Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Urinary Tract Infections W. Eugene Sanders Jr. To cite this article: W. Eugene Sanders Jr. (1991) Urinary Tract Infections, Hospital Practice, 26:sup5, 48-51, DOI: 10.1080/21548331.1991.11707744 To link to this article: http://dx.doi.org/10.1080/21548331.1991.11707744
Published online: 06 Jul 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [Australian Catholic University]
Date: 27 July 2017, At: 10:40
Urinary Tract Infections W. EUGEN E SANDER S, J R.
Creighton University
A number of microbiologie and pharmacologie features of ceftriaxone recommend it for study in the treatment of urinary tract infections. Microbiologtcally, the drug is a patent inhibitor of many common urinary tract pathogens, especially Enterobacteriaceae. Pharmacologtcally, it has a long half-life and produces high levels in urine and proximate tissue.
ln VItro Actlvlty In 1984, Cleeland and Squires reviewed the world literature on the in vitro activity of ceftriaxone (see Table 1 in Dr. Blumer's presentation, page 8). 1 Very law MIC50s and MIC 90s were noted for Eschertchta colt and Klebsiella species. Values were somewhat higher for Enterobacter, Citrobacter, and Serratia species and indole-positive Proteus but were still well within the sensitive range. Pseudomonas and Acinetobacter species were found to be significantly less susceptible, with MICs of sorne strains in the resistant range. Activity against enterococci in general was minimal.
Pharmacologie Features Patel and associates studied the urinary excretion of ceftriaxone (see Figure 1 ).2 They found that for 24 hours after a Dr. Sanders is Professor and Chairman, Department of Medical Microbiology, and Professor of Medicine, Creighton University School of Medicine, Omaha.
48
single dose, urinary levels exceeded the MIC 90 for organisms generally considered sensitive and even for a few, such as sorne strains of Pseudomonas aerugtnosa, that would fall in the resistant category. In a study of ceftriaxone's penetration into prostate adenoma tissue, Adams and Naber found concentrations in the prostate of approximately three- ta sixfold less than the corresponding serum level. 3 However, these concentrations exceeded by manyfold the MI Cs of the majority of organisms that would be considered "sensitive" in routine susceptibility tests.
The Early Years The early literature on ceftriaxone's use in urinary tract infections was reviewed by Richards and associates (see Table 1). 4 Therapeutic successes were noted even with potentially recalcitrant organisms. Perhaps most striking was the 100% eradication rate reported with the Enterobacteriaceae other than Proteus and Providencia. Relapse and reinfection rates varied widely from series ta series. In general, the highest relapse and reinfection rates were found in studies that enrolled the largest proportion of patients with infections that were complicated, chronic, orboth.
Multicenter Clinical Trials After the early encouragmg results, a series of multicenter studies were designed ta evalu-
ate ceftriaxone in the treatment of urinary tract infections caused by Enterobacteriaceae. 5 Three open noncomparative and two open comparative trials were undertaken. Dosages were 2 gm every 24 hours or 1 gm every 12 hours in the noncomparative studies, and 1 gm every 24 hours or 500 mg every 12 hours in the comparative trials. In each of the studies, cultures were obtained before, during, and after completion of therapy. Follow-up cultures were taken five ta nine days later. Bacteriologie results were interpreted as persistent cure (negative culture during therapy, at completion, and at follow-up); partial cure (persistence of one or multiple pathogens); or failure (presence of initial pathogen after completion oftreatment). In retrospect, the term "partial cure" was unnecessary because there were only persistent cures or failures. The definitions for clinical cure, improvement, and failure were standard: Cure-aH abnormal findings had disappeared in "reasonable" Ume and were absent after therapy and follow-up; improvement-significant reduction of abnormal findings in reasonable Ume but incomplete resolution, possibly related ta underlying disease; failure-no response. In the five clinical trials, 242 enteric organisms were isolated from 215 patients. Two hundred forty (99%) of the isolates were eradicated and classified as persistent cures. The two failures were due ta E. colt (one of 156) in a patient with complicated pyelo-
