ANNUAL REVIEWS
Further
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Ann. Rev. Med 1979. 30:22J-39 Copyright © 1979 by Annual Reviews Inc. All rights reserved
Annu. Rev. Med. 1979.30:225-239. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
LOCALIZATION AND
.7318
ANTIBIOTIC MANAGEMENT OF URINARY TRACT INFECTION Leslie S. T. Fang, Ph.D., MD., Nina E. Tolkoff-Rubin, MD., and Robert H. Rubin, MD. Department of Medicine, Harvard Medical School, and the Infectious Disease and Renal Units, Medical Service, Massachusetts General Hospital, Boston, Massachusetts 02114
Over the past three decades the major question dominating the field of urinary tract infection has been, "What is the contribution of such infec tions to the development of chronic renal failure?" The question was ini tially posed because of the frequent demonstration at autopsy or at the time of transplantation of the pathologic changes of chronic pyelonephritis even in patients without a clearcut history of documented urinary tract infection. Because of these pathologic findings, the hypothesis arose that symptomatic or asymptomatic bacteriuria could cause progressive pa renchymal damage and loss of renal function. However, in recent years at least three different lines of evidence have developed, demonstrating that in adults infection is essentially never the primary cause of chronic renal failure (1): 1. The pathologic changes of chronic pyelonephritis are caused by a number of different disease processes, ranging from chronic analgesic abuse and other intoxications to long-standing ischemia (Table 1). Therefore, the term now used to describe these pathologic findings is interstitial nephritis, and only in those cases of interstitial nephritis in which clearcut evidence of infection is present is the diagnosis of chronic pyelonephritis made (1, 2).
2. Long-term clinical studies of both adult males
5) with chronic or recurrent
(3)
and females (1,
4,
bacteriuria have not demonstrated progressive
renal damage in the absence of significant anatomical defects.
225 0066-4219/79/0401-0225$01.00
226
FANG, TOLKOFF-RUBIN & RUBIN
Annu. Rev. Med. 1979.30:225-239. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
Table 1
Etiologies of chronic interstitial nephritis
Analgesic abuse
Nephrolithiasis
Radiation
Hypertension
Hypercalcemia
Lead nephropathy
Renal vascular disease
Hypokalemia
Balkan nephropathy
Obstruction
Sickle cell anemia
3. A retrospective study (6) of 100 consecutive cases of renal failure caused by chronic interstitial nephritis seen at a major medical center failed to reveal a single case in which infection was the primary cause of the renal disease. However, in the presence of the conditions outlined in Table 1, particularly vesicoureteral reflux and obstruction, infection was thought to play an important secondary role. Given this body of evidence, then, the major concerns in the study of adult urinary tract infection today are its pathogenesis and clinical management. Among adult women, urinary tract infection is the most common of all bacterial infections, affecting 10-20% of women at some time in their lives (7), with an estimated 6% of the adult female population developing urinary tract infections each year (8). Treatment of these infections with a wide variety of antimicrobial agents results in bacteriologic control in approxi mately 85% of such infections, but with an unacceptably high rate of recurrence (9). This review, then, is devoted to a consideration of those factors that will lead to the more effective clinical management of this rather universal affiiction of the adult female popUlation. PATHOGENESIS OF URINARY TRACT INFECTION IN WOMEN Stamey (10) and his colleagues showed that colonization of the vaginal introitus by members of the Enterobacteriaceae, particularly Escherichia coli, derived from the fecal reservoir is the essential first step in the produc tion of bacteriuria. Women with recurrent urinary tract infections have a statistically higher rate of introital carriage with Enterobacteriaceae than do women resistant to urinary tract infections (11). Vaginal mucosal cells of susceptible women appear to have a greater affinity for these bacteria than do such cells from resistant women (12). This difference in adherence may, at least in part, be related to an absence of antibodies directed against these organisms in the cervicovaginal secretions of these susceptible women (13). Entry of bacteria into the bladder through the relatively short female urethra can occur spontaneously, but urethral trauma has long been incrim inated as playing a major role in such entry. Bran et al (14), performing suprapubic aspiration in anesthetized patients undergoing gynecological procedures, found a significant increase in the recovery of bacteria from
