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Optimal Duration of Treatment of Urinary Tract Infections
682
INFECTIONS AND ANTIBIOTICS
theless, in at least 1 open population study in the Netherlands with a 5-year followup 55 per cent of the responders with either symptomatic or asymptomatic urinary tract infections harbored at least once a resistant strain in the urine. Of all isolated strains during that period approximately 22 per cent were resistant to 1 or more antimicrobial agents. Of the fecal Escherichia coli 80 per cent were resistant to 1 or more antimicrobial agents. In Holland severe renal failure occurs in about 33 per 100,000 people, or 600 times less than urinary tract infection. Mortality from pyelonephritis in the Netherlands amounts to 3 per 100,000 population, 10 times less than renal failure and 6,000 times less than urinary tract infection. Therefore, the author concludes that 1 in 5,000 to 10,000 urinary tract infections finally becomes severe chronic fatal renal failure. P.M.H. 4 tables, 11 references
Tissue Injury in Inflammation. Oxidants, Proteinases, and Cationic Proteins P. M. HENSON AND R. B. JOHNSTON, JR., National Jewish Center for Immunology and Respiratory Medicine, and Departments of Pediatrics, Pathology and Medicine, University of Colorado School of Medicine, Denver, Colorado
J. Clin. Invest., 79: 669-674 (Mar.) 1987 In circumstances of acute injury to tissues of the body it currently is popular to incriminate byproducts of oxygen metabolism as the ultimate injurious agents. A disparate array of conditions is encompassed in this concept, including injury to the lungs by external agents that induce oxidant formation, such as paraquat, bleomycin and perhaps even endotoxin or agents that contain oxidants, for example cigarette smoke, as well as myocardial damage after infarction and inflammatory tissue injury at sites of accumulation of phagocytic cells, such as that seen in the respiratory distress syndromes. In the lung and heart oxygen metabolites are particularly attractive as intracellular toxic agents because of the high oxygen tensions to which the cells of these tissues are exposed. At these and other sites cells of the inflammatory system (especially neutrophils, mononuclear phagocytes and eosinophils) are invoked as additional sources of such metabolites owing to their ability to undergo the well described respiratory burst that accompanies phagocytosis and other membrane stimulatory events. However, the case for oxygen radicals may not be as clear or as complete in vivo as the existing reports suggest. The authors attempt, at this admittedly intermediate stage of knowledge, to put the issues of oxidant tissue damage into perspective. Earlier concepts of the mechanisms of inflammatory injury, derived from Metchnikov, had focused on release of what currently are known to be lysosomal constituents from inflammatory cells after they had reached the tissue and, subsequently, had lysed. Studies in the 1960s showing the potent injurious effects of injecting neutrophil contents exemplify this approach. A decade later it had become apparent that inflam matory cells were actively capable of secreting these constituents and that the suicide sac concept of lysosome-induced injury was overstated. While initially received with skepticism, it currently is reasonable to suggest that granulocytes often remain intact in inflammatory lesions, exhibit an active secretory process and are removed without lysis by macrophages. During the same recent period the concept that macrophages are secretory cells has become generally accepted. In keeping with
these developments inflammatory injury was seen as resulting from lysosomal discharge, primarily of proteases, but also of low molecular weight cationic proteins and other, largely proteinaceous, mediators or injurious agents. For example destruction of the glomerular basement membrane in experimental nephrotoxic nephritis induced by antibodies directed against the glomerular basement membrane was shown to involve neutrophils and to be accompanied by release in vivo of neutrophil proteases. A mechanism of secretion of such materials subsequent to leukocyte adhesion to surfaces was proposed, which 1 of the authors colloquially termed frustrated phagocytosis. These types of studies, and particularly the concurrent investigation of protease involvement in tissue remodeling and arthritis, stimulated a large field of investigation of leukocyte proteases. Nevertheless, as favored agents of tissue injury they soon were eclipsed by the developing interest in oxygen metabolites. We live in an oxidant-rich, oxygen-dependent environment bequeathed us by the biochemical miracle of photosynthesis. However, excess molecular oxygen and its metabolic byproducts can be highly toxic. These toxic products are formed normally in aerobic cells through a variety of metabolic reactions that are essential for the existence of the cell, including mitochondrial electron transport, reactions of mixed-function oxidases of the endoplasmic reticulum, cytoplasmic reactions of enzymes, such as xanthine oxidase, and so forth. Cellular protective mechanisms against these reactive products include the superoxide dismutases, catalase and the glutathione peroxidase-reductase cycle. A variety of pathological conditions has been proposed to result from accentuation of the intracellular metabolic processes that lead to formation of toxic oxygen metabolites, for example radiation damage and myocardial injury after infarction. The authors have confined the discussion to consideration of damage induced by oxidants released at a focus of inflammation; the common major source of these oxidants is phagocytic cells. G. P. M. 121 references
