- Email: [email protected]
Taking a close look at intractable urinary tract infections
The Veterinary Journal 190 (2011) 11–12
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
Taking a close look at intractable urinary tract infections
The proximal urethra, bladder, ureters and kidneys are considered sterile and, according to the current veterinary standard of care, antimicrobial intervention is indicated whenever microorganisms are isolated from these organs. The rationale of treatment is based on earlier studies, which indicated that urinary bacteria, specifically Escherichia coli, have the potential to cause renal scarring or other sequelae (Kelly et al., 1979; Slotki and Asscher, 1982). But is this true for all urinary isolates? Our knowledge about human and canine urinary isolates has advanced in recent years. As Thompson et al. (2011a) outline in this issue of The Veterinary Journal, we now know that urinary pathogens, particularly E. coli, possess virulence factors, and that these bacteria are phylogenetically distinct from commensal organisms isolated from pets. Thus it might seem logical that we should target pathogens with our treatment; treating harmless urinary bacteria (‘urinary commensals’) may not be necessary. In support of this position, the treatment of asymptomatic bacteriuria (ABU) in humans has been questioned. Therapy of patients with ABU may be ineffective and could lead to the emergence of antimicrobial resistance among bacteria in this environment (Nicolle, 2006). Moreover, harmless biofilm-forming bacteria have been used successfully to prevent recurrent symptomatic urinary tract infections (UTI) in people (Darouiche et al., 2005). Early attempts to adopt this strategy in dogs have been described by Thompson et al. (2011b). Unfortunately, a distinction between a UTI that requires treatment and a colonization of the urinary tract by commensal bacteria cannot easily be made in veterinary practice. It is hampered by the challenge posed in defining an asymptomatic UTI. Furthermore, routine microbiological tests do not determine the presence of virulence factors or identify the phylogenetic groups of bacteria cultured from the urinary tract. So the clinician has limited microbiological information available to plan the appropriate course of treatment. Rapid diagnostic tests that determine genotypic traits of uropathogens have been used in science for some time. Perhaps it is now opportune to consider using these tests routinely in practice in an effort to optimize treatment protocols for veterinary patients with intractable UTI. Thompson et al. (2011a) outline an increase in the occurrence of antimicrobial resistance among bacteria associated with UTI. This trend is worrying, particularly because the availability of new antimicrobials has slowed dramatically in recent years (Alanis, 2005). If we want to minimize the occurrence of treatment failure, we must understand how antimicrobial resistance emerges and devise strategies to control it, thereby preserving the efficacy of our current arsenal of drugs. Whenever antimicrobials are being used, selection pressure is applied to rapidly evolving bacteria, and the subsequent emer1090-0233/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2011.03.001
gence of bacteria resistant to the antimicrobial can be expected. Antimicrobial resistance may be due to any of the following: (1) altered uptake of antimicrobials due to changes in cell wall permeability or porin expression; (2) altered structure or expression of target proteins, resulting in reduced binding of antimicrobials to bacterial ribosomes or DNA; (3) expression of bacterial enzymes that render antimicrobials non-functional, or (4) increased extrusion of antimicrobials by bacterial efflux pumps. Bacteria can exhibit multiple resistance strategies at any given time. For example, one can imagine that increased efflux pump activity will reduce the cytoplasmic content of an antimicrobial compound to such a concentration that the drug can have no effect on the bacterium. This situation will also allow time for the organism to develop intrinsic and/or extrinsic resistance strategies including the development of one or more mutations in housekeeping genes and/or the acquisition of mobile genetic resistance markers. Multidrug resistance (MDR), which is commonly defined as resistance to three or more different classes of antimicrobial agents, may occur if bacteria acquire mobile genetic elements (such as plasmids) that contain several antimicrobial resistanceencoding genes. Alternatively, enhanced expression of intrinsic efflux pumps, demonstrating broad substrate specificity, can also lead to MDR. Other mechanisms, such as the accumulation of multiple genetic elements, multiple mutations, or alterations in the cell membrane may also be identified in some instances. An infection caused by MDR bacteria is of major concern, because it may ultimately lead to treatment failure and death, or it may impose a health risk to other animals or humans sharing the same environment. Patients that are kept in areas where the selection pressure on bacteria is high (as would arise in hospitals) or that receive several different antimicrobial agents over a period of weeks to months, have the highest risk of developing UTI with MDR bacteria. A concurrent predisposing condition can be identified in most of these patients. In many cases, antimicrobial therapy will alleviate some signs of intractable UTI, and the urine may even be cleared of bacterial organisms during the time of treatment. However, does this mean that the UTI has resolved? Recent studies suggest that this may not always be the case, because bacteria may persist in proximity to the uro-epithelium (Gatoria et al., 2006; Justice et al., 2004). Thus, examinations of the patient after completion of a course of antimicrobial treatment constitutes an important part of the overall patient care. Fortunately, UTI caused by MDR is still an uncommon occurrence it is the responsibility of veterinarians to remain vigilant. As a health-caring profession, we should always question why a patient has intractable UTI, seek to use antimicrobials diligently, and opt for suitable non-antimicrobial treatment options when these are available.
