205
TETRACYCLINES IN THE TREATMENT OF GENITOURINARY TRACT INFECTIONS* L. D. SABATH, M.D. Professor of Medicine Head, Section on Infectious Diseases University of Minnesota Medical School Minneapolis, Minnesota
R EVIEW of the clinical problem of urinary tract infections indicates some areas where the tetracyclines or their newer analogues may be appropriate therapeutic choices.
PATIENT POPULATIONS
Urinary tract infection is one of the most commonly found infections in developed countries, and is eight or nine times more frequent among women than men. Among women there is a steady increase in the incidence of urinary tract infection throughout life. Although many physicians believe that this increase is linked to sexual intercourse, particularly when cystitis is seen in young, newly married women, this does not agree with the very high rate of urinary tract infection in women who are 80 years of age or older and at a time of life when they are likely to have less sexual activity. In fact, both sexes have a very high incidence of urinary tract infection during their 70s or 80s; men, however, do not show a steady increase with age. Urinary tract infection is common only in men in their later years, when obstruction of the urinary flow by prostatic disease is likely to occur, and in fact this infection in older men is often complicated by prostatitis. In men with recurrent urinary tract infections, the prostate gland may act as the reservoir of infection from which the pathogens reemerge after the infection appears to have been cleared. In neonates, urinary tract infection is almost unknown. Even in infants *Presented as part of A Symposium on the Tetracyclines: A Major Appraisal sponsored by the New York Academy of Medicine in cooperation with Science and Medicine Publishing Co., Inc. under a grant from Pfizer Laboratories, New York, N.Y., and held at the Academy October 15, 1977. Address for reprint requests: Department of Medicine, University of Minnesota, Mayo Memorial Building, 420 Delaware Street N.E., Minneapolis, Minn. 55455.
Vol. 54, No. 2, February 1978
206
L. D. SABATH
206L.
D.
SABATH
with congenital anomalies of the urinary tract, infections are rare until children reach school age. Thus, in infants and young children, in whom the tetracyclines are not generally used because of the possibility of discoloration of the teeth, there are remarkably few urinary infections to treat. Once the child has entered the age range of eight to 10 years the indications for tetracycline use do not differ from those applied to adults. Clearly, there is a wide range of application for the tetracyclines in urinary tract infections. Women past puberty-except for pregnant women, of course, in whom tetracyclines should not be used-constitute by far the largest population. And both sexes during the later years see a high incidence of infections with the greatest likelihood of complications and the increased probability of recurrent or persistent urinary tract infection. PATHOGENESIS OF URINARY TRACT INFECTION
Site of infection. The diagnosis "urinary tract infection" is a broad term, sometimes leading to vagueness regarding site of infection. Although infection may center anywhere from the kidney to the outlet of the urethra, the most common site is in or near the bladder, and, thus, the term usually refers to such infections in the lower urinary tract as cystitis. Pathogens are thought to enter the urinary tract at the outlet in most instances, even in upper urinary tract infections. This belief seems confirmed by the rapidity with which patients who are catheterized, even under the most sanitary conditions, contract infections in the bladder, which may then extend upward through the ureters to the kidney. Indeed, almost all patients with a catheter in place for two to four days will be infected unless special precautions are taken. The primacy of the lower urinary tract in infections is also indicated by the recurrent and prolonged infections seen in paraplegics, patients with neurogenic bladder, and others who are unable to empty their bladders completely. Predisposing factors. It has been suggested, particularly by Dr. Jack Lapides of Michigan, that the tone of bladder tissue may predispose to infection. This idea would explain why neurogenic or chronically distended bladders often become infected. Predisposition to recurrent genitourinary infection may be due to structural abnormalities, which are found in up to 10% of children with such infections. In adults, however, such abnormalities are probably found in only 1%, at most, of patients with urinary tract infections. Impaired host defenses also predispose to infection. An interesting Bull. N.Y. Acad. Med.