Optimal Duration of Treatment of Urinary Tract Infections
S. A.
LERNER, Department of Medicine, Section of Infectious Diseases, University of Chicago, Chicago, Illinois
Eur. Urol., suppl. 1, 13: 26-31 (Jan.) 1987 Infection of the urinary tract is the most commonly encountered bacterial infection in man. Despite the ease of detecting and quantitating bacteria in the urine, and of delivering high concentrations of active antibacterial agents into the urine, the duration of therapy of urinary tract infections has remained uncertain and, in fact, it recently has been evolving. We now use a spectrum of therapy that spans the interval from singledose to many weeks or even longer term prophylactic treatment. On the other hand, it is acknowledged that some infections require no antibiotic treatment. The antibiotic treatment of urinary tract infections is governed by several principles. The dose and duration of therapy are escalated as the probability of tissue invasion and/or the difficulty of bacterial eradication increases. Goals of treatment include relief of symptoms and associated morbidity, prevention of more serious consequences of infection, minimization of therapeutic side effects, lack of compliance, selection of resistant organisms and cost. A potential advantage of single dose therapy is that failure to eradicate bacteriuria within 2 to
INFECTIONS AND ANTIBIOTICS
3 days may be suggestive of a more invasive tissue infection that requires more intensive treatment and, perhaps, the need for radiological and/or urological investigation. The ideal situation for successful single dose treatment presupposes an appropriate antimicrobial with high urinary concentrations, infection involving only luminal or superficial tissue layers and an absence of complicating factors. Healthy women do not require routine screening for asymptomatic bacteriuria or treatment for the condition if it is noted. Antibiotic treatment is warranted for the pregnant woman with asymptomatic bacteriuria because of the possibility of acute pyelonephritis later in pregnancy and potential fetal complications. Single dose therapy appears to be as effective for an otherwise uncomplicated infection in pregnant women as conventional therapy. Since asymptomatic bacteriuria in children has a high association with underlying anatomical abnormalities, which may potentiate invasive infection and renal damage, such patients like pregnant women are treated for asymptomatic bacteriuria. There is good evidence that single dose therapy is as effective in uncomplicated infection as longer conventional courses. In the symptomatic woman with an acute uncomplicated urinary tract infection single dose therapy was first shown to be practical and efficacious. Patients who present after 6 or more days of symptoms are less likely to respond to single dose therapy. Despite the obvious advantages of single dose therapy, one must ask whether inadvertent inadequate therapy for tissue infection might allow progression of infection with serious consequences for the patient. In other words, would a patient with silent upper tract infection be more difficult to treat after relapse following single dose therapy than upon initial presentation? The answer to this question demands careful prospective studies. P. M. H. 3 tables, 20 references
Spectrum of Bacterial Pathogens in Uncomplicated and Complicated Urinary Tract Infections A. BAUERNFEIND, K. NABER AND D. SAUERWEIN, Max van Pettenkofer-I nstitut, M ilnchen; Elisabeth-Krankenhuis, Urologie, Straubing, and Werner-Wicker-Klinik, Bad Wildungen, Federal Republic of Germany
683
infections. For recommendation of antibiotics for therapy in uncomplicated urinary tract infections, data on bacterial sen sitivities according to region should be considered and kept up to date. In complicated urinary tract infections the spectrum of causative organisms and their susceptibility to antibiotics may vary greatly, making culture and sensitivity data even more crucial. P. M. H. 8 tables, 7 references
