Biocides and pharmacologically active drugs as residues and in the environment: Is there a correlation with antibiotic resistance?
2002; Elsevier BV; Volume: 30; Issue: 8 Linguagem: Inglês
10.1067/mic.2002.124676
ISSN1527-3296
Autores Tópico(s)Pharmaceutical and Antibiotic Environmental Impacts
ResumoAntibiotics, drugs used for the treatment of a variety of human or animal conditions, and biocides find widespread use in human and animal medicine.1Martindale. The complete drug reference. 32nd ed. Pharmaceutical Press, London1999Google Scholar Antibiotics and other chemotherapeutic drugs are employed for the treatment of bacterial, fungal, protozoal, and viral infections.2Greenwood D Antimicrobial chemotherapy.3rd ed. University Press, Oxford1995Google Scholar Pharmacologically active drugs (PADs) are used for a variety of disorders and include products such as central nervous system depressants, intestinal treatments, and cancer chemotherapy medication. Many possess antimicrobial properties.3Russell AD Pharmacologically active drugs other than antibiotics that possess or enhance antimicrobial activity.Hosp Prescriber Europe. 2002; : 37-40Google Scholar Biocides are used as disinfectants for inanimate objects, as antiseptics for application to living tissue, and as preservatives for incorporation into many pharmaceutical, cosmetic, food, and industrial products.4Hugo WB Russell AD Types of antimicrobial agents.in: 3rd ed. Principles and practice of disinfection, preservation, and sterilization. Blackwell Science, Oxford1999: 5-94Google Scholar, 5Handbook of biocide and preservative use. Blackie, London1995Google Scholar It is the purpose of this article to examine the concept that residues of biocides or PADs could be associated with antibiotic resistance. These aspects have previously received scant attention. Bacterial resistance to antibiotics is a widespread phenomenon.6Courvalin P Evasion of antibiotic action by bacteria.J Antimicrob Chemother. 1996; 37: 855-869Crossref PubMed Scopus (60) Google Scholar, 7Hiramatsu K Vancomycin resistance in staphylococci.Drug Resist Updates. 1998; 1: 135-150Abstract Full Text PDF PubMed Scopus (192) Google Scholar One reason for an increase in bacterial resistance to chemotherapeutic drugs is the widespread and often indiscriminate use of antibiotics in humans and animals. The development of fluoroquinolone resistance in animal strains of Campylobacter and Salmonella has been transferred to human strains.8White DG Zhao Z Sudler R et al.The isolation of antibiotic-resistant salmonella from retail ground meat.N Engl J Med. 2001; 345: 1147-1154Crossref PubMed Scopus (398) Google Scholar, 9McDonald LC Rossiter S Mackinson C et al.Quinupristin-dalfopristin-resistant Enterococcus faecium on chicken and in human stool specimens.N Engl J Med. 2001; 345: 1155-1160Crossref PubMed Scopus (84) Google Scholar, 10Sorebsen TL Blom M Monnet DL Frimodt-Moller N Poulsen RL Espersen F Transient intestinal carriage after ingestion of antibiotic-resistant Enterococcus faecium from chicken and pork.N Engl J Med. 2001; 345: 1161-1166Crossref PubMed Scopus (153) Google Scholar There is now considerable evidence to support the concept that antibiotics used as feed additives are partially responsible for the selection of antibiotic-resistant bacteria.11N Engl J Med. 2001; 345: 1202-1203Crossref PubMed Scopus (136) Google Scholar For some time there have been reports that the widespread use of biocides in the hospital, and to a lesser extent, in the home could select for antibiotic-resistant bacteria.12Russell AD Do biocides select for antibiotic resistance?.J Pharm Pharmacol. 2000; 52: 227-233Crossref PubMed Scopus (145) Google Scholar Biocides that might be implicated include the bisphenol (phenylether) triclosan together with the cationic agents chlorhexidine salts and quaternary ammonium compounds (QACs). Triclosan has specific uses in hospitals (eg, body wash for patients infected with methicillin-resistant Staphylococcus aureus ). It is also incorporated into a range of household products. Such widespread use could select for antibiotic-resistant bacteria. Triclosan has been shown to select for low-level antibiotic resistance in Escherichia coli13McMurry LM Oethinger M Levy SB Overexpression of marA, soxS or acrAB produces resistance to triclosan in laboratory and clinical strains of Escherichia coli.FEMS Microbiol Lett. 1998; 166: 305-309Crossref PubMed Scopus (289) Google Scholar and high-level ciprofloxacin resistance in triclosan-sensitive Pseudomonas aeruginosa mutants.14Chuanchen R Beinlich K Hoang TT Becher A Karkhoff-Schweizer RR Schweizer HP Cross-resistance between triclosan and antibiotics in Pseudomonas aeruginosa is mediated by multidrug efflux pumps: exposure of a susceptible mutant strain to triclosan selects nfxB mutants overexpressing MexCD-OprJ.Antimicrob Ag Chemother. 