocomial UTIs a year in this country, the total cost to our society could be approaching $2 billion.
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Quantitating the expenses associated with these infections is complicated, because it is difficult to determine the origin and assess the costs of extra laboratory tests and lengthened hospital stays due to nosocomial infections. There are other imponderables that may also add significantly to the overall total, including those hidden costs associated with loss of work, disability, and mortality. Due to the substantial economic and social burdens caused by nosocomial urinary tract infections, it is imperative that the nature of these infections be analyzed thoroughly. With the proper care of hospitalized patients and the awareness of risk factors, many nosocomial UTIs may be preventable. The origins of nosocomial UTIs, the populations at risk, the bacteriology of the infections and the range of available antibiotic therapy, and the parameters of prevention are reviewed herein. Pathogenesis As mentioned, 80 percent of all nosocomial UTIs can be directly attributed to catheterization of the genitourinary tract.’ Another 4 percent of the hospital population acquire nosocomial UTIs due to other forms of urologic manipulation, including cystoscopy and similar diagnostic techniques. l In a study carried out by Haley et al., 6 it was found that hospitals with higher rates of urine culturing, working up significant fevers, and reporting quantitative urine cultures have higher observed rates of nosocomial urinary tract infections. Some of these infections may be due to equipment contaminated by bacteria from other patients or potential pathogens carried by hospital staff. The indirect cause of these nosocomial UTIs is often the result of the presence of highly resistant strains of bacteria in the hospital environment due to heavy antibiotic usage. In one study of an epidemic outbreak of nosocomial UTIs caused by Serratia marcescens, it was determined that the acquisition of the epidemic strain was associated with the exposure of patients to the intensive care unit, the presence of indwelling bladder catheters, earlier treatment of patients with antibiotics, and exposure of patients and staff to devices used for measuring specific gravity and urine volume.’ Both the method and duration of genitourinary catheterization affect the risk for acquiring nosocomial UTIs. The percentage of infections range as low as 1 percent for a single catheterization to 100 percent for patients with
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indwelling urethral catheters draining into an open system for a period greater than four days8 Analysis of attack rates by day of hospitalization have indicated that the median day of onset for nosocomial UTIs is day 8,’ and that the risk of catheter-associated UTIs ranges from 5 to 10 percent per day of catheterization. 8,eNosocomial UTIs caused by pathogens such as Serratia or Klebsiella, which affect patients undergoing longer periods of catheterization, are also more likely to result in bacteremia and have been associated with a higher incidence of mortality. l While the use of “closed” drainage systems for patients with indwelling urinary catheters has limited the exposure of patients to hospitalacquired pathogens, it has by no means curbed the spread of nosocomial UTIs. There are significant problems associated with maintaining closed drainage systems vis-a-vis the relatively large population at risk. According to studies carried out by Garibaldi et aZ.,1° the mucous sheath between the catheter and urethra is the primary pathway for the entry of organisms into the bladder when a closed drainage system is employed. Colonization of the urethral meatus with potentially pathogenic bacteria is a major risk factor for subsequent bacteriuria. Catheter-associated infections with closed drainage systems account for more than 30 percent of all hospital-acquired infections.” In hospitalized patients with indwelling catheters, the presence of a fever attributed to the original cause of hospitalization may obscure the diagnosis of a urinary tract infection. This could delay treatment and add to the risk of further complications or add to the severity of the underlying disease. Symptoms such as flank tenderness and suprapubic tenderness would suggest a urinary tract infection. While the presence of pyuria has not been analyzed thoroughly in cases of catheter-associated bacteriuria, this condition often indicates a serious UTI.12 Furthermore, it has been found that even mild bacteriuria (as low as lo2 organisms/ mL in urine) may be significant in a patient undergoing catheterization. 12,13 In a comprehensive study on nosocomial infections due to gram-negative bacteria, Stamm, Martin, and Bennett’ found that there are two populations of patients who apparently have the highest risk of developing nosocomial UTIs. The first group is females under fifty, primarily those on gynecology services. Most of these are catheter-associated infections that only rarely
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result in complications. The other group most likely to acquire nosocomial UTIs is elderly male patients. These infections are more often associated with bacteremia or death. According to the study results, 83 percent of bacteremias secondary to nosocomial UTIs and 95 percent of the deaths attributed to complications of UTIs occurred in patients older than fifty years.’ Age and debilitating, underlying illnesses often have been linked to an increased risk of nosocomial urinary tract infection. Frequently, hospitalized patients themselves are the sources of pathogenetic organisms, though cross-infections are not uncommon. It has been shown that elderly, debilitated patients are prone to increasing colonization of the skin and mucous membrane by gram-negative bacilli.8 The weakened immune systems of these patients subsequently contribute to developing infec-