Microbiological Aspects of Chemotherapy of Lower Urinary Tract Infections R. G6MEz-Lus AND M. C. RUBIO CALVO, Faculty of Medicine, Department of Microbiology and Parasitology, University of Zaragoza, Zaragoza, Spain Eur. Urol., suppl. 1, 13: 13-16 (Jan.) 1987 Uncomplicated urinary tract infections represent an excellent model for the use of new antimicrobials or of new dosage regimens with already known antibiotics or chemotherapeutics. In the bacteriological control of urinary tract infection the culture performed on day 3 after 2 days of treatment usually is predictive, since there is a clear correlation with the final result. The authors compared the results obtained after 2 days of conventional treatment with amoxicillin, cefaclor, cefamandole and cefuroxime to the results of other studies after single dose treatment with the same drugs. They note a striking likeness between the bacteriological response after 2 days of conventional treatment and the final clinicobacteriological results obtained with a single dose of the same antibiotics. Given the importance of urinary tract infection caused by multiresistant nosocomial strains with an R plasmid, the authors suggest that single dose and short-term courses of antibiotics for acute urinary tract infection, when possible, might tend to reduce the development of resistant bacterial strains. In another study the authors evaluated 122 strains of coagulase-negative staphylococci obtained from urine specimens containing 105 bacteria per ml. Of the strains 51 per cent were Staph. epidermidis and only 10 patients had Staph. saprophyticus. P. M. H. 3 tables, 21 references
Eur. Urol., suppl. 1, 13: 9-12 (Jan.) 1987 Data from the United Kingdom and Federal Republic of Germany are examined with regard to the spectra of bacterial organisms of urinary tract infections in patients with and without abnormalities in the urinary tract (complicated and uncomplicated urinary tract infections), and with regard to antibiotic susceptibility of organisms. The spectrum of causative organisms in uncomplicated and complicated urinary tract infections is markedly different. Non-Escherichia coli organisms are more frequent in patients with abnormalities of various types. In patients with spinal injuries Pseudomonas aeruginosa may prove to be the most important causative species. Although the proportion of isolates from nonhospitalized patients with un complicated urinary tract infections susceptible to oral antibiotics is higher than from inpatients, the authors caution that therapy without an antibiotic may be inadequate in a number of cases. There are major differences in the antibiotic susceptibility of isolates from uncomplicated urinary tract infections in different countries. This may be partly owing to variations in the antibiotics usually prescribed for treatment of these
Lower Urinary Tract Infection: Rationale and Efficacy of Single-Dose Antibacterial Therapy J. D. WILLIAMS, Department of Medical Microbiology, London Hospital Medical College, London, United Kingdom Eur. Urol., suppl. 1, 13: 54-55 (Jan.) 1987 Much effort currently is spent on determining the minimum effective dose for treatment of infection. Critics of excessive antibiotic use suggest that one would not treat every patient with the maximum dose of therapy needed to produce an overall cure rate approaching 100 per cent but that therapy should be tailored to suit the individual patient. With urinary tract infection it may be possible to balance minimum therapy with acceptable failure rates given the relatively low morbidity of the process (compared to bacterial endocarditis). Ideally, it may be possible to predict which patients require prolonged therapy and in which single dose therapy might suffice. Minimum effective dose treatment has the advantages of reduced side effects, toxicity, resistance and cost, and better compliance. P.M.H.