2001; 45: 428-432Crossref PubMed Scopus (328) Google Scholar No evidence has been presented to show that the incorporation of triclosan into dentrifices has led to the acquisition of bacterial resistance in the supragingival and oral microflora.15Report.Biol Ther Dent. 2000; 16: 17-20Google Scholar Oral concentrations of triclosan are liable to vary considerably over periods of time. Triclosan and isoniazid appear to share a common target site in Mycobacterium tuberculosis and Mycobacterium smegmatis.16McMurry LM McDermott PF Levy SB Genetic evidence that InhA of Mycobacterium smegmatis is a target for triclosan.Antimicrob Ag Chemother. 1999; 43: 711-713Crossref PubMed Scopus (16) Google Scholar Studies from Skurray's group17Paulsen IT Brown MH Skurray RA Characterisation of the earliest known Staphylococcus aureus plasmid encoding a multidrug efflux system.J Bacteriol. 1998; 180: 3477-3479Crossref PubMed Google Scholar have suggested that the introduction of cationic biocides into clinical practice has been associated with the selection of S aureus strains containing qacA/qacB genes. Stickler and colleagues18Stickler DJ Thomas B Clayton CL Chawla JC Studies on the genetic basis of chlorhexidine resistance.Br J Clin Pract. 1983; 25 Suppl: 23-28Google Scholar proposed that the widespread use of chlorhexidine could select for gram-negative bacteria with multiple antibiotic resistance. In our laboratory,19Tattawasart U Maillard J-Y Furr JR Russell AD Development of resistance to chlorhexidine diacetate and cetylpyridinium chloride in Pseudomonas stutzeri and changes in antibiotic susceptibility.J Hosp Infect. 1999; 42: 219-229Abstract Full Text PDF PubMed Scopus (132) Google Scholar, 20Tattawasart U Maillard J-Y Furr JR Russell AD Outer membrane changes in Pseudomonas aeruginosa stutzeri resistant to chlorhexidine diacetate and cetylpyridinium chloride.Int J Antimicrob Ag. 2000; 16: 233-238Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar studies with biocide-sensitive, antibiotic-sensitive Pseudomonas stutzeri trained to biocide resistance showed an increased insusceptibility to some antibiotics. However, training to insusceptibility and selection for resistance must be distinguished: in the former case, a "blanket" increase in resistance or tolerance could result from outer membrane changes that reduce cellular permeability. Other studies with gram-negative bacteria21Higgins CS Murtough SM Williamson E et al.Resistance to antibiotics and biocides among non-fermenting gram-negative bacteria.Clin Microbiol Infect. 2001; 7: 308-315Crossref PubMed Google Scholar, 22Lambert RJW Joynson J Forbes B The relationships and susceptibilities of some industrial, laboratory, and clinical isolates of Pseudomonas aeruginosa to some antibiotics and biocides.J Appl Microbiol. 2001; 91: 972-984Crossref PubMed Scopus (54) Google Scholar have often been unable to find a relationship between reduced biocide insusceptibility and increased antibiotic resistance. Furthermore, Lambert et al22Lambert RJW Joynson J Forbes B The relationships and susceptibilities of some industrial, laboratory, and clinical isolates of Pseudomonas aeruginosa to some antibiotics and biocides.J Appl Microbiol. 2001; 91: 972-984Crossref PubMed Scopus (54) Google Scholar compared the responses to several antibiotics, a QAC, and chlorhexidine of P aeruginosa isolates from clinical (hospital) or industrial environments, with those obtained from culture collections. They concluded that antibiotic resistance was related to the use of antibiotics rather than to that of biocides. This is a little studied but potentially important aspect. Disinfectants are widely employed to reduce microbial levels on inanimate objects. Some chemical agents may occasionally act as chemosterilants, and many are employed as high-level disinfectants.23Rutala WA Weber DJ New methods in disinfection and sterilization.Emerg Infect Dis. 2001; 7: 348-353Crossref PubMed Scopus (144) Google Scholar, 24Favero MS Chemical germicides in the healthcare field: the perspective from the Centers for Disease Control and Prevention.in: Chemical germicides in health care. Polyscience, Morin Heights1995: 33-42Google Scholar It is unlikely that bacterial resistance could rise to "in-use" biocide concentrations (ie, levels used in practice); however, organisms within biofilms may not always be inactivated.25Stickler