tions . While it has never been clearly substantiated that diabetics are more prone to infection than nondiabetic individuals, it has been documented that bacteriuria occurs with increased frequency in diabetic patients. l4 The results of a number of studies have indicated a two- to fourfold higher incidence of bacteriuria in diabetic women than in control groups.’ Nosocomial urinary tract infections also occur more frequently in diabetic patients. l This predisposition for UTIs in hospitalized diabetics is probably due to several factors: (1) bladder dysfunction resulting from diabetic neuropathy; (2) the increased need for urologic manipulation; (3) vascular disease, which can disrupt cellular metabolism and debilitate the host defense system; and (4) high concentrations of urinary glucose, which can impair polymorphonuclear leukocyte and phagocyte function.14 Causative Organisms While over 80 percent of nosocomial urinary tract infections are caused by gram-negative bacilli, the gram-positive bacteria are reemerging as potential pathogens for nosocomial UTIs, especially staphylococci and enterococci. l5 Escherichia coli is the most common urinary tract pathogen among hospitalized patients, and is responsible for approximately 50 percent of nosocomial bacteriuria.8 Proteus sp., Klebsiella sp., Pseudomonas aeruginosa, Enterobacter, and Serratia are responsible for most of the remaining infections caused by gram-negative bacilli. The majority of bacteria responsible for
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nosocomial UTIs, both gram-negative and are beta-lactamase-producing gram-positive, organisms. In a study of 34 patients with complicated nosocomial UTIs, which was carried out by Gebhart, Duma, and Patterson,le it was found that 93 percent of the pathogens identified produced beta-lactamases. Among the group of female patients under fifty years old described by Stamm et al. l as being at high risk for nosocomial UTIs developing, most contracted their infections early in the course of hospitalization, and the infections were primarily due to E. coli and Proteus sp. Among the second group at high risk, elderly men over fifty years old with underlying diseases, infections were frequently due to Serratia, Klebsiella sp., and P. aeruginosa. As mentioned earlier, nosocomial UTIs caused by Serratia or Klebsiella were more likely to be associated with secondary bacteremia (3.7 % and 1.5 % , respectively), and nosocomial UTIs caused by Serratia, P aeruginosa, and Klebsiella showed the highest rate of fatalities.’ Antibiotic Therapy It is considered prudent to treat simple outpatient UTIs with narrow-spectrum antibiotic drugs for a short period of time, and there is a large body of work supporting the use of singledose therapy for UTIs, particularly in women patients. l7 The advantages of short-term, narrow-spectrum antibiotic treatment for these simple UTIs include (1) the ability to quickly and conveniently screen patients who may have serious renal infections, (2) less development of drug resistance, (3) fewer side effects, (4) lower costs, and (5) better compliance. Even in simple nosocomial UTIs, however, the advantages of the short-term regimen may be superseded by the necessity for broad-spectrum treatment for longer periods of time. First of all, the occurrence of a nosocomial urinary tract infection requires close attention, and the possibility of a serious, underlying renal infection such as pyelonephritis must be investigated immediately and comprehensively in all cases. Second, drug resistance among hospitalized patients with UTIs, particularly those who have undergone previous antibiotic therapy, is high already, and a broad-spectrum antibiotic is more appropriate therapy. Moreover, nosocomial UTIs are caused by a wider spectrum of bacteria than simple UTIs contracted by outpatients, and broader spectrum drugs are needed to counter
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the additional potential pathogens. Third, the disadvantages of possible side effects and the higher cost of broad-spectrum, parenteral antibiotics are offset by the potentially devastating complications and expense of serious nosocomial UTIs. The majority of antibiotic agents used in treating UTIs are excreted by the urinary tract and, consequently, reach extremely high levels in the urine. Normally, even antibiotics that are excreted by the hepatobiliary system achieve high enough urine levels to inhibit the growth of pathogenic bacteria in the urinary tract.12 In debilitated patients with compromised renal functions, however, it is important to choose a broad-spectrum antibiotic that maintains not only a high serum level in the urinary tract, but also in the blood and tissues as well, to insure the eradication of both the urinary tract infection and other infectious complications such as bacteremia. In the case of complicated nosocomial UTIs in seriously ill patients, it may be necessary to employ empiric therapy with broad-spectrum drugs. Because of the difficulty in predicting the presumed pathogens and antibiotic susceptibilities in patients for whom immediate care is essential, drugs that cover the whole range of gram-negative bacilli-as well as the gram-positive staphylococci and enterococci-are preferred. Single-agent broad-spectrum drugs are favored over multiple drug combinations because of fewer possibilities of side effects, easier recognition of potential side effects, and lower