nephritis and to Proteus mirabilis (one of29) in a patient with a complicated lower urinary tract infection. Bacteriologie results were analyzed ace ording to specifie diagnoses: uncomplicated and complicated lower urinary tract infections, uncomplicated and complicated pyelonephritis, and "remaining diagnoses," which were primarily prostatitis. Pathogens-including E. coli, Klebsiella pneumoniae, and P. mirabilis-were totally eradicated in all diagnostic categories, with two exceptions: in one of 16 cases of complicated pyelonephritis caused byE. coli and in one of 19 cases of complicated lower tract infection involvingP. mirabilis. There were no differences in outcome when the results were analyzed by total daily dosage or by frequency of administration. All 215 patients were clinically cured or improved (see Table 2). There were no major differences in cure or improvement rates in comparisons between the various diagnoses or dosage regtmens. In the two multicenter comparative trials, cefazolin, 500 mg to 1 gm every six to eight hours, was compared with ceftriaxone, 500 mg to 1 gm every 12 to 24 hours. Cefazolin eradicated 101 of 112 (90%) enteric organisms. Failures were noted with sensitive isolates of E. coli ( 10) and Klebsiella oxytoca ( 1 l and were distributed equally between complicated and uncomplicated infections. Ceftriaxone eliminated 110 of 112 (98% l isolates. The failures were with an E. coli and a P. mirabilis, both of which were sensitive to the study drugs and isolated from complicated infections. In the cefazolin-treated groups, 104 of 110 patients were clinically cured or improved and six
Table 1. Eradication of Urinary Tract Pathogens by Ceftriaxone (Early Clinical Trials) Initial Therapy
71 o/o -1 00%
Proteus/Providencia
71 o/o
Enterococci
83%
Pseudomonas aeruginosa
85%
Ali others
100%
Relapse (same bug)
4%--36%
Reinfection (another bug)
Oo/o--50%
Adapted from Richards DM et a1 4
were not. The clinical failures were distrtbuted equally between complicated and uncomplicated infections. Ceftriaxone therapy resulted in cure or improvement in each of the 100 patients enrolled. Although clinical failures occurred exclusively in the cefazolin-treated groups, the ob-
served differences were not statlstically signiftcant. For purposes of evaluation, the Food and DrugAdministratlon requires that organisms be sensitive to a new drug and comparative agents, each of which must be selected from among older, approved classes. This in-
Figure 1. For 24 hours after a single dose of ceftriaxone, urinary levels are seen to exceed the MIC90 for sensitive organlsrns as weil as for a few ofthose generally considered resistant, such as Pseudomonas aeruglnosa. (Adapted from PateiiH et aP)
49
Figure 2. An unexplained rebound ln susceptibillty of isolates of Enterobacter c#oacae and Pseudomonas aeruginosa from 1987 to 1989 occurred at the Omaha Veterans Affairs Medical Center, whereas in the university hospital only a few miles away, the susceptibility picture remained essentially unchanged.
troduces bath positive and negative blases toward the new agent. Organisms resistant to the older drugs, but sensitive to the new agent, are excluded. On the other hand, organisms that might represent "the Achilles' heel" of the new agent are also excluded. Such exclusions are justifiable in serions systemic infections but
may not be applicable in infections confined to the urinary tract. where extremely high concentrations of antimicrobial agents are often achieved. In the multicenter trials, clintcal and bacteriologie successes were noted in more than 99% of complicated or uncomplicated infections of the upper or lower
Table 2. Clinical Outcome in 215 Patients Treated with Ceftriaxone in Multicenter Clinical Studies Diagnosis
50
Number
Cu red
lmproved
Uncomplicated pyelonephritis
25
25
0
Uncomplicated UTI
78
71
7
Complicated pyelonephritis
21
17
4
Complicated UTI
77
68
9
Others
14
14
0
tracts. These results are excellent by any standard of camparison, especially constdering the number of complicated infections included. However, one must recall that all organisms were sensitive de nova and that the follow-up period was five to nine days (the maximum required by the FDA). Without longer follow-up. most relapses and reinfections go undetected. The rates of these complications, reported in the early studies of ceftriaxone, were generally consonant with those encountered historically with other agents. 4 Nevertheless, longer follow-up would have strengthened the multicenter trials and, gtven the failures with cefazolin, may have detected potential advantages of ceftriaxone. Future studies should certainly address this possibility. The multicenter trials of ceftriaxone included very few children. Detailed information was available for only 23 patients. Data from the manufacturer included 12 cases of childhood urinary tract infection, in all of which treatment with ceftriaxone resulted in eradication of the organism and clinical cure. 5 Bradley and associates 6 and Dagan and co-workers7 reported similar results in six and five children, respectively. Most of the infections were judged to be serions, requiring parenteral therapy. The majority were due to E. colt. Although the data are limited, results to date are comparable to those observed in adults.