Annu. Rev. Med. 1979.30:225-239. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
URINARY TRACT INFECTION
227
these aspirates after urethral milking. The organisms retrieved in the blad der aspirates correlated quite well with those simultaneously demonstrated to be present in the distal urethra. Similarly, serial determinations of urine bacterial counts before and after sexual intercourse also demonstrated sig nificant increases in bacterial counts following 30% of the intercourse episodes. Again, the positive urine cultures reflected the prevailing distal urethral flora, and it was concluded that transient bacteriuria occurs frequently in the sexually active female (15). The assumption has been made that, in the urinary-tract-infection-resistant woman, the organisms introduced into the bladder with such urethral manipulation are the diphtheroids, Staphylococcus epidermidis, lactobacilli, etc that normally colonize the distal urethra-rare causes of urinary tract infection. The approximately 20% of women who are susceptible to the development of true urinary tract infection have E. coli and/or other gram negative bacilli colonizing the area, so that a significant inoculum of these more virulent organisms may be introduced with intercourse, and clinical infection devel ops. Following the entry of potential pathogens into the urine, a number of host defense factors act together to decrease the likelihood of more than transient infection (16). Normal voiding will eliminate some organisms, while the bladder mucosal surface itself, through mucus trapping of the organisms and polymorphonuclear leukocyte response, has antibacterial properties. In addition, urine of low pH, high or very low osmolarity, high urea concentration, and high organic acid content, supports bacterial growth quite poorly. Even when infection is sustained, the site of involve ment is frequently restricted to the bladder, but in approximately 30--50% of instances there is further extension of the infection into and up the ureter to the kidney (10). Although urine usually does not reflux into the ureters from an uninfected bladder, cystitis itself, in addition to anatomic defects, may produce reflux. Once bacteria are introduced into the ureter, they may ascend to the kidney unaided, but this would be greatly increased by any process that interferes with normal ureteral peristaltic function. Gram neg ative bacteria and their endotoxins have a marked antiperistaltic effect, as do pregnancy and ureteral obstruction (1, 10). Once infected urine gains access to the renal pelvis, it can enter the renal parenchyma via the ducts of Bellini at the papillary tips, and then spread outward along the collecting tubules. Clearly, this whole process is hastened and exacerbated by any element of significant vesicoureteral reflux. This is particularly so since even moderate degrees of such reflux may be associated with intrarenal reflux, thus escalating the process further (1, 2). From a therapeutic point of view, this pathogenetic scheme suggests an important difference between infection confined to the bladder and that
Annu. Rev. Med. 1979.30:225-239. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
228
FANG, TOLKOFF-RUBIN & RUBIN
extending into the kidneys. In particular, it needs to be emphasized that infection within the bladder primarily involves the superficial mucosa, and is constantly bathed by urine in which exceedingly high concentrations of effective antimicrobial agents may be easily achieved. Not surprisingly, there is little immunologic response to such superficial infection. In contrast, renal infection is a deep tissue infection in which a significant immunologic response is the rule, and where delivery of effective concentra tions of antimicrobial agents may be more of a problem. Therefore, the definition of the anatomic site of urinary tract infection is of more than academic interest. LOCALIZATION OF THE SITE OF URINARY TRACT INFECTION Clinical Evaluation The ability of the clinician to distinguish between kidney infection and infection restricted to the bladder on the basis of presenting signs and symptoms is quite limited. Not only will many patients with renal infection present only with complaints referable to the lower urinary tract (dysuria, frequency, and urgency), but also some patients with bladder infection will complain of flank pain, fever, and systemic symptoms usually associated with pyelonephritis (Table 2). In addition, patients with the so-called acute urethral syndrome (symptomatic abacteriuria) will have similar symptoms in the face of urine cultures showing insignificant or no growth of bacteria Table 2
Acute urinary tract infection in general practice (in %) a No bacteriuria or