costs. Empiric broad-spectrum therapy should be discontinued when positive cultures and susceptibilities have been determined. Subsequent, narrow-spectrum therapy should be directed at specific pathogens. As mentioned, there is higher drug resistance among patients with nosocomial UTIs because of the likelihood of prior antibiotic therapy and the resistant nature of most nosocomial pathogens. One of the keys to drug resistance in nosocomial urinary tract infections is the prevalence of beta-lactamase-producing organisms. The beta-lactamase enzymes in these pathogens have the ability to hydrolyze the beta-lactam molecules in a wide range of antibiotics, rendering them useless in fighting infection. Several approaches have been taken to solve this problem. One has been the introduction of compounds such as the aminoglycosides. Resistance to these antimicrobials has developed steadily over time, however, and there is in-
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creasing recognition of their toxic side effects, including nephrotoxicity and ototoxicity. Another approach to beta-lactamase-induced resistance has been the development of compounds with stable beta-lactams, such as the second- and third-generation cephalosporins.4 Cefamandole, a second-generation cephalosporin, has expanded gram-negative coverage, but is ineffective against Pseudomonas sp. The third-generation cephalosporins apparently have excellent activity against most of the gram-negative bacilli that are relevant pathogens in nosocomial UTIs. These cephalosporins include cefoperazone, which has good activity against Pseudomonas sp., and cefotaxime and moxalactam, which are more active against Enterobacteriaceae.12 The use of cefamandole, moxalactam, and cefoperazone has been associated with disulfiram reactions, and moxalactam usage has been shown to prolong prothrombin time and increase the risk of bleeding. l2 Another drug that shows promise in fighting beta-lactamase-induced drug resistance is imipenem, a member of a new family of beta-lactams, the carbapenems.15 This antibiotic possesses a broad spectrum of activity against both gram-negative bacilli and gram-positive bacteria such as staphylococci and enterococci. It is susceptible to hydrolysis by dehydropeptidase1, an enzyme found in the kidneys, but in combination with a dehydropeptidase-1 inhibitor, cilastatin, the antibiotic achieves reasonably high concentrations in the urine. While the number of studies using this drug are limited, there have been no indications of serious side effects.15 One of the most interesting solutions to the problem of beta-lactamase drug resistance has been the introduction of antimicrobials that include beta-lactamase inhibitors.4 Clavulanic acid (clavulanate potassium) is one such agent. It acts as a “suicide” inhibitor by binding to beta-lactamase enzymes in bacteria and inactivating the enzymes, so that an accompanying beta-lactam antibiotic can attack and destroy the bacteria. When clavulanate potassium is used in combination with ticarcillin, a semisynthetic penicillin, a potent broad-spectrum antibiotic is created. Studies have shown ticarcillinclavulanate potassium to be active against a wide range of gram-negative bacilli, including Pseudomonas sp., and the gram-positive staphylococci and enterococci.1eJ8Je Furthermore, the basic ingredient, ticarcillin, achieves
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high serum and urine levels, and has no serious side effects. l8 Prevention In a study sponsored by the Center for Infectious Diseases, U.S. Department of Health and Human Services, Haley et uL20 found that “the establishment of intensive infection surveillance and control programs was strongly associated with reduction in rates of nosocomial urinary tract infection, surgical wound infection, pneumonia, and bacteremia between 1970 and 1975-1976.” Hospitals involved in this program employed a well-trained infection control physician, as well as an infection control nurse for every 250 beds. The physician and nurses were responsible for maintaining organized surveillance and control activities to examine routine hospital practices and for implementing a system to report infection rates to practicing surgeons. The study showed that such programs reduced hospital infection rates by 32 percent. In hospitals without surveillance and control programs, overall infection rates increased by 18 percent from 1970 to 1976.20 Other steps can be taken in addition to surveillance and control programs to lower the rate of nosocomial urinary tract infections. Because most nosocomial UTIs are catheter-related, it is important to concentrate efforts in this area. As mentioned previously, a major pathway for pathogenic bacteria into the bladder in a closed drainage system is the mucous sheath between the catheter and urethrae21 In addition to developing methods of maintaining sterile closed-catheter drainage systems, studies should be carried out to determine the factors influencing the bacteria flora of the meatus and urethra to develop ways to inhibit ascending infection between the catheter and the urethral epithelium.21 While there may be some advantages to the use of prophylactic antibiotics in seriously ill patients who are undergoing urinary catheterization, the routine use of such prophylactic antibiotics only contributes to higher drug resistance. Other alternatives may soon be available, however. In an analysis of epidemiologic studies carried out by Stamm et al.,’ it was determined that a vaccine or hyperimmune serum effective against the six common nosocomial pathogens could limit morbidity and mortality due to hospital-acquired infections that are not preventable by other available measures.
