Effect of a Metaphylactic Pulse Dosing In-Feed Antimicrobial Strategy on ﬁnishing Pig Health and Performance Don Walter, DVM; J

Original research The effect of a metaphylactic pulse dosing in-feed antimicrobial strategy on ﬁnishing pig health and performance Don Walter, DVM; J. Tyler Holck DVM, MS, MBA; Steve Sornsen, DVM, MS; Chad Hagen, PhD; Isabel Turney Harris, DVM, PhD

Summary antimicrobials may improve growth perfor- we are unaware of any data supporting this Purpose: To compare the effect of meta- mance while permitting exposure to and specific hypothesized immune mechanism. phylactic pulse dosing with either a con- stimulation of active immunity against en- The present study was conducted to deter- tinuous-feed antimicrobial medication demic mycoplasmal pneumonia. mine strategy or no feed medication on finishing pig health and performance. Keywords: swine, pulse dosing, metaphy- • whether in-feed pulse dosing was as laxis, antibiotic, feed medication, tiamulin, effective in controlling the clinical and Methods: Barrows (n = 1092) from a herd chlortetracycline, serology, Mycoplasma growth-limiting effects of respiratory naturally infected with endemic respiratory hyopneumoniae. disease as continuous in-feed medica- pathogens were assigned by pen to one of tion; and three treatment groups: a “Continuous” Received: May 12, 1999 • whether pulse dosing allowed pigs to group that received alternating doses of Accepted: December 15, 1999 mount an immune response to natural tiamulin plus chlortetracycline on weeks exposure to respiratory pathogens. 2,4,7,10, and 13 interspersed with a re- he effectiveness of tiamulin or the duced concentration of chlortetracycline tetracycline derivatives in control- alone during weeks 3,5,6,8,9,11, and 12; a Materials and methods ling porcine bacterial and myco- This 16-week study was conducted in a “Pulse” group, which received in-feed pulse T plasmal pneumonia is markedly enhanced commercial, single-source, age-segregated dosing with tiamulin plus chlortetracycline when the two antibiotics are given concur- sow farm/nursery/finisher (three-site sys- only in weeks 2,4,7,10, and 13 with no rently.1–6 Nontraditional medication strate- tem) in the Midwest. The rate and effi- medication during the other study weeks; gies, such as pulse dosing with this combi- ciency of weight gain in this herd was typi- or nonmedicated Controls that received nation of antibiotics, have been shown to cally depressed approximately 8–12 weeks nonmedicated feed throughout the trial. be effective for controlling a variety of pig after pigs were placed into finishing. Feed Growth performance, survivability, and diseases.6–9 Pulse dosing is the practice of consumption, however, remained close to seroconversion to various pathogens were providing a limited number of short-term normal during this period. Diagnostic evi- measured. medication “pulses” at therapeutic doses, dence of infectious respiratory disease due Results: Both metaphylactic Pulse and separated by nonmedicated intervals. Pulse to viral, mycoplasmal, and bacterial patho- Continuous medication strategies im- doses may vary in number and duration gens was common but inconsistent. proved growth rate, feed intake, feed con- depending upon the circumstances. version efficiency, and survivability in the Treatments Pulse dosing is predicated upon the hy- presence of naturally occurring mycoplas- One thousand one hundred and four pothesis that intermittent therapeutic anti- mal and viral (swine influenza virus, por- (1104) 11-week-old barrows from a single microbial medication allows natural expo- cine reproductive and respiratory syndrome source were placed in the building over a 2- sure to endemic pathogens, but will virus) respiratory disease compared to Con- day period in August 1997. On the first abbreviate the infection incubation process trols. Pulse but not Continuous medication day after placement, all pigs were individu- before a costly clinical disease outbreak can permitted sufficient natural exposure to ally weighed and identified with an eartag. occur. Allowing natural exposure to stimu- Mycoplasma hyopneumoniae to stimulate One thousand ninety-two (1092) pigs were late acquired active immunity provides ani- active humoral immunity. selected for the study (one dead pig and 11 mals with long-term protection (e.g., to pigs with extreme high or low weights were Implications: Both feed medication strate- slaughter or entry into the breeding herd) excluded from allotment). gies significantly improved performance once the short-term protection of medica- versus nonmedicated controls. Metaphy- tion is discontinued. While the rationale Selected pigs were blocked by weight and lactic pulse dosing with appropriate behind pulse dosing is intuitively logical, randomly allotted to pens within blocks on the day after the initial weighing. Pens DW: Boehringer Ingelheim