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Guest Editorial / The Veterinary Journal 190 (2011) 11–12
Thurid Freitag Djursjukhuset Malmö, Cypressvägen 11, Malmö, Sweden E-mail address: [email protected]
References Alanis, A.J., 2005. Resistance to antibiotics: are we in the post-antibiotic era? Archives of Medical Research 36, 697–705. Darouiche, R.O., Thornby, J.I., Cerra-Stewart, C., Donovan, W.H., Hull, R.A., 2005. Bacterial interference for prevention of urinary tract infection: a prospective, randomized, placebo-controlled, double-blind pilot trial. Clinical Infectious Diseases 41, 1531–1534.
Gatoria, I.S., Saini, N.S., Rai, T.S., Dwivedi, P.N., 2006. Comparison of three techniques for the diagnosis of urinary tract infections in dogs with urolithiasis. Journal of Small Animal Practice 47, 727–732. Justice, S.S., Hung, C., Theriot, J.A., Fletcher, D.A., Anderson, G.G., Footer, M.J., Hultgren, S.J., 2004. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proceedings of the National Academy of Sciences USA 101, 1333–1338. Kelly, D.F., Lucke, V.M., McCullagh, K.G., Roberts, J.A., Kaack, M.B., Baskin, G., Svenson, S.B., 1979. Experimental pyelonephritis in the cat. 2. Ultrastructural observations. Journal of Comparative Pathology 89, 563–579. Nicolle, L.E., 2006. Asymptomatic bacteriuria: review and discussion of the IDSA guidelines. International Journal of Antimicrobial Agents 28, 42–48. Slotki, I.N., Asscher, A.W., 1982. Prevention of scarring in experimental pyelonephritis in the rat by early antibiotic therapy. Nephron 30, 262–268. Thompson, M.F., Litster, A.L., Platell, J.L., Trott, D.J., 2011a. Canine bacterial urinary tract infections: new developments in old pathogens. The Veterinary Journal 190, 22–27. Thompson, M.F., Totsika, M., Schembri, M.A., Mills, P.C., Seton, E.J., Trott, D.J., 2011b. Experimental colonization of the canine urinary tract with the asymptomatic bacteriuria Escherichia coli strain 83972. Veterinary Microbiology 147, 205–208.
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
Taking a close look at intractable urinary tract infections
The proximal urethra, bladder, ureters and kidneys are considered sterile and, according to the current veterinary standard of care, antimicrobial intervention is indicated whenever microorganisms are isolated from these organs. The rationale of treatment is based on earlier studies, which indicated that urinary bacteria, specifically Escherichia coli, have the potential to cause renal scarring or other sequelae (Kelly et al., 1979; Slotki and Asscher, 1982). But is this true for all urinary isolates? Our knowledge about human and canine urinary isolates has advanced in recent years. As Thompson et al. (2011a) outline in this issue of The Veterinary Journal, we now know that urinary pathogens, particularly E. coli, possess virulence factors, and that these bacteria are phylogenetically distinct from commensal organisms isolated from pets. Thus it might seem logical that we should target pathogens with our treatment; treating harmless urinary bacteria (‘urinary commensals’) may not be necessary. In support of this position, the treatment of asymptomatic bacteriuria (ABU) in humans has been questioned. Therapy of patients with ABU may be ineffective and could lead to the emergence of antimicrobial resistance among bacteria in this environment (Nicolle, 2006). Moreover, harmless biofilm-forming bacteria have been used successfully to prevent recurrent symptomatic urinary tract infections (UTI) in people (Darouiche et al., 2005). Early attempts to adopt this strategy in dogs have been described by Thompson et al. (2011b). Unfortunately, a distinction between a UTI that requires treatment and a colonization of the urinary tract by commensal bacteria cannot easily be made in veterinary practice. It is hampered by the challenge posed in defining an asymptomatic UTI. Furthermore, routine microbiological tests do not determine the presence of virulence factors or identify the phylogenetic groups of bacteria cultured from the urinary tract. So the clinician has limited microbiological information available to plan the appropriate course of treatment. Rapid diagnostic tests that determine genotypic traits of uropathogens have been used in science for some time. Perhaps it is now opportune to consider using these tests routinely in practice in an effort to optimize treatment protocols for veterinary patients with intractable UTI. Thompson et al. (2011a) outline an increase in the occurrence of antimicrobial resistance among bacteria associated with UTI. This trend is worrying, particularly because the availability of new antimicrobials has slowed dramatically in recent years (Alanis, 2005). If we want to minimize the occurrence of treatment failure, we must understand how antimicrobial resistance emerges and devise strategies to control it, thereby preserving the efficacy of our current arsenal of drugs. Whenever antimicrobials are being used, selection pressure is applied to rapidly evolving bacteria, and the subsequent emer1090-0233/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2011.03.001
