sou · GLB3132d3 · 1998-01-01 00:00:00 — Some authors have investigated the possible effects of orally administered bacitracin on the immune response to certain forms of challenge (Harmon ET AL , 1973; Wasinska, 1980). Harmon and co-workers (1973) compared non- medicated pigs to pigs fed bacitracin at a concentration of 55 ppm during various lengths of periods. After repeated intraperitoneal injections of sheep red blood cells or phenolised Salmonella Pullorum, serum antibody titers were tested by agglutination and hemagglutination. The authors stated that the immunological response to sheep erythrocytes was affected by bacitracin in the feed, whereas the antibody response to Salmonella Pullorum was significantly enhanced by medicated feed. Various explanations for this were discussed in the paper. Wasinska (1980) investigated the antibody response and resistance to infection after vaccinating pigs against erysipelas, colibacillosis and swine In addition, non-vaccinated controls were included in the study. Pigs were fed bacitracin at a concentration of 70 ppm for six months, and compared to pigs fed no antimicrobial. It was concluded that the supplementation of feed with bacitracin did not exert any negative effects on the antibody response in vaccinated pigs, nor did it decrease the effectiveness of immunisation, as determined by experimental infection. B.6 Impact of resistance on animal and human health Increased resistance to bacitracin in clostridia and enterococci could lead to therapeutic failures when bacitracin is used for the treatment of infections with these organisms in animals and humans. Without further information about the extent of the therapeutic use of bacitracin, the impact on human and animal health of such incidents is impossible to assess. B.7 Other effects on the microflora B.7.1 Effects on salmonella colonisation Only a few published studies investigating the association between salmonella colonisation of the gut and bacitracin in the feed have been found (Nurmi and Rantala, 1974; and , 1975; and , 1980; and , 1981; , 1991; Manning ET AL , 1994). All use poultry as the experimental animal species and in-feed bacitracin at the concentrations used for growth promotion. Unfortunately, like other studies in this area, most of these suffer from weaknesses in study design and the results are often inconclusive and inconsistent. The results in the study by Manning and co-workers (1994) indicated that in chickens fed 490 ppm bacitracin, a significantly (p<0.05) larger proportion were infected with salmonella at the end of the experiment, as compared to non-medicated All animals were kept on used , and challenged with 106 organisms of 3ALMONELLA Enteritidis. The concentration of bacitracin used was considerably higher than what is used for growth promotion, and the selective culture technique used appears to be based on visual examination only. This makes the results difficult to evaluate. In the study by and co-workers (1991) bacitracin was given at a concentration of 50 ppm to groups of chickens, with chickens receiving no antimicrobial in the feed serving as controls. Another factor in the experiment was treatment with bacterial flora from 12-week old Specific Pathogen Free-chicks (competitive exclusion, CE). All birds were challenged with 104-105 organisms of 3ALMONELLA Typhimurium. Half of the animals were killed on day 3 for bacteriological examination of the caeca. The rest were killed and examined on day 6. The results show a small increase in the amount of salmonella shed by medicated birds, but a slight decrease when the medicated birds were also given CE. However, in the groups not receiving CE treatment, the proportion of salmonella positive birds was in both medicated and non-medicated groups. Thus, no conclusions on the influence on the prevalence of colonisation can be drawn