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Conclusions The best way to stop nosocomial urinary tract infections is to prevent them. In light of the results from epidemiologic studies, it is important to set up and maintain surveillance and control programs, particularly in hospitals and locales where nosocomial infection rates are high. The additional costs entailed in such programs are justified by the tremendous savings that can be attained. In addition, studies should be carried out to develop vaccines to combat the most common nosocomial pathogens. Close attention must be paid to insure that basic, sound practices are followed by hospital staff. Emphasis should be placed on reducing animate and inanimate reservoirs for potential pathogens. The use of indwelling catheters should be limited as much as possible, and studies should be carried out to increase the safety and effectiveness of the closed-drainage catheter system. The dangers of widespread drug resistance must be controlled as well, in part by the more judicious use of antibiotics. When nosocomial infections cannot be prevented, prompt therapy with antibiotics that are effective against resistant organisms is necessary. In seriously ill patients with underlying diseases, empiric broad-spectrum antibiotic therapy is often essential. In any case when complications are suspected, clinical and bacteriologic studies must be done immediately to eliminate the possibilities of acute pyelonephritis, septicemia, or other dangerous complica-
tions . 956 Court Avenue Memphis, Tennessee 38163 References 1. Stamm WE, Martin SM, and Bennett JV: Epidemiology of nosocomial infections due to gram-negative bacilli: aspects relevant to development and use of vaccines, J Infect Dis (Suppl) 136: s151 (1977). 2. Centers for Disease Control: National Nosocomial Infections Study Report, Atlanta, U.S. Department of Health and Human Services, Public Health Service, November, 1979. 3. Rutledge KA, and McDonald HP Jr: Costs of treating simple nosocomial urinary tract infection, Urology (Suppl) 24: 24 (1985). 4. Neu HC: Contribution of beta-lactamases to bacterial resistance and mechanisms to inhibit beta-lactamases, Am J Med 79(B): 1 (1985). 5. Platt It, et al: Mortality associated with nosocomial urinarytract infection, N Engl J Med 307: 637 (1982). 6. Haley RW, et al: Increased recognition of infectious diseases in US hospitals through increased use of diagnostic tests, 19701976, Am J Epidemiol 121: 168 (1985). 7. Rutala WA, et al: Serratia marcescens nosocomial infections of the urinary tract associated with urine-measuring containers and urinometers, Am J Med 70: 659 (1981).
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8. ‘Iluck M, and Stamm W: Nosocomial infection of the urinary tract, Am J Med 70: 651 (1981). 9. Garibaldi RA, et al: Factors predisposing to bacteriuria during indwelling urethral catheterization, N Engl J Med 291: 215 (1974). 10. Garibaldi RA, et al: Meatal colonization and catheter-associated bacteriuria, N Engl J Med 303: 316 (1980). 11. Stamm WE: Guidelines for prevention of catheter-associated urinary tract infections, Ann intern Med 82: 386 (1975). 12. File TM Jr, and Tan JS: Empiric antimicrobial therapy of serious urianry tract infections, Urology 27: 80 (1986). 13. Takeuchi H, and Tomoyoshi T: Torulopsis infection extensively involving urinary tract, Urology 22: 173 (1983). 14. Wheat JL: Infection and diabetes mellitus, Diabetes Care 3: 187 (1980). 15. Cox CE: Safety and efficacy of imipenem/cilastatin in treatment of complicated urinary tract infections, Am J Med 78(6A): 92 (1985).
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16. Gebhart RJ, Duma RJ, and Patterson PM: Timentin in the treatment of symptomatic complicated urinary tract infections in adult patients; Am J Med 79(5%): 101 (1985): 17. Sheehan G. Harding GKM. and Ronald AR: Advances in the treatment of’urinary-tract infection, Am J Med (Suppl) 76(5A): 141 (1984). 18. Cox CE: Comparative study of ticarcillin plus clavulanate potassium versus piperacillin in the treatment of hospitalized patients with urinary tract infections, Am J Med 79(5B): 88 (1985). 19. Paisley Jw, and Washington JA II: Combined activity of clavulanic acid and ticarcillin against ticarcillin-resistant, gramnegative bacilli, Antimicrob Agents Chemother 14: 224 (1978). 20. Haley RW, et al: The efficacy of infection surveillance and control programs in preventing nosocomial infections in US hospitals, Am J Epidemiol 121: 182 (1985). 21. Burke JR et al: Prevention of catheter-associated urinary tract infections: efficacy of daily meatal care regimens, Am J Med 70: 655 (1981).
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ABSTRACT-Hospital-acquired urinary tract infections, which account for approximately 40 percent of all nosocomial infections, often result in serious complications and ultimately lead to rising hospital costs. To combat the high incidence of nosocomial urinary tract infections, surveillance and control programs must be developed and carefully maintained by hospitals. When urinary tract infections cannot be prevented, empiric therapy with broad-spectrum antibiotics effective against beta-lactamase-producing bacteria should begin immediately.