GENITOURINARY TRACT INFECTIONS
207
investigation in this area deals with prostatic antibacterial factor. This substance, first isolated from canine prostatic fluid and then from human, has bactericidal properties against a wide variety of Gram-positive and Gram-negative organisms. The substance is found in men without a history of urinary infection but is scanty or absent in patients who have been treated for chronic bacterial prostatitis. Prostatic antibacterial factor, while a protein, seems completely independent of the antibody system and, although bactericidal, does not seem to possess any specificity. Whether women have a similar substance, perhaps secreted by paraurethral structures, is not known. 1 Organisms implicated in urinary tract infections. The hypothesis that most infections begin in the lower urinary tract agrees with the finding that most organisms isolated from both urinary tract and prostatic infections originate in the lower intestine and usually can be found in the feces. Thus, Escherichia coli is the pathogen in 90% of first-time, uncomplicated lower urinary tract infections involving Gram-negative rods. It is well known that the aerobic organism E. coli is a common inhabitant of the bowel, although the anaerobic Bacteroides are actually far more common. Organisms that flourish in the bowel and would be most likely to occur following instrumentation, after antibiotic treatment failure, or in persistent or recurring infections include E. coli, Klebsiella, Proteus, Pseudomonas, Serratia, and enterococcus but rarely include anaerobes, even though they are more numerous in the bowel. Controversy exists over the role of staphylococcus in urinary tract infections as some authorities hold that the organism is usually a skin contaminant in the culture, and others see it as a true pathogen. In any case, staphylococcus has been isolated in fewer than 1% of patients with urinary tract infections. Prostatic infections. Infections of the prostate are not nearly so well studied as those of the urinary tract, although the pathogens seem to be mostly the same in both infections. This makes sense if prostatic infection is seen as a complication of urinary tract infection. A major problem here is establishing the diagnosis of prostatitis. GENERAL PRINCIPLES OF TREATMENT
In choosing the drug to combat these organisms we must ask where in the body is the drug going to attack these bacteria? Twenty years ago it was thought that the most important site for antibacterial action was in the Vol. 54, No. 2, February 1978
L. D. SABATH
208
208
TABLE I. DOXYCYCLINE: MINIMAL INHIBITORY CONCENTRATIONS (MICs) OF 93 URINARY BACTERIAL ISOLATES* IN ,ug./ml.
No. of isolates 0.2
0.4
0.8
1.6
3.1
6.2
Escherichia coli Coag. neg. Staph. Proteus Enterococcus Klebsiella
75 1 12 4.
22 3
16 1
9
4
4
-
Total
93
Organism
1
25
50
1O00
4
7 2
1 1 1
12
3
14
-
1
-
.1 1
-
1
12.5
4
26
2
-
17
9
4
6
9
*In each instance 2 104 organisms/ml.
Reproduced by permission from Williams, D. N., Lockey, J. E., Boxmeyer, M., et al.: Treatment of
urinary infections with doxycycline. Excerpta Medica 3:51, 1977.
tissue surrounding the lumina of the genitourinary tract. Subsequent investigation suggests that treatment aim at the contents of the lumina, the urine contained by the bladder, ureters, and collecting ducts. Content of antibiotic in urine, thus, is more important than antibiotic content of blood in effecting a cure of urinary tract infections. The role of urine pH. Drug activity in the urine depends to a large extent upon the makeup of the urine, and pH strongly influences antibacterial activity of the urine itself and especially that of some antibiotics. Some antibacterials, including tetracycline, are much more active in acid urine than in neutral or basic urine. The pH of urine of most Americans is acid-apH of 5.5 to 6.5-because of the typically heavy ingestion of meat in the diet. One should recall that laboratory tests, usually performed at neutral pH, may mislead by failing to reflect the biologic activity of drugs in clinical situations. For instance, tetracycline is much more active atpH 5 to 6 than it is at neutral pH of 7. Yet when this drug is tested for sensitivity in the laboratory, it is measured at a neutral pH, where it may be far less active than it is clinically in the patient's acid urine. Erythromycin, to cite another example, is seldom used to treat urinary tract infections because laboratory tests performed at pH 7.4 have shown little activity, and the activity of this drug in the normally acid urine is especially poor. However, if the urine is made alkaline, reaching apH of 8 or more, erythromycin can be quite effective in these infections. Although efforts to manipulate the pH of the urine to improve the activity of certain drugs can permit a lower dosage and possibly increase Bull. N.Y. Acad. Med.
GENITOURINARY TRACT INFECTIONS
209
TABLE II. DOXYCYCLINE: pH EFFECT ON MICs (gg./ml.), SEVEN (OF 93) ORGANISMS SHOWING A TWOFOLD OR GREATER MIC DIFFERENCE OVER pH RANGE OF 5.5 TO 7.4 Organism
Coagulase neg. Staph. Coagulase neg. Staph. Coagulase neg. Staph. Escherichia coli Escherichia coli Escherichia coli Klebsiella
MICs at pH 5.5 or 6.0 1.6 0.8
TETRACYCLINES IN THE TREATMENT OF GENITOURINARY TRACT INFECTIONS* L. D. SABATH, M.D. Professor of Medicine Head, Section on Infectious Diseases University of Minnesota Medical School Minneapolis, Minnesota
R EVIEW of the clinical problem of urinary tract infections indicates some areas where the tetracyclines or their newer analogues may be appropriate therapeutic choices.