and the study period of 6 days is too short for conclusions about differences in excretion time. The bacterial counts are presented as log means for each group, so it is not possible to determine whether the differences are caused by changes in the amount of excretion in just a few individuals or if it is an overall effect. Another minor weakness is the selective method used for salmonella isolation where the recording of salmonella was based on visual inspection and without further confirmation. Nurmi and Rantala (1974) compared the re-isolation of 3ALMONELLA Infantis, after experimental infection, from the caeca of non-medicated birds and of birds fed 10 ppm or 20 ppm bacitracin with and without concurrent treatment with CE. The results indicate a decrease in the amount and prevalence of 3ALMONELLA shedding in birds receiving bacitracin, as compared to non-medicated birds. The feeding of bacitracin did not inhibit the positive effect of the CE treatment. The groups were very small and the percentage of salmonella shedding in the non-medicated control group varied between experiments making interpretation of the results difficult. and reported two studies including bacitracin (and , 1975; and , 1980). In the first (and , 1975) birds were fed bacitracin at concentrations of either 10 or 100 ppm and inoculated with 3. Faecal samples were compared with samples from similarly infected non-medicated birds. It was found that the feeding of bacitracin only slightly increased the prevalence and length of salmonella shedding. In another study by the same authors (and , 1980) chickens were challenged with five different salmonella serovars (3 3 Infantis 3 Oranienburg, 3 Senftenberg and 3 Typhimurium). The percentage of re-isolation of the challenge organism from faeces and caecal contents of birds fed bacitracin (10 ppm) was compared to that of non- medicated birds until 50 days of age. The study also included a comparison of salmonella infection in medicated and non-medicated birds of four different breeds fed four different feed mixes. The results indicate that bacitracin at worst slightly favours salmonella colonisation. No remarkable differences were noted between the various bacterial strains used for challenge, or between different feed mixes and different poultry breeds. The isolation procedure used in this study includes selective culturing and identification by visual examination only. As in the study by and co-workers, it cannot be excluded that some coliforms can be mistaken for salmonella. Since one cannot be sure that this error would be the same in all groups, there is a slight risk that this may have affected the outcome of the study. and (1981) used ducks as experimental animals. Two concentrations of in-feed bacitracin were tested, 10 and 100 ppm, and medicated birds were compared to non-medicated birds. The challenge organism was 3ALMONELLA Typhimurium, 107-1010 organisms per bird, and cloacal swabs were taken throughout the experiment. The results did not show a definite trend. In two experiments there was difference between the bacitracin-medicated groups and the controls and in two other the samples from medicated birds yielded significantly (p<0.05) more salmonellae than the untreated animals. However, the groups were small and the variability between the control groups in the various experiments regarding re-isolation of the infecting organism make the results difficult to evaluate. Bailey and co-workers (1988) investigated resistance to salmonella infection in broilers fed various . However, all groups of animals received combinations of , together with competitive exclusion microflora, and therefore the effect of a single antibiotic (in this case, bacitracin) could not be determined. No studies investigating the effect of bacitracin on the infectious dose necessary to achieve of salmonella