Multihospital studies have indicated that nosocomial infections develop in 3 to 15 percent of all hospitalized patients in the United States. l Approximately 40 percent of these infections originate in the urinary tract2 It has been estimated that as many as one million patients a year suffer from hospital-acquired urinary tract infections (UTI) .3 It is ironic that modern medical technologies that have provided solutions for so many diseases should be so large a part of the problem in the spread of nosocomial urinary tract infections. Urinary catheterization, invasive diagnostic techniques, and the heavy use of antibiotic drugs are the primary sources for the overwhelming majority of nosocomial urinary tract infections. Genitourinary catheterization is responsible for as much as 80 percent of all hospital-acquired UTIs. l Resistance to antibiotic drugs, particularly the beta-lactam antibiotics, is increasing rapidly in the hospital environment and has been associated with the rise in hospital-acquired infections4 Many of the most commonly used beta-lactam antibiotics are no longer effective against the strains of beta-lactamase-producing organisms that are most often responsible for hospital-acquired UTIs. While many hospital-acquired urinary tract infections are asymptomatic, certain populations are at risk for developing serious complications. Among these groups at risk are patients
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with underlying diseases such as diabetes, or those elderly male patients who have undergone lengthy hospitalization. Potential complications may include chronic bacteriuria, renal disease, antibiotic toxicity, septicemia, bacteremia, and death. The acquisition of urinary tract infections associated with indwelling bladder catheterization has been linked to a threefold greater risk of mortality in hospitalized patients. 5 Unresolved nosocomial UTIs may account for as many as 56,000 deaths per year. 5 The number of serious complications due to nosocomial UTIs is significant, and the costs are rising rapidly. Due to the DRG system currently in use for Medicare patients, moreover, additional costs that accrue from the development of complicated nosocomial UTIs among the elderly population may have to be absorbed by the patients or the hospital. The costs for all nosocomial UTIs, both simple and complicated, are staggering. According to data analyzed in a study by Rutledge and McDonald,3 nosocomial UTIs prolong hospitalization by an average of 2.5 days. With the average total hospital cost running approximately $750/day, the additional total bill for a hospital-acquired urinary tract infection would be approximately $1,875. Using even the conservative estimate of one million nosocomial UTIs a year in this country, the total cost to our society could be approaching $2 billion.
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Quantitating the expenses associated with these infections is complicated, because it is difficult to determine the origin and assess the costs of extra laboratory tests and lengthened hospital stays due to nosocomial infections. There are other imponderables that may also add significantly to the overall total, including those hidden costs associated with loss of work, disability, and mortality. Due to the substantial economic and social burdens caused by nosocomial urinary tract infections, it is imperative that the nature of these infections be analyzed thoroughly. With the proper care of hospitalized patients and the awareness of risk factors, many nosocomial UTIs may be preventable. The origins of nosocomial UTIs, the populations at risk, the bacteriology of the infections and the range of available antibiotic therapy, and the parameters of prevention are reviewed herein. Pathogenesis As mentioned, 80 percent of all nosocomial UTIs can be directly attributed to catheterization of the genitourinary tract.’ Another 4 percent of the hospital population acquire nosocomial UTIs due to other forms of urologic manipulation, including cystoscopy and similar diagnostic techniques. l In a study carried out by Haley et al., 6 it was found that hospitals with higher rates of urine culturing, working up significant fevers, and reporting quantitative urine cultures have higher observed rates of nosocomial urinary tract infections. Some of these infections may be due to equipment contaminated by bacteria from other patients or potential pathogens carried by hospital staff. The indirect cause of these nosocomial UTIs is often the result of the presence of highly resistant strains of bacteria in the hospital environment due to heavy antibiotic usage. In one study of an epidemic outbreak of nosocomial UTIs caused by Serratia marcescens, it was determined that the acquisition of the epidemic strain was associated with the exposure of patients to the intensive care unit, the presence of indwelling bladder catheters, earlier treatment of patients with antibiotics, and exposure of patients and staff to devices used for measuring specific gravity and urine volume.’ Both the method and duration of genitourinary catheterization affect the risk for acquiring nosocomial UTIs. The percentage of infections range as low as 1 percent for a single catheterization to 100 percent for patients with
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indwelling urethral catheters draining into an open system for a period greater than four days8 Analysis of attack rates by day of hospitalization have indicated that the median day of onset for nosocomial UTIs is day 8,’ and that the risk of catheter-associated UTIs ranges from 5 to 10 percent per day of catheterization. 8,eNosocomial UTIs caused by pathogens such as Serratia or Klebsiella, which affect patients undergoing longer periods of catheterization, are also more likely to result in bacteremia and have been associated with a higher incidence of mortality. l While the use of “closed” drainage systems for patients with indwelling urinary catheters has limited the exposure of patients to hospitalacquired pathogens, it has by no means curbed the spread of nosocomial UTIs. There are significant problems associated with maintaining closed drainage systems vis-a-vis the relatively large population at risk. According to studies carried out by Garibaldi et aZ.,1° the mucous sheath between the catheter and urethra is the primary pathway for the entry of organisms into the bladder when a closed drainage system is employed. Colonization of the urethral meatus with potentially pathogenic bacteria is a major risk factor for subsequent bacteriuria. Catheter-associated infections with closed drainage systems account for more than 30 percent of all hospital-acquired infections.” In hospitalized patients with indwelling catheters, the presence of a fever attributed to the original cause of hospitalization may obscure the diagnosis of a urinary tract infection. This could delay treatment and add to the risk of further complications or add to the severity of the underlying disease. Symptoms such as flank tenderness and suprapubic tenderness would suggest a urinary tract infection. While the presence of pyuria has not been analyzed thoroughly in cases of catheter-associated bacteriuria, this condition often indicates a serious UTI.12 Furthermore, it has been found that even mild bacteriuria (as low as lo2 organisms/ mL in urine) may be significant in a patient undergoing catheterization. 