Further
Quick links to online content
Ann. Rev. Med 1979. 30:22J-39 Copyright © 1979 by Annual Reviews Inc. All rights reserved
Annu. Rev. Med. 1979.30:225-239. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
LOCALIZATION AND
.7318
ANTIBIOTIC MANAGEMENT OF URINARY TRACT INFECTION Leslie S. T. Fang, Ph.D., MD., Nina E. Tolkoff-Rubin, MD., and Robert H. Rubin, MD. Department of Medicine, Harvard Medical School, and the Infectious Disease and Renal Units, Medical Service, Massachusetts General Hospital, Boston, Massachusetts 02114
Over the past three decades the major question dominating the field of urinary tract infection has been, "What is the contribution of such infec tions to the development of chronic renal failure?" The question was ini tially posed because of the frequent demonstration at autopsy or at the time of transplantation of the pathologic changes of chronic pyelonephritis even in patients without a clearcut history of documented urinary tract infection. Because of these pathologic findings, the hypothesis arose that symptomatic or asymptomatic bacteriuria could cause progressive pa renchymal damage and loss of renal function. However, in recent years at least three different lines of evidence have developed, demonstrating that in adults infection is essentially never the primary cause of chronic renal failure (1): 1. The pathologic changes of chronic pyelonephritis are caused by a number of different disease processes, ranging from chronic analgesic abuse and other intoxications to long-standing ischemia (Table 1). Therefore, the term now used to describe these pathologic findings is interstitial nephritis, and only in those cases of interstitial nephritis in which clearcut evidence of infection is present is the diagnosis of chronic pyelonephritis made (1, 2).
2. Long-term clinical studies of both adult males
5) with chronic or recurrent
(3)
and females (1,
4,
bacteriuria have not demonstrated progressive
renal damage in the absence of significant anatomical defects.
225 0066-4219/79/0401-0225$01.00
226
FANG, TOLKOFF-RUBIN & RUBIN
Annu. Rev. Med. 1979.30:225-239. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
Table 1
Etiologies of chronic interstitial nephritis
Analgesic abuse
Nephrolithiasis
Radiation
Hypertension
Hypercalcemia
Lead nephropathy
Renal vascular disease
Hypokalemia
Balkan nephropathy
Obstruction
Sickle cell anemia
3. A retrospective study (6) of 100 consecutive cases of renal failure caused by chronic interstitial nephritis seen at a major medical center failed to reveal a single case in which infection was the primary cause of the renal disease. However, in the presence of the conditions outlined in Table 1, particularly vesicoureteral reflux and obstruction, infection was thought to play an important secondary role. Given this body of evidence, then, the major concerns in the study of adult urinary tract infection today are its pathogenesis and clinical management. Among adult women, urinary tract infection is the most common of all bacterial infections, affecting 10-20% of women at some time in their lives (7), with an estimated 6% of the adult female population developing urinary tract infections each year (8). Treatment of these infections with a wide variety of antimicrobial agents results in bacteriologic control in approxi mately 85% of such infections, but with an unacceptably high rate of recurrence (9). This review, then, is devoted to a consideration of those factors that will lead to the more effective clinical management of this rather universal affiiction of the adult female popUlation. PATHOGENESIS OF URINARY TRACT INFECTION IN WOMEN Stamey (10) and his colleagues showed that colonization of the vaginal introitus by members of the Enterobacteriaceae, particularly Escherichia coli, derived from the fecal reservoir is the essential first step in the produc tion of bacteriuria. Women with recurrent urinary tract infections have a statistically higher rate of introital carriage with Enterobacteriaceae than do women resistant to urinary tract infections (11). Vaginal mucosal cells of susceptible women appear to have a greater affinity for these bacteria than do such cells from resistant women (12). This difference in adherence may, at least in part, be related to an absence of antibodies directed against these organisms in the cervicovaginal secretions of these susceptible women (13). Entry of bacteria into the bladder through the relatively short female urethra can occur spontaneously, but urethral trauma has long been incrim inated as playing a major role in such entry. Bran et al (14), performing suprapubic aspiration in anesthetized patients undergoing gynecological procedures, found a significant increase in the recovery of bacteria from