DJ King JB Bacterial sensitivity and resistance. A. Intrinsic resistance.in: 3rd ed. Principles and practice of disinfection, preservation, and sterilization. Blackwell Science, Oxford1999: 284-296Google Scholar The question then is whether biocide residues on inanimate objects are likely to select for biocide-resistant and/or antibiotic-resistant bacteria. Residual concentrations are likely to be low, but a marked fluctuation in such levels is conceivable as a consequence of the frequent use or reuse of disinfectants. The limited evidence available suggests that, for chlorhexidine salts and QACs, residues on surfaces are not a problem insofar as selection of resistant P aeruginosa cells are concerned.26Thomas L Lambert RJW Maillard JY Russell AD Development of resistance to chlorhexidine diacetate in Pseudomonas aeruginosa and the effect of a residual concentration.J Hosp Infect. 2000; 46: 297-303Abstract Full Text PDF PubMed Scopus (133) Google Scholar Likewise, the effects (if any) of the concentrations of biocides discarded via effluent systems are poorly understood. The only information to date relates to:1.Chlorine-releasing agents: Bacteria that are resistant to multiple antibiotics have been isolated from drinking water.27Armstrong JL Shigend DS Calomaris JJ Seidler PJ Antibiotic-resistant bacteria in drinking water.Appl Environ Microbiol. 1981; 42: 277-283PubMed Google Scholar It was subsequently suggested28Murray GE Tobin RS Jenkins B Kusher DJ Effect of chlorination on antibiotic resistance profiles of sewage-related bacteria.Appl Environ Microbiol. 1984; 48: 73-77PubMed Google Scholar that disinfection and purification of water could augment the occurrence of such bacteria and that chlorination was responsible for selecting or inducing such changes. The concentrations of chlorine-releasing agents in such systems are likely to show considerable fluctuation.2.Triclosan and para -chloro-meta -xylenol (PCMX; 4-chloro-3,5-dimethylphenol): Bacteria tolerant to these agents have been isolated from industrial sources; most were naturally insusceptible P aeruginosa species with PCMX-tolerant P stutzeri and triclosan-tolerant isolates of Citrobacter freundii and Acinetobacter johnonii.29Lear JC Maillard J-Y Goddard PA Dettmar PW Russell AD Isolation and study of chloroxylenol- and triclosan-resistant strains of bacteria.J Pharm Pharmacol. 2000; 52: 126Google Scholar, 30Lear JC Maillard JY Goddard PA Dettmar PW Russell AD Studies on chloroxylenol- and triclosan-tolerant strains of bacteria.in: ASM 101st General Meeting2001Google Scholar No evidence was produced, however, to suggest that the presence of residual biocide in the industrial environment encouraged the emergence of bacterial resistance. Residues are also likely to occur in the home where there could be widespread use of biocides as antibacterial washing liquids, surface wipes, on chopping boards, etc. Again, such residues could act as a selective pressure for antibiotic resistance although there does not appear to be any strong scientific evidence to support this currently. Preservatives are included in many products, including pharamaceuticals and cosmetics. Concentrations are generally below those used as antiseptics or disinfectants because they are used as inhibitory agents rather than as agents to produce rapid bacterial inactivation. Biocides in the form of antiseptics and occasionally as skin disinfectants are also applied topically.31Larson E Hygiene of the skin: when is clean too clean?.Emerging Infect Dis. 2001; 7: 225-230Crossref PubMed Scopus (78) Google Scholar This includes dermatologic application in the therapy of burn and wound infections. Antibacterial agents used for this purpose include silver compounds, chlorhexidine salts, QACs, benzoyl peroxide, and povidone-iodine. Bacterial resistance to some of these agents may arise32Bowler PG Duerden BI Armstrong DG Wound microbiology and associated approaches to wound management.Clin Microbiol Rev. 2001; 14: 244-269Crossref PubMed Scopus (1234) Google Scholar and organisms resistant to antibiotics may be selected.33Eady EA Farmery MR Ross JI Cove JH Cunliffe WJ Effects of benzoyl peroxide and erythromycin alone and in combination against antibiotic-sensitive and -resistant skin bacteria from skin patients.Br J Dermatol. 1994; 131: 331-336Crossref PubMed Scopus (130) Google Scholar, 34Farmery MR Jones CE Eady EA Cove JH Cunliffe WJ In vitro activity of azeleic acid, benzoyl peroxide and zinc acetate against antibiotic-resistant propionibacteria from acne patients.Br J Dermatol Treat. 