PATIENT POPULATIONS
Urinary tract infection is one of the most commonly found infections in developed countries, and is eight or nine times more frequent among women than men. Among women there is a steady increase in the incidence of urinary tract infection throughout life. Although many physicians believe that this increase is linked to sexual intercourse, particularly when cystitis is seen in young, newly married women, this does not agree with the very high rate of urinary tract infection in women who are 80 years of age or older and at a time of life when they are likely to have less sexual activity. In fact, both sexes have a very high incidence of urinary tract infection during their 70s or 80s; men, however, do not show a steady increase with age. Urinary tract infection is common only in men in their later years, when obstruction of the urinary flow by prostatic disease is likely to occur, and in fact this infection in older men is often complicated by prostatitis. In men with recurrent urinary tract infections, the prostate gland may act as the reservoir of infection from which the pathogens reemerge after the infection appears to have been cleared. In neonates, urinary tract infection is almost unknown. Even in infants *Presented as part of A Symposium on the Tetracyclines: A Major Appraisal sponsored by the New York Academy of Medicine in cooperation with Science and Medicine Publishing Co., Inc. under a grant from Pfizer Laboratories, New York, N.Y., and held at the Academy October 15, 1977. Address for reprint requests: Department of Medicine, University of Minnesota, Mayo Memorial Building, 420 Delaware Street N.E., Minneapolis, Minn. 55455.
Vol. 54, No. 2, February 1978
206
L. D. SABATH
206L.
D.
SABATH
with congenital anomalies of the urinary tract, infections are rare until children reach school age. Thus, in infants and young children, in whom the tetracyclines are not generally used because of the possibility of discoloration of the teeth, there are remarkably few urinary infections to treat. Once the child has entered the age range of eight to 10 years the indications for tetracycline use do not differ from those applied to adults. Clearly, there is a wide range of application for the tetracyclines in urinary tract infections. Women past puberty-except for pregnant women, of course, in whom tetracyclines should not be used-constitute by far the largest population. And both sexes during the later years see a high incidence of infections with the greatest likelihood of complications and the increased probability of recurrent or persistent urinary tract infection. PATHOGENESIS OF URINARY TRACT INFECTION
Site of infection. The diagnosis "urinary tract infection" is a broad term, sometimes leading to vagueness regarding site of infection. Although infection may center anywhere from the kidney to the outlet of the urethra, the most common site is in or near the bladder, and, thus, the term usually refers to such infections in the lower urinary tract as cystitis. Pathogens are thought to enter the urinary tract at the outlet in most instances, even in upper urinary tract infections. This belief seems confirmed by the rapidity with which patients who are catheterized, even under the most sanitary conditions, contract infections in the bladder, which may then extend upward through the ureters to the kidney. Indeed, almost all patients with a catheter in place for two to four days will be infected unless special precautions are taken. The primacy of the lower urinary tract in infections is also indicated by the recurrent and prolonged infections seen in paraplegics, patients with neurogenic bladder, and others who are unable to empty their bladders completely. Predisposing factors. It has been suggested, particularly by Dr. Jack Lapides of Michigan, that the tone of bladder tissue may predispose to infection. This idea would explain why neurogenic or chronically distended bladders often become infected. Predisposition to recurrent genitourinary infection may be due to structural abnormalities, which are found in up to 10% of children with such infections. In adults, however, such abnormalities are probably found in only 1%, at most, of patients with urinary tract infections. Impaired host defenses also predispose to infection. An interesting Bull. N.Y. Acad. Med.