colonisation have been found, nor any studies investigating dose-response relationships or the effect on prevalence of salmonella in animal products. B.7.2 Other enteric pathogens No studies on the possible effects on colonisation by other enteric pathogens have been found. Bacitracin is highly nephrotoxic when administered parenterally (1993), but as it is poorly absorbed from the gut, no adverse effects would be expected after oral administration. B.8.1 Adverse effects in ruminants Bacitracin is used as a feed additive in calves, lambs and kids. Adult cattle, however, react adversely to bacitracin in the feed. Sudden milk drops, in herds fed concentrate feed contaminated with bacitracin at the feed mill, have been reported (Woodger, 1979). Higher mortality and decreased effectiveness of antimicrobial therapy was noticed in calves fed 50 ppm bacitracin in the milkreplacement in a study by and (1973). It is discussed whether resistant bacteria or immunosuppression in the medicated animals were the cause, but no investigations to determine the cause were included in the article. In sheep, biotransformation of plant toxins, that occurs in the rumen of some alkaloid-resistant sheep, can be impaired by oral administration of bacitracin (Wachenheim ET AL , 1992). No conclusions can be based on these few reports, but there seems to be cause for further investigations into the possible risks for adverse effects when using bacitracin in ruminants. Allergic reactions to bacitracin are frequently reported (and , 1987; Grandinetti and , 1990; Knowles and Shear, 1995). Both anaphylaxis, eczema, urticaria and delayed reactions may be seen (and , 1987). Most reports concern patients treated with bacitracin ointment. It has been stated that bacitracin is the topical agent most commonly implicated in anaphylactic reactions (and , 1987). Considering this, it is somewhat surprising that no reports have been found on allergic reactions in people who come in contact with bacitracin professionally, such as farmers, hospital personnel and people working in the pharmaceutical industry. Like for other , if bacitracin reduces the amount of feed consumed per kg weight gain in the target animal, it would also be expected to reduce the amount of nitrogen output per kg weight gain. of ingested bacitracin is absorbed and most is excreted unmetabolised in the faeces (Donoso ET AL , 1970; Froyshov ET AL , 1986). Gavalchin and (1994) studied the degradation of bacitracin in sandy loam from a non-agricultural area, mixed with chicken faeces, at different temperatures. Sterile soil-faeces mixtures were used as controls. At , inactivation of bacitracin occurred rapidly, only remained after 30 days. At , however, of the initial concentration was still present after 30 days of incubation. The half life for bacitracin at 4 and was calculated to 12.5 and 22 days, respectively. The inverse temperature relation of the degradation was tentatively explained by the isolation of a psycrotrophic pseudomonad capable of degrading bacitracin from the soil-faeces matrix. Similar results have been obtained earlier by Jagnow (1978) reporting half life in soil of 22,5 days at and 12 days at . Vogtmann and co-workers (1978) reported that bacitracin had no adverse effects on composting but detected some depression of plant growth when fresh manure containing bacitracin was used as a fertiliser. Bacitracin has a bactericidal effect mainly on gram-positive bacteria, by inhibiting the formation of bacterial cell wall peptidoglycan. It is used, albeit not to any large extent, in both human and animal therapy. Lately it has been increasingly used for the treatment of vancomycin-resistant enterococci in humans. In-feed bacitracin affects the antimicrobial resistance of the intestinal microflora, mainly in E. faecium but possibly also in other species. Data available