Recent Trends in Susceptibility A number of years have passed since ceftriaxone was marketed and its in vitro activity described. As a result, my col-
Ceftriaxone is active against many gram-negative bacillary uropathogens. lt achieves very high levels in urine and proximate tissue .... Clinical and bacteriologie results in infections due to susceptible organisms have been excellent.
leagues and 1 revtewed the susceptibility of organisms isolated in our two major teaching hospitals in Omaha during 1987, 1988, and 1989. At our university hospital (St. Joseph), where testing is done by the disk diffusion method, the major uropathogens (Escherichia, Klebsiella, and Proteus) remain highly sensitive. Other gram-negative isolates, including Enterobacter aerogenes (74% susceptible in 1989), Serratia species (95%), and Citrobacter species (88%), are somewhat less susceptible, but not markedly less so than in the early 1980s. 1 Only the susceptibility of Enterobacter cloacae appears to be declininggradually, from 85% in 1987 to 73% in 1989. The situation was dramatically different at the Omaha Veterans Affairs Medical Center, just a few miles away. Although the major uropathogens remained uniformly sensitive, there appeared to have been a major rebound in susceptibility of isolates of E. cloacae and P. aeruginosa (see Figure 2). We are unable to fully explain these observations. Severa! possibilities exist. First. the method of testing differed between the two institutions. An automated system (Vitek) is used at the VA Medical
Center; however, there have been no obvtous changes in the methodology in recent years. Use of antimicrobial agents in general is more highly restricted in the Veterans hospital, and this may have contributed to grea ter sensitivtty of sorne of the isolates. It would be interesting to determine whether this is a local phenomenon or one that mirrors a more widespread change in susceptibility over the course oftlme.
Summary Ceftriaxone is active against many gram-negative bacillary uropathogens. It achieves very
high levels in urine and proximate tissue following single daily doses. Clinical and bacteriologie results in infections due to susceptible organisms have been excellent. Additional comparative studies with longer follow-up may assist in further delineating the relative role of ceftriaxone in management of infections of the urinary tract. D
The au thor acknowledges the kind assistance ofDrs. Stephen Cavalleri and Donald Giger, who provided suscepttb1Uty test results from St. Joseph Hospital and the Omaha Veterans Affairs Medical Center, respectlvely.
References 1. Cleeland R, Squlres E: Antlmlcroblal actlvlty of ceftrlaxone: A revlew. Am J Med 77(Suppl4C): 3, 1984 2. PatellH et al: Pharmacoklnetics of ceftrlaxone ln humans. Antimlcrob Agents Chemother 20: 634, 1981 3. Adams D. Naber KG: Concentrations of ceftrlaxone ln prostate adenoma tissue. Chemotherapy 30: 1, 1984 4. Richards DM et al: Ceftrlaxone: A revlew of lts antibacterial activlty. pharmacologlcal propertles and therapeutlc use. Drugs 27: 469, 1984 5. Roche Sclentlfic Summary: The cllnlcal evaluation ofRocephln (ceftrlaxone sodium/Roche). Hoffmann-La Roche lnc., Nutley, New Jersey. 1988 6. Bradley JS et al: Outpatient therapy of serlous pediatrie Infections with ceftrlaxone. Pedlatr Infect Dis J 7: 160. 1988 7. Dagan Ret al: Outpatient treatment of serlous communlty-acqulred pediatrie Infections using once daily lntrarnuscular ceftrlaxone. Pedlatr Infect Dis J 6: 1080, 1987
51
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Urinary Tract Infections W. Eugene Sanders Jr. To cite this article: W. Eugene Sanders Jr. (1991) Urinary Tract Infections, Hospital Practice, 26:sup5, 48-51, DOI: 10.1080/21548331.1991.11707744 To link to this article: http://dx.doi.org/10.1080/21548331.1991.11707744
Published online: 06 Jul 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [Australian Catholic University]
Date: 27 July 2017, At: 10:40
Urinary Tract Infections W. EUGEN E SANDER S, J R.