INFECTIONS AND ANTIBIOTICS
theless, in at least 1 open population study in the Netherlands with a 5-year followup 55 per cent of the responders with either symptomatic or asymptomatic urinary tract infections harbored at least once a resistant strain in the urine. Of all isolated strains during that period approximately 22 per cent were resistant to 1 or more antimicrobial agents. Of the fecal Escherichia coli 80 per cent were resistant to 1 or more antimicrobial agents. In Holland severe renal failure occurs in about 33 per 100,000 people, or 600 times less than urinary tract infection. Mortality from pyelonephritis in the Netherlands amounts to 3 per 100,000 population, 10 times less than renal failure and 6,000 times less than urinary tract infection. Therefore, the author concludes that 1 in 5,000 to 10,000 urinary tract infections finally becomes severe chronic fatal renal failure. P.M.H. 4 tables, 11 references
Tissue Injury in Inflammation. Oxidants, Proteinases, and Cationic Proteins P. M. HENSON AND R. B. JOHNSTON, JR., National Jewish Center for Immunology and Respiratory Medicine, and Departments of Pediatrics, Pathology and Medicine, University of Colorado School of Medicine, Denver, Colorado
J. Clin. Invest., 79: 669-674 (Mar.) 1987 In circumstances of acute injury to tissues of the body it currently is popular to incriminate byproducts of oxygen metabolism as the ultimate injurious agents. A disparate array of conditions is encompassed in this concept, including injury to the lungs by external agents that induce oxidant formation, such as paraquat, bleomycin and perhaps even endotoxin or agents that contain oxidants, for example cigarette smoke, as well as myocardial damage after infarction and inflammatory tissue injury at sites of accumulation of phagocytic cells, such as that seen in the respiratory distress syndromes. In the lung and heart oxygen metabolites are particularly attractive as intracellular toxic agents because of the high oxygen tensions to which the cells of these tissues are exposed. At these and other sites cells of the inflammatory system (especially neutrophils, mononuclear phagocytes and eosinophils) are invoked as additional sources of such metabolites owing to their ability to undergo the well described respiratory burst that accompanies phagocytosis and other membrane stimulatory events. However, the case for oxygen radicals may not be as clear or as complete in vivo as the existing reports suggest. The authors attempt, at this admittedly intermediate stage of knowledge, to put the issues of oxidant tissue damage into perspective. Earlier concepts of the mechanisms of inflammatory injury, derived from Metchnikov, had focused on release of what currently are known to be lysosomal constituents from inflammatory cells after they had reached the tissue and, subsequently, had lysed. Studies in the 1960s showing the potent injurious effects of injecting neutrophil contents exemplify this approach. A decade later it had become apparent that inflam matory cells were actively capable of secreting these constituents and that the suicide sac concept of lysosome-induced injury was overstated. While initially received with skepticism, it currently is reasonable to suggest that granulocytes often remain intact in inflammatory lesions, exhibit an active secretory process and are removed without lysis by macrophages. During the same recent period the concept that macrophages are secretory cells has become generally accepted. In keeping with
these developments inflammatory injury was seen as resulting from lysosomal discharge, primarily of proteases, but also of low molecular weight cationic proteins and other, largely proteinaceous, mediators or injurious agents. For example destruction of the glomerular basement membrane in experimental nephrotoxic nephritis induced by antibodies directed against the glomerular basement membrane was shown to involve neutrophils and to be accompanied by release in vivo of neutrophil proteases. A mechanism of secretion of such materials subsequent to leukocyte adhesion to surfaces was proposed, which 1 of the authors colloquially termed frustrated phagocytosis. These types of studies, and particularly the concurrent investigation of protease involvement in tissue remodeling and arthritis, stimulated a large field of investigation of leukocyte proteases. Nevertheless, as favored agents of tissue injury they soon were eclipsed by the developing interest in oxygen metabolites. We live in an oxidant-rich, oxygen-dependent environment bequeathed us by the biochemical miracle of photosynthesis. However, excess molecular oxygen and its metabolic byproducts can be highly toxic. These toxic products are formed normally in aerobic cells through a variety of metabolic reactions that are essential for the existence of the cell, including mitochondrial electron transport, reactions of mixed-function oxidases of the endoplasmic reticulum, cytoplasmic reactions of enzymes, such as xanthine oxidase, and so forth. Cellular protective mechanisms against these reactive products include the superoxide dismutases, catalase and the glutathione peroxidase-reductase cycle. A variety of pathological conditions has been proposed to result from accentuation of the intracellular metabolic processes that lead to formation of toxic oxygen metabolites, for example radiation damage and myocardial injury after infarction. The authors have confined the discussion to consideration of damage induced by oxidants released at a focus of inflammation; the common major source of these oxidants is phagocytic cells. G. P. M. 121 references