on colonisation by enteric pathogens in animals fed bacitracin is too inconsistent and too scarce to form the basis of any firm conclusions about the effects of bacitracin. Bacitracin administered at growth promoting concentrations has prophylactic and therapeutic effects on necrotic enteritis in poultry. Allergic reactions to bacitracin are documented in humans undergoing bacitracin treatment. People who are exposed to the substance on a daily basis may be at risk of being sensitised. Bacitracin is degraded in soil. The environmental degradation appears to be inversely related to soil temperature. In conclusion, available information is to scarce for an assessment of the possible risks of bacitracin usage to human and animal health. Bacitracin usage does not appear to represent any substantial danger to the environment. % AND (OBBS * . *R , 1995. Induction of vancomycin resistance in Enterococcus faecium by non-glycopeptide antibiotics. &%-3 -ICROBIOLOGY ,ETTERS "AILEY * 3 "LANKENSHIP , # 3TERN . * #OX . ! AND -C(AN & , 1988. Effect og anticoccidial and antimicrobial feed additives on prevention of Salmonella colonization of chicks treated with anaerobic cultures of chicken faeces. !VIAN $ISEASES 324-329. "% - -EAD ' # )MPEY # 3 AND !DAMS " 7 , 1978. The effect of dietary bacitracin on the incidence of Streptococcus faecalis subspecies liquefaciens and related streptococci in the intestines of young chicks. "RITISH 0OULTRY 3CIENCE "9 %NDO + AND -ITSUOKA 4 , 1988. Isolation of fecal Clostridium perfringens from broiler chickens and their susceptibility to eight antimicrobial agents for growth promotion. *APANESE *OURNAL OF 6ETERINARY 3CIENCE 832-834. #" $ .ORTON 0 * %UBANKS 7 .ICK ( 3 AND !LLEN # - , 1993. Amplification of the bacA gene confers bacitracin resistance to Escherichia coli. *OURNAL OF "ACTERIOLOGY 3784-3789. #APUTO ' - 7EITEKAMP - 2 "ACON ! % 2 AND 7HITENER # , 1994. difficile infection: a common clinical problem for the general internist. *OURNAL OF 'ENERAL )NTERNAL -EDICINE 528-533. #2 * AND 7ILKINS 4 $ , 1991. )N susceptibility of rabbit strains of #LOSTRIDIUM SPIROFORME to antimicrobial agents. 6ETERINARY -ICROBIOLOLOGY 391- 397. #HIA * + 3 .AKATA - - 0ARK 3 3 ,EWIS 2 0 AND -C+EE " , 1995. Use of bacitracin therapy for infection due to vancomycin-resistant %NTEROCOCCUS FAECIUM. #LINICAL )NFECTIOUS $ISEASES 1520. $!.-!0, 1997. Consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in . Sensitivity of staphylococci from farm animals to antibacterial agents used for growth promotion and therapy - a ten year study. !NNALES DE 2ECHERCHES 6ETERINAIRES 399-408. $AUBE ' (OMMEZ * AND (AESEBROUCK & , 1993. In vitro susceptibility of #LOSTRIDIUM PERFRINGENS isolated from farm animals to growth- enhancing antibiotics. *OURNAL OF !PPLIED "ACTERIOLOGY 55-57. $ONOSO * #RAIG ' / AND "2 3 , 1970. The distribution and excretion of zinc bacitracin-14C in rats and swine. 4OXICOLOGY AND !PPLIED 0HARMACOLOGY 366- AND $EVRIESE , ! Susceptibility of fecal streptococci of poultry origin to nine growth-promoting agents. !PPLIED AND %NVIRONMENTAL -ICROBIOLOGY AND $EVRIESE , ! Observations on the IN sensitivity and resistance of positive intestinal bacteria of farm animals to growth promoting antimicrobial agents. *OURNAL OF !PPLIED "ACTERIOLOGY 117-123. %VERETT 3 , +OWALSKI 2 0 +ARENCHAK , - ,ANDSITTEL $ $AY 2 AND 'ORDON 9 * , 1995. An IN comparison of the susceptibilities of bacterial isolates from patients with conjunctivitis and blepharitis to newer and established topical antibiotics. #ORNEA 382-387. &ROYSHOV / 0EDERSEN 3 AND (+ , 1986. Absorption, metabolism and excretion of zinc 14C-bacitracin fed to young pigs. *OURNAL OF !NIMAL 0HYSIOLOGY AND !NIMAL &UKUDA 9 4SUJI 4 &UJITA 4 9AMAMOTO ! AND -URANISHI 3 , 1995. Susceptibility of insulin to proteolysis in rat lung homogenate and its protection from proteolysis by various protease inhibitors. "IOL 0HARM "891-894. 