Creighton University
A number of microbiologie and pharmacologie features of ceftriaxone recommend it for study in the treatment of urinary tract infections. Microbiologtcally, the drug is a patent inhibitor of many common urinary tract pathogens, especially Enterobacteriaceae. Pharmacologtcally, it has a long half-life and produces high levels in urine and proximate tissue.
ln VItro Actlvlty In 1984, Cleeland and Squires reviewed the world literature on the in vitro activity of ceftriaxone (see Table 1 in Dr. Blumer's presentation, page 8). 1 Very law MIC50s and MIC 90s were noted for Eschertchta colt and Klebsiella species. Values were somewhat higher for Enterobacter, Citrobacter, and Serratia species and indole-positive Proteus but were still well within the sensitive range. Pseudomonas and Acinetobacter species were found to be significantly less susceptible, with MICs of sorne strains in the resistant range. Activity against enterococci in general was minimal.
Pharmacologie Features Patel and associates studied the urinary excretion of ceftriaxone (see Figure 1 ).2 They found that for 24 hours after a Dr. Sanders is Professor and Chairman, Department of Medical Microbiology, and Professor of Medicine, Creighton University School of Medicine, Omaha.
48
single dose, urinary levels exceeded the MIC 90 for organisms generally considered sensitive and even for a few, such as sorne strains of Pseudomonas aerugtnosa, that would fall in the resistant category. In a study of ceftriaxone's penetration into prostate adenoma tissue, Adams and Naber found concentrations in the prostate of approximately three- ta sixfold less than the corresponding serum level. 3 However, these concentrations exceeded by manyfold the MI Cs of the majority of organisms that would be considered "sensitive" in routine susceptibility tests.
The Early Years The early literature on ceftriaxone's use in urinary tract infections was reviewed by Richards and associates (see Table 1). 4 Therapeutic successes were noted even with potentially recalcitrant organisms. Perhaps most striking was the 100% eradication rate reported with the Enterobacteriaceae other than Proteus and Providencia. Relapse and reinfection rates varied widely from series ta series. In general, the highest relapse and reinfection rates were found in studies that enrolled the largest proportion of patients with infections that were complicated, chronic, orboth.
Multicenter Clinical Trials After the early encouragmg results, a series of multicenter studies were designed ta evalu-
ate ceftriaxone in the treatment of urinary tract infections caused by Enterobacteriaceae. 5 Three open noncomparative and two open comparative trials were undertaken. Dosages were 2 gm every 24 hours or 1 gm every 12 hours in the noncomparative studies, and 1 gm every 24 hours or 500 mg every 12 hours in the comparative trials. In each of the studies, cultures were obtained before, during, and after completion of therapy. Follow-up cultures were taken five ta nine days later. Bacteriologie results were interpreted as persistent cure (negative culture during therapy, at completion, and at follow-up); partial cure (persistence of one or multiple pathogens); or failure (presence of initial pathogen after completion oftreatment). In retrospect, the term "partial cure" was unnecessary because there were only persistent cures or failures. The definitions for clinical cure, improvement, and failure were standard: Cure-aH abnormal findings had disappeared in "reasonable" Ume and were absent after therapy and follow-up; improvement-significant reduction of abnormal findings in reasonable Ume but incomplete resolution, possibly related ta underlying disease; failure-no response. In the five clinical trials, 242 enteric organisms were isolated from 215 patients. Two hundred forty (99%) of the isolates were eradicated and classified as persistent cures. The two failures were due ta E. colt (one of 156) in a patient with complicated pyelo-