12,13 In a comprehensive study on nosocomial infections due to gram-negative bacteria, Stamm, Martin, and Bennett’ found that there are two populations of patients who apparently have the highest risk of developing nosocomial UTIs. The first group is females under fifty, primarily those on gynecology services. Most of these are catheter-associated infections that only rarely
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result in complications. The other group most likely to acquire nosocomial UTIs is elderly male patients. These infections are more often associated with bacteremia or death. According to the study results, 83 percent of bacteremias secondary to nosocomial UTIs and 95 percent of the deaths attributed to complications of UTIs occurred in patients older than fifty years.’ Age and debilitating, underlying illnesses often have been linked to an increased risk of nosocomial urinary tract infection. Frequently, hospitalized patients themselves are the sources of pathogenetic organisms, though cross-infections are not uncommon. It has been shown that elderly, debilitated patients are prone to increasing colonization of the skin and mucous membrane by gram-negative bacilli.8 The weakened immune systems of these patients subsequently contribute to developing infec-
tions . While it has never been clearly substantiated that diabetics are more prone to infection than nondiabetic individuals, it has been documented that bacteriuria occurs with increased frequency in diabetic patients. l4 The results of a number of studies have indicated a two- to fourfold higher incidence of bacteriuria in diabetic women than in control groups.’ Nosocomial urinary tract infections also occur more frequently in diabetic patients. l This predisposition for UTIs in hospitalized diabetics is probably due to several factors: (1) bladder dysfunction resulting from diabetic neuropathy; (2) the increased need for urologic manipulation; (3) vascular disease, which can disrupt cellular metabolism and debilitate the host defense system; and (4) high concentrations of urinary glucose, which can impair polymorphonuclear leukocyte and phagocyte function.14 Causative Organisms While over 80 percent of nosocomial urinary tract infections are caused by gram-negative bacilli, the gram-positive bacteria are reemerging as potential pathogens for nosocomial UTIs, especially staphylococci and enterococci. l5 Escherichia coli is the most common urinary tract pathogen among hospitalized patients, and is responsible for approximately 50 percent of nosocomial bacteriuria.8 Proteus sp., Klebsiella sp., Pseudomonas aeruginosa, Enterobacter, and Serratia are responsible for most of the remaining infections caused by gram-negative bacilli. The majority of bacteria responsible for
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nosocomial UTIs, both gram-negative and are beta-lactamase-producing gram-positive, organisms. In a study of 34 patients with complicated nosocomial UTIs, which was carried out by Gebhart, Duma, and Patterson,le it was found that 93 percent of the pathogens identified produced beta-lactamases. Among the group of female patients under fifty years old described by Stamm et al. l as being at high risk for nosocomial UTIs developing, most contracted their infections early in the course of hospitalization, and the infections were primarily due to E. coli and Proteus sp. Among the second group at high risk, elderly men over fifty years old with underlying diseases, infections were frequently due to Serratia, Klebsiella sp., and P. aeruginosa. As mentioned earlier, nosocomial UTIs caused by Serratia or Klebsiella were more likely to be associated with secondary bacteremia (3.7 % and 1.5 % , respectively), and nosocomial UTIs caused by Serratia, P aeruginosa, and Klebsiella showed the highest rate of fatalities.’ Antibiotic Therapy It is considered prudent to treat simple outpatient UTIs with narrow-spectrum antibiotic drugs for a short period of time, and there is a large body of work supporting the use of singledose therapy for UTIs, particularly in women patients. l7 The advantages of short-term, narrow-spectrum antibiotic treatment for these simple UTIs include (1) the ability to quickly and conveniently screen patients who may have serious renal infections, (2) less development of drug resistance, (3) fewer side effects, (4) lower costs, and (5) better compliance. Even in simple nosocomial UTIs, however, the advantages of the short-term regimen may be superseded by the necessity for broad-spectrum treatment for longer periods of time. First of all, the occurrence of a nosocomial urinary tract infection requires close attention, and the possibility of a serious, underlying renal infection such as pyelonephritis must be investigated immediately and comprehensively in all cases. Second, drug resistance among hospitalized patients with UTIs, particularly those who have undergone previous antibiotic therapy, is high already, and a broad-spectrum antibiotic is more appropriate therapy. Moreover, nosocomial UTIs are caused by a wider spectrum of bacteria than simple UTIs contracted by outpatients, and broader spectrum drugs are needed to counter