Optimal Duration of Treatment of Urinary Tract Infections
S. A.
LERNER, Department of Medicine, Section of Infectious Diseases, University of Chicago, Chicago, Illinois
Eur. Urol., suppl. 1, 13: 26-31 (Jan.) 1987 Infection of the urinary tract is the most commonly encountered bacterial infection in man. Despite the ease of detecting and quantitating bacteria in the urine, and of delivering high concentrations of active antibacterial agents into the urine, the duration of therapy of urinary tract infections has remained uncertain and, in fact, it recently has been evolving. We now use a spectrum of therapy that spans the interval from singledose to many weeks or even longer term prophylactic treatment. On the other hand, it is acknowledged that some infections require no antibiotic treatment. The antibiotic treatment of urinary tract infections is governed by several principles. The dose and duration of therapy are escalated as the probability of tissue invasion and/or the difficulty of bacterial eradication increases. Goals of treatment include relief of symptoms and associated morbidity, prevention of more serious consequences of infection, minimization of therapeutic side effects, lack of compliance, selection of resistant organisms and cost. A potential advantage of single dose therapy is that failure to eradicate bacteriuria within 2 to
INFECTIONS AND ANTIBIOTICS
3 days may be suggestive of a more invasive tissue infection that requires more intensive treatment and, perhaps, the need for radiological and/or urological investigation. The ideal situation for successful single dose treatment presupposes an appropriate antimicrobial with high urinary concentrations, infection involving only luminal or superficial tissue layers and an absence of complicating factors. Healthy women do not require routine screening for asymptomatic bacteriuria or treatment for the condition if it is noted. Antibiotic treatment is warranted for the pregnant woman with asymptomatic bacteriuria because of the possibility of acute pyelonephritis later in pregnancy and potential fetal complications. Single dose therapy appears to be as effective for an otherwise uncomplicated infection in pregnant women as conventional therapy. Since asymptomatic bacteriuria in children has a high association with underlying anatomical abnormalities, which may potentiate invasive infection and renal damage, such patients like pregnant women are treated for asymptomatic bacteriuria. There is good evidence that single dose therapy is as effective in uncomplicated infection as longer conventional courses. In the symptomatic woman with an acute uncomplicated urinary tract infection single dose therapy was first shown to be practical and efficacious. Patients who present after 6 or more days of symptoms are less likely to respond to single dose therapy. Despite the obvious advantages of single dose therapy, one must ask whether inadvertent inadequate therapy for tissue infection might allow progression of infection with serious consequences for the patient. In other words, would a patient with silent upper tract infection be more difficult to treat after relapse following single dose therapy than upon initial presentation? The answer to this question demands careful prospective studies. P. M. H. 3 tables, 20 references
Spectrum of Bacterial Pathogens in Uncomplicated and Complicated Urinary Tract Infections A. BAUERNFEIND, K. NABER AND D. SAUERWEIN, Max van Pettenkofer-I nstitut, M ilnchen; Elisabeth-Krankenhuis, Urologie, Straubing, and Werner-Wicker-Klinik, Bad Wildungen, Federal Republic of Germany
683
infections. For recommendation of antibiotics for therapy in uncomplicated urinary tract infections, data on bacterial sen sitivities according to region should be considered and kept up to date. In complicated urinary tract infections the spectrum of causative organisms and their susceptibility to antibiotics may vary greatly, making culture and sensitivity data even more crucial. P. M. H. 8 tables, 7 references