nephritis and to Proteus mirabilis (one of29) in a patient with a complicated lower urinary tract infection. Bacteriologie results were analyzed ace ording to specifie diagnoses: uncomplicated and complicated lower urinary tract infections, uncomplicated and complicated pyelonephritis, and "remaining diagnoses," which were primarily prostatitis. Pathogens-including E. coli, Klebsiella pneumoniae, and P. mirabilis-were totally eradicated in all diagnostic categories, with two exceptions: in one of 16 cases of complicated pyelonephritis caused byE. coli and in one of 19 cases of complicated lower tract infection involvingP. mirabilis. There were no differences in outcome when the results were analyzed by total daily dosage or by frequency of administration. All 215 patients were clinically cured or improved (see Table 2). There were no major differences in cure or improvement rates in comparisons between the various diagnoses or dosage regtmens. In the two multicenter comparative trials, cefazolin, 500 mg to 1 gm every six to eight hours, was compared with ceftriaxone, 500 mg to 1 gm every 12 to 24 hours. Cefazolin eradicated 101 of 112 (90%) enteric organisms. Failures were noted with sensitive isolates of E. coli ( 10) and Klebsiella oxytoca ( 1 l and were distributed equally between complicated and uncomplicated infections. Ceftriaxone eliminated 110 of 112 (98% l isolates. The failures were with an E. coli and a P. mirabilis, both of which were sensitive to the study drugs and isolated from complicated infections. In the cefazolin-treated groups, 104 of 110 patients were clinically cured or improved and six
Table 1. Eradication of Urinary Tract Pathogens by Ceftriaxone (Early Clinical Trials) Initial Therapy
71 o/o -1 00%
Proteus/Providencia
71 o/o
Enterococci
83%
Pseudomonas aeruginosa
85%
Ali others
100%
Relapse (same bug)
4%--36%
Reinfection (another bug)
Oo/o--50%
Adapted from Richards DM et a1 4
were not. The clinical failures were distrtbuted equally between complicated and uncomplicated infections. Ceftriaxone therapy resulted in cure or improvement in each of the 100 patients enrolled. Although clinical failures occurred exclusively in the cefazolin-treated groups, the ob-
served differences were not statlstically signiftcant. For purposes of evaluation, the Food and DrugAdministratlon requires that organisms be sensitive to a new drug and comparative agents, each of which must be selected from among older, approved classes. This in-
Figure 1. For 24 hours after a single dose of ceftriaxone, urinary levels are seen to exceed the MIC90 for sensitive organlsrns as weil as for a few ofthose generally considered resistant, such as Pseudomonas aeruglnosa. (Adapted from PateiiH et aP)
49
Figure 2. An unexplained rebound ln susceptibillty of isolates of Enterobacter c#oacae and Pseudomonas aeruginosa from 1987 to 1989 occurred at the Omaha Veterans Affairs Medical Center, whereas in the university hospital only a few miles away, the susceptibility picture remained essentially unchanged.
troduces bath positive and negative blases toward the new agent. Organisms resistant to the older drugs, but sensitive to the new agent, are excluded. On the other hand, organisms that might represent "the Achilles' heel" of the new agent are also excluded. Such exclusions are justifiable in serions systemic infections but
may not be applicable in infections confined to the urinary tract. where extremely high concentrations of antimicrobial agents are often achieved. In the multicenter trials, clintcal and bacteriologie successes were noted in more than 99% of complicated or uncomplicated infections of the upper or lower
Table 2. Clinical Outcome in 215 Patients Treated with Ceftriaxone in Multicenter Clinical Studies Diagnosis
50
Number
Cu red
lmproved
Uncomplicated pyelonephritis
25
25
0
Uncomplicated UTI
78
71
7
Complicated pyelonephritis
21
17
4
Complicated UTI
77
68
9
Others
14
14
0
tracts. These results are excellent by any standard of camparison, especially constdering the number of complicated infections included. However, one must recall that all organisms were sensitive de nova and that the follow-up period was five to nine days (the maximum required by the FDA). Without longer follow-up. most relapses and reinfections go undetected. The rates of these complications, reported in the early studies of ceftriaxone, were generally consonant with those encountered historically with other agents. 4 Nevertheless, longer follow-up would have strengthened the multicenter trials and, gtven the failures with cefazolin, may have detected potential advantages of ceftriaxone. Future studies should certainly address this possibility. The multicenter trials of ceftriaxone included very few children. Detailed information was available for only 23 patients. Data from the manufacturer included 12 cases of childhood urinary tract infection, in all of which treatment with ceftriaxone resulted in eradication of the organism and clinical cure. 5 Bradley and associates 6 and Dagan and co-workers7 reported similar results in six and five children, respectively. Most of the infections were judged to be serions, requiring parenteral therapy. The majority were due to E. colt. Although the data are limited, results to date are comparable to those observed in adults.