gence of bacteria resistant to the antimicrobial can be expected. Antimicrobial resistance may be due to any of the following: (1) altered uptake of antimicrobials due to changes in cell wall permeability or porin expression; (2) altered structure or expression of target proteins, resulting in reduced binding of antimicrobials to bacterial ribosomes or DNA; (3) expression of bacterial enzymes that render antimicrobials non-functional, or (4) increased extrusion of antimicrobials by bacterial efflux pumps. Bacteria can exhibit multiple resistance strategies at any given time. For example, one can imagine that increased efflux pump activity will reduce the cytoplasmic content of an antimicrobial compound to such a concentration that the drug can have no effect on the bacterium. This situation will also allow time for the organism to develop intrinsic and/or extrinsic resistance strategies including the development of one or more mutations in housekeeping genes and/or the acquisition of mobile genetic resistance markers. Multidrug resistance (MDR), which is commonly defined as resistance to three or more different classes of antimicrobial agents, may occur if bacteria acquire mobile genetic elements (such as plasmids) that contain several antimicrobial resistanceencoding genes. Alternatively, enhanced expression of intrinsic efflux pumps, demonstrating broad substrate specificity, can also lead to MDR. Other mechanisms, such as the accumulation of multiple genetic elements, multiple mutations, or alterations in the cell membrane may also be identified in some instances. An infection caused by MDR bacteria is of major concern, because it may ultimately lead to treatment failure and death, or it may impose a health risk to other animals or humans sharing the same environment. Patients that are kept in areas where the selection pressure on bacteria is high (as would arise in hospitals) or that receive several different antimicrobial agents over a period of weeks to months, have the highest risk of developing UTI with MDR bacteria. A concurrent predisposing condition can be identified in most of these patients. In many cases, antimicrobial therapy will alleviate some signs of intractable UTI, and the urine may even be cleared of bacterial organisms during the time of treatment. However, does this mean that the UTI has resolved? Recent studies suggest that this may not always be the case, because bacteria may persist in proximity to the uro-epithelium (Gatoria et al., 2006; Justice et al., 2004). Thus, examinations of the patient after completion of a course of antimicrobial treatment constitutes an important part of the overall patient care. Fortunately, UTI caused by MDR is still an uncommon occurrence it is the responsibility of veterinarians to remain vigilant. As a health-caring profession, we should always question why a patient has intractable UTI, seek to use antimicrobials diligently, and opt for suitable non-antimicrobial treatment options when these are available.
12
Guest Editorial / The Veterinary Journal 190 (2011) 11–12
Thurid Freitag Djursjukhuset Malmö, Cypressvägen 11, Malmö, Sweden E-mail address: [email protected]
References Alanis, A.J., 2005. Resistance to antibiotics: are we in the post-antibiotic era? Archives of Medical Research 36, 697–705. Darouiche, R.O., Thornby, J.I., Cerra-Stewart, C., Donovan, W.H., Hull, R.A., 2005. Bacterial interference for prevention of urinary tract infection: a prospective, randomized, placebo-controlled, double-blind pilot trial. Clinical Infectious Diseases 41, 1531–1534.
Gatoria, I.S., Saini, N.S., Rai, T.S., Dwivedi, P.N., 2006. Comparison of three techniques for the diagnosis of urinary tract infections in dogs with urolithiasis. Journal of Small Animal Practice 47, 727–732. Justice, S.S., Hung, C., Theriot, J.A., Fletcher, D.A., Anderson, G.G., Footer, M.J., Hultgren, S.J., 2004. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proceedings of the National Academy of Sciences USA 101, 1333–1338. Kelly, D.F., Lucke, V.M., McCullagh, K.G., Roberts, J.A., Kaack, M.B., Baskin, G., Svenson, S.B., 1979. Experimental pyelonephritis in the cat. 2. Ultrastructural observations. Journal of Comparative Pathology 89, 563–579. Nicolle, L.E., 2006. Asymptomatic bacteriuria: review and discussion of the IDSA guidelines. International Journal of Antimicrobial Agents 28, 42–48. Slotki, I.N., Asscher, A.W., 1982. Prevention of scarring in experimental pyelonephritis in the rat by early antibiotic therapy. Nephron 30, 262–268. Thompson, M.F., Litster, A.L., Platell, J.L., Trott, D.J., 2011a. Canine bacterial urinary tract infections: new developments in old pathogens. The Veterinary Journal 190, 22–27. Thompson, M.F., Totsika, M., Schembri, M.A., Mills, P.C., Seton, E.J., Trott, D.J., 2011b. Experimental colonization of the canine urinary tract with the asymptomatic bacteriuria Escherichia coli strain 83972. Veterinary Microbiology 147, 205–208.