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the additional potential pathogens. Third, the disadvantages of possible side effects and the higher cost of broad-spectrum, parenteral antibiotics are offset by the potentially devastating complications and expense of serious nosocomial UTIs. The majority of antibiotic agents used in treating UTIs are excreted by the urinary tract and, consequently, reach extremely high levels in the urine. Normally, even antibiotics that are excreted by the hepatobiliary system achieve high enough urine levels to inhibit the growth of pathogenic bacteria in the urinary tract.12 In debilitated patients with compromised renal functions, however, it is important to choose a broad-spectrum antibiotic that maintains not only a high serum level in the urinary tract, but also in the blood and tissues as well, to insure the eradication of both the urinary tract infection and other infectious complications such as bacteremia. In the case of complicated nosocomial UTIs in seriously ill patients, it may be necessary to employ empiric therapy with broad-spectrum drugs. Because of the difficulty in predicting the presumed pathogens and antibiotic susceptibilities in patients for whom immediate care is essential, drugs that cover the whole range of gram-negative bacilli-as well as the gram-positive staphylococci and enterococci-are preferred. Single-agent broad-spectrum drugs are favored over multiple drug combinations because of fewer possibilities of side effects, easier recognition of potential side effects, and lower costs. Empiric broad-spectrum therapy should be discontinued when positive cultures and susceptibilities have been determined. Subsequent, narrow-spectrum therapy should be directed at specific pathogens. As mentioned, there is higher drug resistance among patients with nosocomial UTIs because of the likelihood of prior antibiotic therapy and the resistant nature of most nosocomial pathogens. One of the keys to drug resistance in nosocomial urinary tract infections is the prevalence of beta-lactamase-producing organisms. The beta-lactamase enzymes in these pathogens have the ability to hydrolyze the beta-lactam molecules in a wide range of antibiotics, rendering them useless in fighting infection. Several approaches have been taken to solve this problem. One has been the introduction of compounds such as the aminoglycosides. Resistance to these antimicrobials has developed steadily over time, however, and there is in-
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creasing recognition of their toxic side effects, including nephrotoxicity and ototoxicity. Another approach to beta-lactamase-induced resistance has been the development of compounds with stable beta-lactams, such as the second- and third-generation cephalosporins.4 Cefamandole, a second-generation cephalosporin, has expanded gram-negative coverage, but is ineffective against Pseudomonas sp. The third-generation cephalosporins apparently have excellent activity against most of the gram-negative bacilli that are relevant pathogens in nosocomial UTIs. These cephalosporins include cefoperazone, which has good activity against Pseudomonas sp., and cefotaxime and moxalactam, which are more active against Enterobacteriaceae.12 The use of cefamandole, moxalactam, and cefoperazone has been associated with disulfiram reactions, and moxalactam usage has been shown to prolong prothrombin time and increase the risk of bleeding. l2 Another drug that shows promise in fighting beta-lactamase-induced drug resistance is imipenem, a member of a new family of beta-lactams, the carbapenems.15 This antibiotic possesses a broad spectrum of activity against both gram-negative bacilli and gram-positive bacteria such as staphylococci and enterococci. It is susceptible to hydrolysis by dehydropeptidase1, an enzyme found in the kidneys, but in combination with a dehydropeptidase-1 inhibitor, cilastatin, the antibiotic achieves reasonably high concentrations in the urine. While the number of studies using this drug are limited, there have been no indications of serious side effects.15 One of the most interesting solutions to the problem of beta-lactamase drug resistance has been the introduction of antimicrobials that include beta-lactamase inhibitors.4 Clavulanic acid (clavulanate potassium) is one such agent. It acts as a “suicide” inhibitor by binding to beta-lactamase enzymes in bacteria and inactivating the enzymes, so that an accompanying beta-lactam antibiotic can attack and destroy the bacteria. When clavulanate potassium is used in combination with ticarcillin, a semisynthetic penicillin, a potent broad-spectrum antibiotic is created. Studies have shown ticarcillinclavulanate potassium to be active against a wide range of gram-negative bacilli, including Pseudomonas sp., and the gram-positive staphylococci and enterococci.1eJ8Je Furthermore, the basic ingredient, ticarcillin, achieves
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high serum and urine levels, and has no serious side effects. l8 Prevention In a study sponsored by the Center for Infectious Diseases, U.S. Department of Health and Human Services, Haley et uL20 found that “the establishment of intensive infection surveillance and control programs was strongly associated with reduction in rates of nosocomial urinary tract infection, surgical wound infection, pneumonia, and bacteremia between 1970 and 1975-1976.” Hospitals involved in this program employed a well-trained infection control physician, as well as an infection control nurse for every 250 beds. The physician and nurses were responsible for maintaining organized surveillance and control activities to examine routine hospital practices and for implementing a system to report infection rates to practicing surgeons. The study showed that such programs reduced hospital infection rates by 32 percent. In hospitals without surveillance and control programs, overall infection rates increased by 18 percent from 1970 to 1976.20 Other steps can be taken in addition to surveillance and control programs to lower the rate of nosocomial urinary tract infections. Because most nosocomial UTIs are catheter-related, it is important to concentrate efforts in this area. As mentioned previously, a major pathway for pathogenic bacteria into the bladder in a closed drainage system is the mucous sheath between the catheter and urethrae21 In addition to developing methods of maintaining sterile closed-catheter drainage systems, studies should be carried out to determine the factors influencing the bacteria flora of the meatus and urethra to develop ways to inhibit ascending infection between the catheter and the urethral epithelium.21 While there may be some advantages to the use of prophylactic antibiotics in seriously ill patients who are undergoing urinary catheterization, the routine use of such prophylactic antibiotics only contributes to higher drug resistance. Other alternatives may soon be available, however. In an analysis of epidemiologic studies carried out by Stamm et al.,’ it was determined that a vaccine or hyperimmune serum effective against the six common nosocomial pathogens could limit morbidity and mortality due to hospital-acquired infections that are not preventable by other available measures.