Recent Trends in Susceptibility A number of years have passed since ceftriaxone was marketed and its in vitro activity described. As a result, my col-
Ceftriaxone is active against many gram-negative bacillary uropathogens. lt achieves very high levels in urine and proximate tissue .... Clinical and bacteriologie results in infections due to susceptible organisms have been excellent.
leagues and 1 revtewed the susceptibility of organisms isolated in our two major teaching hospitals in Omaha during 1987, 1988, and 1989. At our university hospital (St. Joseph), where testing is done by the disk diffusion method, the major uropathogens (Escherichia, Klebsiella, and Proteus) remain highly sensitive. Other gram-negative isolates, including Enterobacter aerogenes (74% susceptible in 1989), Serratia species (95%), and Citrobacter species (88%), are somewhat less susceptible, but not markedly less so than in the early 1980s. 1 Only the susceptibility of Enterobacter cloacae appears to be declininggradually, from 85% in 1987 to 73% in 1989. The situation was dramatically different at the Omaha Veterans Affairs Medical Center, just a few miles away. Although the major uropathogens remained uniformly sensitive, there appeared to have been a major rebound in susceptibility of isolates of E. cloacae and P. aeruginosa (see Figure 2). We are unable to fully explain these observations. Severa! possibilities exist. First. the method of testing differed between the two institutions. An automated system (Vitek) is used at the VA Medical
Center; however, there have been no obvtous changes in the methodology in recent years. Use of antimicrobial agents in general is more highly restricted in the Veterans hospital, and this may have contributed to grea ter sensitivtty of sorne of the isolates. It would be interesting to determine whether this is a local phenomenon or one that mirrors a more widespread change in susceptibility over the course oftlme.
Summary Ceftriaxone is active against many gram-negative bacillary uropathogens. It achieves very
high levels in urine and proximate tissue following single daily doses. Clinical and bacteriologie results in infections due to susceptible organisms have been excellent. Additional comparative studies with longer follow-up may assist in further delineating the relative role of ceftriaxone in management of infections of the urinary tract. D
The au thor acknowledges the kind assistance ofDrs. Stephen Cavalleri and Donald Giger, who provided suscepttb1Uty test results from St. Joseph Hospital and the Omaha Veterans Affairs Medical Center, respectlvely.
References 1. Cleeland R, Squlres E: Antlmlcroblal actlvlty of ceftrlaxone: A revlew. Am J Med 77(Suppl4C): 3, 1984 2. PatellH et al: Pharmacoklnetics of ceftrlaxone ln humans. Antimlcrob Agents Chemother 20: 634, 1981 3. Adams D. Naber KG: Concentrations of ceftrlaxone ln prostate adenoma tissue. Chemotherapy 30: 1, 1984 4. Richards DM et al: Ceftrlaxone: A revlew of lts antibacterial activlty. pharmacologlcal propertles and therapeutlc use. Drugs 27: 469, 1984 5. Roche Sclentlfic Summary: The cllnlcal evaluation ofRocephln (ceftrlaxone sodium/Roche). Hoffmann-La Roche lnc., Nutley, New Jersey. 1988 6. Bradley JS et al: Outpatient therapy of serlous pediatrie Infections with ceftrlaxone. Pedlatr Infect Dis J 7: 160. 1988 7. Dagan Ret al: Outpatient treatment of serlous communlty-acqulred pediatrie Infections using once daily lntrarnuscular ceftrlaxone. Pedlatr Infect Dis J 6: 1080, 1987
51