'AVALCHIN * AND +ATZ , 1994. The persistence of fecal-borne antibiotics in soil. *OURNAL OF THE !SSOCIATION OF /FFICIAL !NALYTICAL #HEMISTS 481-485. '" , 1981. Factors influencing multiple resistance in enteric bacteria in animals. )N PROCEEDINGS OF 4EN YEARS ON FROM 3WANN 5th-6th October, . 'RANDINETTI 0 * AND &OWLER * & *R , 1990. Simultaneous contact allergy to neomycin, bacitracin, and polymyxin. *OURNAL OF !MERICAN !CADEMY OF $ERMATOLOGY 646- (ARMON " ' *ENSEN ! ( AND "AKER $ ( , 1973. Influence of dietary antibiotics on antibody response to specific antigens. *OURNAL OF !NIMAL 3CIENCE 1155-1158. (,ALANDE & L (OSPITALIER 2 3ALVAT ' AND "ENNEJEAN ' , 1991. of four antibiotic additives on the Salmonella contamination of chicks protected by an adult caecal flora. !VIAN 0ATHOLOGY 577-584. *AGNOW ' , 1978. Microbial degradation of the feed antibiotics zinc-bacitracin, flavophospholipol, spiramycin, and of tetracycline in chicken manure, damp-stored and mixed with soil. ,ANDWIRTSCHAFTLICHE &ORSCHUNG 3ONDERHEFT 227-234. *ENKINS % - AND &$ , ))), 1985. Comparing carbadox and bacitracin in the prevention of clinical signs of swine dysentery. 6ETERINARY -EDICINE 90, 92-94. *ONSON ' AND *ACOBSSON , 1973. Foderantibiotikas inverkan på kalvdödlighet. 3VENSK 6ETERIN¤RTIDNING 17-22. +ATZ " % AND &ISHER ! ! Bacitracin: a unique topical antibiotic sensitizer. *OURNAL OF !MERICAN !CADEMY OF $ERMATOLOGY 1016-1024. (INTON - AND ,INTON ! ( , 1988. The effect of growth-promoting antibiotics on the faecal enterococci of healthy young chickens. *OURNAL OF !PPLIED "ACTERIOLOGY 57-64. +NOWLES 3 2 AND 3HEAR . ( , 1995. Anaphylaxis from bacitracin and polymyxin B (Polysporin) ointment. )NTERNATIONAL *OURNAL OF $ERMATOLOGY 572-573. +ROGSTAD $ * AND 0ARGWETTE ! 2 , 1980. Defective killing of enterococci: a common property of antimicrobial agents acting on the cell wall. !NTIMICROBIAL !GENTS AND #HEMOTHERAPY 965-8. +YRIAKIS 3 # 4SINAS ! ,EKKAS 3 3ARRIS + AND "OURTZIHATZOPOULOU % , 1996. Clinical evaluation of in feed zinc bacitracin for the control of porcine intestinal adenomatosis in growing/fattening pigs. 6ETERINARY 2ECORD 489-492. ,AI - ( AND +IRSCH $ 2 , 1996. Induction signals for vancomycin resistance encoded by the vanA gene cluster in Enterococcus faecium. !NTIMICROBIAL !GENTS AND #HEMOTHERAPY 1645-1648. ,ATOUR 0 " AND "ARNUM $ ! Use of ducks as a model to study the effect of antibiotics in feed on the fecal shedding of 3ALMONELLA. !MERICAN *OURNAL OF 6ETERINARY 2ESEARCH 2105-2108. ( (INTON - ( AND !L #HALABY : ! - , 1985. resistance in enterococci consequent upon feeding growth promoters against gram-positive bacteria. *OURNAL OF 6ETERINARY 0HARMACOLOGY AND 4HERAPEUTICS -ANNING * ' (ARGIS " - (INTON ! *R #ORRIER $ % $E,OACH * 2 AND ## 2 , 1994. Effect of selected antibiotics and anticoccidials on 3ALMONELLA ENTERITIDIS cecal colonization and organ invasion in Leghorn chicks. -APLE 0 ! (-ILLER * - AND "RUMFITT 7 , 1989. 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Bacillus licheniformis bacitracin-resistance ABC transporter: relationship to mammalian multidrug resistance. -OLECULAR -ICROBIOLOGY 969- 0OLLOCK 4 * 4HORNE , 9AMAZAKI - -IKOLAJCZAK - * AND !RMENTROUT 2 7 , Mechanism of bacitracin resistance in gram-negative bacteria that synthesize exopolysaccharides. *OURNAL OF "ACTERIOL 6229-6237 0RESCOTT * & AND "AGGOT * $ EDS , 1993. !NTIMICROBIAL THERAPY IN VETERINARY MEDICINE 2nd ed. 0RESCOTT * & 3IVENDRA 2 AND "ARNUM $ ! The use of bacitracin in the prevention and treatment of experimentally-induced necrotic enteritis in the chicken. #ANADIAN 6ETERINARY *OURNAL 181-183. 1UINLAN ' * AND 'UTTERIDGE * - , 1989. Bacitracin and a bacitracin-zinc complex damage DNA and carbohydrate in the presence of iron and copper salts. &REE 2ADICALS 2ESEARCH #OMMUNATIONS 37-44. 