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Conclusions The best way to stop nosocomial urinary tract infections is to prevent them. In light of the results from epidemiologic studies, it is important to set up and maintain surveillance and control programs, particularly in hospitals and locales where nosocomial infection rates are high. The additional costs entailed in such programs are justified by the tremendous savings that can be attained. In addition, studies should be carried out to develop vaccines to combat the most common nosocomial pathogens. Close attention must be paid to insure that basic, sound practices are followed by hospital staff. Emphasis should be placed on reducing animate and inanimate reservoirs for potential pathogens. The use of indwelling catheters should be limited as much as possible, and studies should be carried out to increase the safety and effectiveness of the closed-drainage catheter system. The dangers of widespread drug resistance must be controlled as well, in part by the more judicious use of antibiotics. When nosocomial infections cannot be prevented, prompt therapy with antibiotics that are effective against resistant organisms is necessary. In seriously ill patients with underlying diseases, empiric broad-spectrum antibiotic therapy is often essential. In any case when complications are suspected, clinical and bacteriologic studies must be done immediately to eliminate the possibilities of acute pyelonephritis, septicemia, or other dangerous complica-
tions . 956 Court Avenue Memphis, Tennessee 38163 References 1. Stamm WE, Martin SM, and Bennett JV: Epidemiology of nosocomial infections due to gram-negative bacilli: aspects relevant to development and use of vaccines, J Infect Dis (Suppl) 136: s151 (1977). 2. Centers for Disease Control: National Nosocomial Infections Study Report, Atlanta, U.S. Department of Health and Human Services, Public Health Service, November, 1979. 3. Rutledge KA, and McDonald HP Jr: Costs of treating simple nosocomial urinary tract infection, Urology (Suppl) 24: 24 (1985). 4. Neu HC: Contribution of beta-lactamases to bacterial resistance and mechanisms to inhibit beta-lactamases, Am J Med 79(B): 1 (1985). 5. Platt It, et al: Mortality associated with nosocomial urinarytract infection, N Engl J Med 307: 637 (1982). 6. Haley RW, et al: Increased recognition of infectious diseases in US hospitals through increased use of diagnostic tests, 19701976, Am J Epidemiol 121: 168 (1985). 7. Rutala WA, et al: Serratia marcescens nosocomial infections of the urinary tract associated with urine-measuring containers and urinometers, Am J Med 70: 659 (1981).
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8. ‘Iluck M, and Stamm W: Nosocomial infection of the urinary tract, Am J Med 70: 651 (1981). 9. Garibaldi RA, et al: Factors predisposing to bacteriuria during indwelling urethral catheterization, N Engl J Med 291: 215 (1974). 10. Garibaldi RA, et al: Meatal colonization and catheter-associated bacteriuria, N Engl J Med 303: 316 (1980). 11. Stamm WE: Guidelines for prevention of catheter-associated urinary tract infections, Ann intern Med 82: 386 (1975). 12. File TM Jr, and Tan JS: Empiric antimicrobial therapy of serious urianry tract infections, Urology 27: 80 (1986). 13. Takeuchi H, and Tomoyoshi T: Torulopsis infection extensively involving urinary tract, Urology 22: 173 (1983). 14. Wheat JL: Infection and diabetes mellitus, Diabetes Care 3: 187 (1980). 15. Cox CE: Safety and efficacy of imipenem/cilastatin in treatment of complicated urinary tract infections, Am J Med 78(6A): 92 (1985).
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16. Gebhart RJ, Duma RJ, and Patterson PM: Timentin in the treatment of symptomatic complicated urinary tract infections in adult patients; Am J Med 79(5%): 101 (1985): 17. Sheehan G. Harding GKM. and Ronald AR: Advances in the treatment of’urinary-tract infection, Am J Med (Suppl) 76(5A): 141 (1984). 18. Cox CE: Comparative study of ticarcillin plus clavulanate potassium versus piperacillin in the treatment of hospitalized patients with urinary tract infections, Am J Med 79(5B): 88 (1985). 19. Paisley Jw, and Washington JA II: Combined activity of clavulanic acid and ticarcillin against ticarcillin-resistant, gramnegative bacilli, Antimicrob Agents Chemother 14: 224 (1978). 20. Haley RW, et al: The efficacy of infection surveillance and control programs in preventing nosocomial infections in US hospitals, Am J Epidemiol 121: 182 (1985). 21. Burke JR et al: Prevention of catheter-associated urinary tract infections: efficacy of daily meatal care regimens, Am J Med 70: 655 (1981).
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