Microbiological Aspects of Chemotherapy of Lower Urinary Tract Infections R. G6MEz-Lus AND M. C. RUBIO CALVO, Faculty of Medicine, Department of Microbiology and Parasitology, University of Zaragoza, Zaragoza, Spain Eur. Urol., suppl. 1, 13: 13-16 (Jan.) 1987 Uncomplicated urinary tract infections represent an excellent model for the use of new antimicrobials or of new dosage regimens with already known antibiotics or chemotherapeutics. In the bacteriological control of urinary tract infection the culture performed on day 3 after 2 days of treatment usually is predictive, since there is a clear correlation with the final result. The authors compared the results obtained after 2 days of conventional treatment with amoxicillin, cefaclor, cefamandole and cefuroxime to the results of other studies after single dose treatment with the same drugs. They note a striking likeness between the bacteriological response after 2 days of conventional treatment and the final clinicobacteriological results obtained with a single dose of the same antibiotics. Given the importance of urinary tract infection caused by multiresistant nosocomial strains with an R plasmid, the authors suggest that single dose and short-term courses of antibiotics for acute urinary tract infection, when possible, might tend to reduce the development of resistant bacterial strains. In another study the authors evaluated 122 strains of coagulase-negative staphylococci obtained from urine specimens containing 105 bacteria per ml. Of the strains 51 per cent were Staph. epidermidis and only 10 patients had Staph. saprophyticus. P. M. H. 3 tables, 21 references
Eur. Urol., suppl. 1, 13: 9-12 (Jan.) 1987 Data from the United Kingdom and Federal Republic of Germany are examined with regard to the spectra of bacterial organisms of urinary tract infections in patients with and without abnormalities in the urinary tract (complicated and uncomplicated urinary tract infections), and with regard to antibiotic susceptibility of organisms. The spectrum of causative organisms in uncomplicated and complicated urinary tract infections is markedly different. Non-Escherichia coli organisms are more frequent in patients with abnormalities of various types. In patients with spinal injuries Pseudomonas aeruginosa may prove to be the most important causative species. Although the proportion of isolates from nonhospitalized patients with un complicated urinary tract infections susceptible to oral antibiotics is higher than from inpatients, the authors caution that therapy without an antibiotic may be inadequate in a number of cases. There are major differences in the antibiotic susceptibility of isolates from uncomplicated urinary tract infections in different countries. This may be partly owing to variations in the antibiotics usually prescribed for treatment of these
Lower Urinary Tract Infection: Rationale and Efficacy of Single-Dose Antibacterial Therapy J. D. WILLIAMS, Department of Medical Microbiology, London Hospital Medical College, London, United Kingdom Eur. Urol., suppl. 1, 13: 54-55 (Jan.) 1987 Much effort currently is spent on determining the minimum effective dose for treatment of infection. Critics of excessive antibiotic use suggest that one would not treat every patient with the maximum dose of therapy needed to produce an overall cure rate approaching 100 per cent but that therapy should be tailored to suit the individual patient. With urinary tract infection it may be possible to balance minimum therapy with acceptable failure rates given the relatively low morbidity of the process (compared to bacterial endocarditis). Ideally, it may be possible to predict which patients require prolonged therapy and in which single dose therapy might suffice. Minimum effective dose treatment has the advantages of reduced side effects, toxicity, resistance and cost, and better compliance. P.M.H.