GENITOURINARY TRACT INFECTIONS
207
investigation in this area deals with prostatic antibacterial factor. This substance, first isolated from canine prostatic fluid and then from human, has bactericidal properties against a wide variety of Gram-positive and Gram-negative organisms. The substance is found in men without a history of urinary infection but is scanty or absent in patients who have been treated for chronic bacterial prostatitis. Prostatic antibacterial factor, while a protein, seems completely independent of the antibody system and, although bactericidal, does not seem to possess any specificity. Whether women have a similar substance, perhaps secreted by paraurethral structures, is not known. 1 Organisms implicated in urinary tract infections. The hypothesis that most infections begin in the lower urinary tract agrees with the finding that most organisms isolated from both urinary tract and prostatic infections originate in the lower intestine and usually can be found in the feces. Thus, Escherichia coli is the pathogen in 90% of first-time, uncomplicated lower urinary tract infections involving Gram-negative rods. It is well known that the aerobic organism E. coli is a common inhabitant of the bowel, although the anaerobic Bacteroides are actually far more common. Organisms that flourish in the bowel and would be most likely to occur following instrumentation, after antibiotic treatment failure, or in persistent or recurring infections include E. coli, Klebsiella, Proteus, Pseudomonas, Serratia, and enterococcus but rarely include anaerobes, even though they are more numerous in the bowel. Controversy exists over the role of staphylococcus in urinary tract infections as some authorities hold that the organism is usually a skin contaminant in the culture, and others see it as a true pathogen. In any case, staphylococcus has been isolated in fewer than 1% of patients with urinary tract infections. Prostatic infections. Infections of the prostate are not nearly so well studied as those of the urinary tract, although the pathogens seem to be mostly the same in both infections. This makes sense if prostatic infection is seen as a complication of urinary tract infection. A major problem here is establishing the diagnosis of prostatitis. GENERAL PRINCIPLES OF TREATMENT
In choosing the drug to combat these organisms we must ask where in the body is the drug going to attack these bacteria? Twenty years ago it was thought that the most important site for antibacterial action was in the Vol. 54, No. 2, February 1978
L. D. SABATH
208
208
TABLE I. DOXYCYCLINE: MINIMAL INHIBITORY CONCENTRATIONS (MICs) OF 93 URINARY BACTERIAL ISOLATES* IN ,ug./ml.
No. of isolates 0.2
0.4
0.8
1.6
3.1
6.2
Escherichia coli Coag. neg. Staph. Proteus Enterococcus Klebsiella
75 1 12 4.
22 3
16 1
9
4
4
-
Total
93
Organism
1
25
50
1O00
4
7 2
1 1 1
12
3
14
-
1
-
.1 1
-
1
12.5
4
26
2
-
17
9
4
6
9
*In each instance 2 104 organisms/ml.
Reproduced by permission from Williams, D. N., Lockey, J. E., Boxmeyer, M., et al.: Treatment of
urinary infections with doxycycline. Excerpta Medica 3:51, 1977.
tissue surrounding the lumina of the genitourinary tract. Subsequent investigation suggests that treatment aim at the contents of the lumina, the urine contained by the bladder, ureters, and collecting ducts. Content of antibiotic in urine, thus, is more important than antibiotic content of blood in effecting a cure of urinary tract infections. The role of urine pH. Drug activity in the urine depends to a large extent upon the makeup of the urine, and pH strongly influences antibacterial activity of the urine itself and especially that of some antibiotics. Some antibacterials, including tetracycline, are much more active in acid urine than in neutral or basic urine. The pH of urine of most Americans is acid-apH of 5.5 to 6.5-because of the typically heavy ingestion of meat in the diet. One should recall that laboratory tests, usually performed at neutral pH, may mislead by failing to reflect the biologic activity of drugs in clinical situations. For instance, tetracycline is much more active atpH 5 to 6 than it is at neutral pH of 7. Yet when this drug is tested for sensitivity in the laboratory, it is measured at a neutral pH, where it may be far less active than it is clinically in the patient's acid urine. Erythromycin, to cite another example, is seldom used to treat urinary tract infections because laboratory tests performed at pH 7.4 have shown little activity, and the activity of this drug in the normally acid urine is especially poor. However, if the urine is made alkaline, reaching apH of 8 or more, erythromycin can be quite effective in these infections. Although efforts to manipulate the pH of the urine to improve the activity of certain drugs can permit a lower dosage and possibly increase Bull. N.Y. Acad. Med.
GENITOURINARY TRACT INFECTIONS
209
TABLE II. DOXYCYCLINE: pH EFFECT ON MICs (gg./ml.), SEVEN (OF 93) ORGANISMS SHOWING A TWOFOLD OR GREATER MIC DIFFERENCE OVER pH RANGE OF 5.5 TO 7.4 Organism
Coagulase neg. Staph. Coagulase neg. Staph. Coagulase neg. Staph. Escherichia coli Escherichia coli Escherichia coli Klebsiella
MICs at pH 5.5 or 6.0 1.6 0.8