1994; 5: 63-65Crossref Scopus (25) Google Scholar, 35Cook N Methicillin-resistant Staphylococcus aureus versus the burn patient.Burns. 1998; 24: 91-98Abstract Full Text PDF PubMed Scopus (87) Google Scholar, 36Douglas MW Mulholland K Denger V Gottlieb T Multi-drug resistant Pseudomonas aeruginosa outbreak in a burns unit— an infection control study.Burns. 2001; 27: 131-135Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar This aspect has not been researched adequately. Residues on the skin could be responsible for applying a selective pressure on bacteria, but there is no evidence that this is a problem in the clinical context. Benzoyl peroxide is likely to have a broadly based mechanism of action so that bacteria resistant to its action would not be expected to develop. Medicines containing PADs are taken or applied by patients throughout the world. Some PADs are prescription-only formulations and others are purchased as over-the-counter products. PADs may be administered orally, intravenously, or topically. A surprising number of PADs possess antimicrobial activity,3Russell AD Pharmacologically active drugs other than antibiotics that possess or enhance antimicrobial activity.Hosp Prescriber Europe. 2002; : 37-40Google Scholar although this is not the primary purpose for which they are used. Some PADs have effects on microbial cells that resemble those of antibiotics. For example, chlorpromazine and ampicillin both induce filaments in E coli.37Amaral L Lorian V Effects of chlorpromazine on the envelope proteins of Escherichia coli.Antimicrob Ag Chemother. 1991; 35: 1923-1924Crossref PubMed Scopus (43) Google Scholar A degree of cross-resistance between PADs and antibiotics has been found; however, this has been poorly researched. For instance, there is one report38Dastidar G Ganguly M Chakrabarty AN Bhattacharya S Cross-resistance among non-antibiotics with respect to themselves and antibiotics.in: Non-antibiotics : a new class of unrecognised antimicrobics. National Institute of Science Communication (CSIR), New Delhi1998: 201-208Google Scholar that demonstrates that exposure of bacteria to some PADs resulted in the development of increased resistance to nonselecting antibiotics including penicillins, aminoglycosides, chloramphenicol, and tetracycline. This may be a contributory factor clinically. PADs are eliminated from the body either partially (eg, as a metabolite) or wholly unchanged. Added to the probably vast volume of medicine that is discarded unused, a situation could arise whereby the environment is continuously changing (although possibly imperceptibly) in such a manner that microbes are subjected to an ecosystem that acts as a form of selective process. The possibility of such an event needs to be explored. After all, some drugs, notably salicylic acid and acetylsalicylic acid (aspirin), can switch on efflux pumps.39Poole K Overcoming antimicrobial resistance by targeting resistance mechanisms.J Pharm Pharmacol. 2001; 53: 283-294Crossref PubMed Scopus (96) Google Scholar Bacteria may develop resistance to biocides, although it is puzzling that, despite repeated attempts to increase resistance, some strains of bacteria retain a high degree of biocide sensitivity. It is not known whether this reflects the absence of an active efflux system, the inability to switch on appropriate genes, the lack of outer membrane changes, or the fact that target sites remain unaltered. Far too little attention has been paid to this issue. Likewise, there is little published research about the possible role played by biocide residues (present on inanimate objects or skin or associated with teeth) acting as a selective influence for antibiotic-resistant bacteria. The small amount of published research suggests that there could be a possible link between bacterial resistance to PADs and to antibiotics. Some PADs and antibiotics ostensibly share common target sites so that resistance to the former might also be shown to the latter. Nevertheless, the current evidence suggests that it is the widespread use of antibiotics in animal and human medicine and the incorporation of antibiotics in animal feeds that are primarily responsible for the alarming increase in bacterial resistance to these chemotherapeutic drugs. The future control of antibiotic-resistant bacteria depends on adequate surveillance, improved prescribing, and more responsible use, as well as the development of new chemotherapeutic drugs.40Andremont A The future control of bacterial resistance to antimicrobial agents.Am J Infect Control. 2001; 29: 256-258Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar
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