Annu. Rev. Med. 1979.30:225-239. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
URINARY TRACT INFECTION
227
these aspirates after urethral milking. The organisms retrieved in the blad der aspirates correlated quite well with those simultaneously demonstrated to be present in the distal urethra. Similarly, serial determinations of urine bacterial counts before and after sexual intercourse also demonstrated sig nificant increases in bacterial counts following 30% of the intercourse episodes. Again, the positive urine cultures reflected the prevailing distal urethral flora, and it was concluded that transient bacteriuria occurs frequently in the sexually active female (15). The assumption has been made that, in the urinary-tract-infection-resistant woman, the organisms introduced into the bladder with such urethral manipulation are the diphtheroids, Staphylococcus epidermidis, lactobacilli, etc that normally colonize the distal urethra-rare causes of urinary tract infection. The approximately 20% of women who are susceptible to the development of true urinary tract infection have E. coli and/or other gram negative bacilli colonizing the area, so that a significant inoculum of these more virulent organisms may be introduced with intercourse, and clinical infection devel ops. Following the entry of potential pathogens into the urine, a number of host defense factors act together to decrease the likelihood of more than transient infection (16). Normal voiding will eliminate some organisms, while the bladder mucosal surface itself, through mucus trapping of the organisms and polymorphonuclear leukocyte response, has antibacterial properties. In addition, urine of low pH, high or very low osmolarity, high urea concentration, and high organic acid content, supports bacterial growth quite poorly. Even when infection is sustained, the site of involve ment is frequently restricted to the bladder, but in approximately 30--50% of instances there is further extension of the infection into and up the ureter to the kidney (10). Although urine usually does not reflux into the ureters from an uninfected bladder, cystitis itself, in addition to anatomic defects, may produce reflux. Once bacteria are introduced into the ureter, they may ascend to the kidney unaided, but this would be greatly increased by any process that interferes with normal ureteral peristaltic function. Gram neg ative bacteria and their endotoxins have a marked antiperistaltic effect, as do pregnancy and ureteral obstruction (1, 10). Once infected urine gains access to the renal pelvis, it can enter the renal parenchyma via the ducts of Bellini at the papillary tips, and then spread outward along the collecting tubules. Clearly, this whole process is hastened and exacerbated by any element of significant vesicoureteral reflux. This is particularly so since even moderate degrees of such reflux may be associated with intrarenal reflux, thus escalating the process further (1, 2). From a therapeutic point of view, this pathogenetic scheme suggests an important difference between infection confined to the bladder and that
Annu. Rev. Med. 1979.30:225-239. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/24/15. For personal use only.
228
FANG, TOLKOFF-RUBIN & RUBIN
extending into the kidneys. In particular, it needs to be emphasized that infection within the bladder primarily involves the superficial mucosa, and is constantly bathed by urine in which exceedingly high concentrations of effective antimicrobial agents may be easily achieved. Not surprisingly, there is little immunologic response to such superficial infection. In contrast, renal infection is a deep tissue infection in which a significant immunologic response is the rule, and where delivery of effective concentra tions of antimicrobial agents may be more of a problem. Therefore, the definition of the anatomic site of urinary tract infection is of more than academic interest. LOCALIZATION OF THE SITE OF URINARY TRACT INFECTION Clinical Evaluation The ability of the clinician to distinguish between kidney infection and infection restricted to the bladder on the basis of presenting signs and symptoms is quite limited. Not only will many patients with renal infection present only with complaints referable to the lower urinary tract (dysuria, frequency, and urgency), but also some patients with bladder infection will complain of flank pain, fever, and systemic symptoms usually associated with pyelonephritis (Table 2). In addition, patients with the so-called acute urethral syndrome (symptomatic abacteriuria) will have similar symptoms in the face of urine cultures showing insignificant or no growth of bacteria Table 2
Acute urinary tract infection in general practice (in %) a No bacteriuria or