3ANDERMANN *R ( AND 3TROMINGER * , , 1971. C55-Isoprenoid alcohol phosphokinase: an extremely hydrophobic protein from the bacterial membrane. .ATIONAL !CADEMY OF 3CIENCES 53! 3MITH 7 ( AND 4UCKER * & , 1975. The effect of feeding diets containing permitted antibiotics on the faecal excretion of 3ALMONELLA TYPHIMURIUM by experimentally infected chickens. *OURNAL OF (YGIENE 293-301. 3MITH 7 ( AND 4UCKER * & , 1980. Further observations on the effect of feeding diets containing avoparcin, bacitracin and sodium arsenilate on the colonization of the alimentary tract of poultry by salmonella organisms. *OURNAL OF (YGIENE 137- 3TUART * ' AND &ERRETTI * * , 1978. Genetic analysis of antibiotic resistance in *OURNAL OF "ACTERIOLOGY 852-859. 3TUTZ - 7 *OHNSON 3 , AND *UDITH & 2 , 1983. Effects of diet and bacitracin on growth, feed efficiency, and populations of #LOSTRIDIUM PERFRINGENS in the intestine of broiler chicks. 0OULTRY 3CIENCE 1619-1625. AND :ANATI % , 1970. Multiple antibiotic resistance in a bacterium with suppressed autolytic system. 7ACHENHEIM $ % "LYTHE , , AND #RAIG ! - , 1992. Effect of antibacterial agents on in vitro ovine ruminal biotransformation of the hepatotoxic pyrrolizidine alkaloid . !PPLIED AND %NVIRONMENTAL -ICROBIOLOGY 2559-2564. 7ALTON * 2 , 1978. The effect of zinc bacitracin on the susceptibility of selected gram negative and gram positive bacteria to therapeutic antibiotics. :ENTRALBLATT F¼R 6ETERIN¤RMEDIZINE 2EIHE " 329-331. 7ALTON * 2 , 1984. The effect of dietary zinc bacitracin on the resistance status of intestinal %SCHERICHIA COLI and enterococci from broiler chickens. :ENTRALBLATT F¼R 6ETERIN¤RMEDIZINE 2EIHE " 1-8. 7ALTON * 2 AND 7HEELER * % , 1987. Loss of resistance to the tetracyclines from porcine %SCHERICHIA COLI in contact with dietary bacitracin methylene disalicylate. :ENTRALBLATT F¼R 6ETERIN¤RMEDIZINE 2EIHE " 161-164. 7ASINSKA " , 1980. Effect of prolonged feeding of mixtures supplemented with Zn- bactracin and ronidazole on specific immunity in pigs after their vaccination against swine fever, erysipelas and colibacillosis. )N PROCEEDINGS OF TH )063 #ONGRESS. 7ICKER $ , )SGRIGG 7 . AND 4RAMMEL * ( , 1977. The control and prevention of necrotic enteritis in broilers with zinc bacitracin. 0OULTRY 3CIENCE 1229-1231. 6OGTMANN ( /BRIST 7 (AUSER + 0FIRTER ( 0 AND !UGSTBURGER & , 1978. Composting and plant growth: use of chicken manure containing antibiotics. #OMPOST 3CIENCE ,AND 5TILIZATION 22-25. 7OODGER ' * ! Antibiotic contamination of compound cattle feed. 6ETERINARY 2ECORD 173. Flavomycin, also known as flavophospholipol, bambermycins or moenomycin, is a phosphorus-containing glycolipid, mostly obtained as complexes of very similar components. It is produced by a group of 3TREPTOMYCES SPP, including 3 BAMBERGENSIS, 3 GHANAENSIS, 3 GEYSIRENSIS and 3 EDERENSIS . At the moment it is used for growth promoting purposes only and is not included in any therapeutic drug either in human or veterinary medicine. Flavomycin inhibits cell wall synthesis, mainly in gram-positive bacteria. Concentrations used for growth promotion are between 1 and 20 ppm for swine, 0.5-20 ppm for poultry, 2-4 ppm for fur animals, 2-16 ppm for cattle and 2-4 ppm for rabbits. Flavomycin is not absorbed to any great extent after oral administration. When parenterally administrated it is excreted in the urine at a very slow rate and has, therefore, a prolonged activity in blood. The antimicrobial activity is reduced by serum and is optimal at pH - 6.5. (Huber, 1979) C.2 Mode of action and resistance mechanisms Flavomycin exerts its effect by inhibiting bacterial cell wall synthesis. The transglycosylation reaction necessary for peptidoglycan synthesis, that is catalysed by the penicillin-binding protein PBP 1b, is impaired in the presence of flavomycin (van Heijenoort ET AL , 1987, Huber, 1979 #339).