Vetmedica Inc., 1051 Barrington Road, Iowa City, Iowa 52245; JTH: within blocks were randomly assigned to Novartis Animal Health US, Inc. SS: Seaboard Farms; CH, Iowa Select Farms; ITH: Iowa State one of the following treatments: University •“Continuous” group, which received This article is available online at http://www.aasp.org/shap.html. tiamulin hydrogen fumarate ™ Walter D, Holck JT, Sornsen S et al. The effect of a metaphylactic pulse dosing in-feed antimicrobial (Denagard 10 Medicated Premix, strategy on finishing pig health and performance. Swine Health Prod. 2000;8(2):65–71. Boehringer Ingelheim Vetmedica Inc.; Swine Health and Production — Volume 8, Number 2 65 St. Joseph, Missouri) at 35 g per ton approximately 0.69 m2 (7.3 sq. ft) per pig. fluorescent antibody (IFA) assay during weeks 2, 4, 7, 10, and 13 of (performed by Boehringer Ingelheim the study (Table 1). During these Growth Vetmedica); and weeks, barrows also received continu- Pigs were individually weighed at allotment • transmissible gastroenteritis virus ous in-feed chlortetracycline hydro- and at the end of the study (16 weeks post- hemagglutination-inhibition assay chloride (HCl)(AUREOMYCIN® 90 allotment). Pen weights were collected by (TGEV HI) (performed by Iowa State Granular Premix, Roche Vitamins moving the entire pen of pigs onto a pen University Veterinary Diagnostic Inc.; Parsippany, New Jersey) at a dose scale located at the end of the barn on a Laboratory). of 22 mg per kg (10 mg per lb) biweekly basis. Pigs were not vaccinated for any of the bodyweight (BW) daily. During weeks monitored diseases. In conformity with 3, 5, 6, 8, 9, 11, and 12, chlortetracy- Feed standard site procedure, affected pigs were cline HCl was added to the feed daily Feed was offered ad libitum to all pigs in injected with tylosin during weeks 1–6 of at a rate of 100 g per ton. Nonmedi- all pens. Feed was delivered to each pen the study; all injections of tylosin were dis- cated feed was offered during weeks 1 feeder using a Mosdal feed cart and the continued by week 6 of the study. During and 14–16. weight of feed delivered to each feeder was weeks 7–14, individual pigs affected with • “Pulse” group, which received recorded. Identical diets were offered to all respiratory diseases were injected with pen- concurrent feed medication of three treatment groups at all times during icillin derivatives. tiamulin hydrogen fumarate at 35 g the study with the exception of the added per ton plus chlortetracycline HCl at a medication (Table 1). Diet formulations Statistical analysis dose of 22 mg per kg (10 mg per lb) were adjusted on a biweekly basis, and re- Performance data were analyzed using re- BW daily during weeks 2, 4, 7, 10, maining feed was removed, weighed, and peated-measures ANOVA techniques using and 13 as a ‘pulse’ medication (Table subtracted from the amount of feed deliv- the pen as the experimental unit for all 1). Nonmedicated feed was provided ered to determine net feed disappearance. production data. χ2 analysis was used to during the remaining weeks (1, 3, 5, assess mortality data. Serologic data were 6, 8, 9, 11, 12, and 14–16); or Health evaluated using statistical process control • nonmedicated “Control” group, which Two pigs from each pen were randomly methods10,11 to estimate the timing of se- received nonmedicated feed through- selected and serially bled biweekly begin- rologic changes. out the study. ning on allotment day. The sera were stored until testing at -70°C. Samples were Economic analysis Housing tested using Potential economic benefits of antibiotic The research barn was a tunnel-ventilated • porcine respiratory and reproductive inclusion in the feed were analyzed with a finishing facility with natural ventilation syndrome enzyme-linked immuno- partial budget.12–15 Partial budget analysis capability. It contained 44 pens, each mea- sorbent assay (Herd Check™ PRRSV provides a powerful tool to assess the cost suring 3 × 6 m (10 × 19 feet) and equip- Antibody Test Kit, IDEXX Corp.; effectiveness of therapeutic interventions.16 ped with one five-hole dry feeder and two Westbrook, Maine), It requires that only those factors affected nipple waterers. The floor was totally slat- • Mycoplasma hyopneumoniae Tween 20 by the treatment be included in the analy- ted concrete with under-slat scrapers for ELISA (performed by Boehringer sis, such that: manure removal. The barn was managed in Ingelheim Vetmedica), an all-in–all-out (AIAO) manner and was Net benefit or loss of an intervention = • swine influenza hemagglutination- one of 10 barns on a continuous-flow fin- associated changes in revenues – inhibition assay (SIV HI) (performed ishing site. associated changes in cost by Iowa State University Veterinary Two replicate pens of pigs for each of three Diagnostic Laboratory), Because in this study we determined that treatment groups were represented within • Salmonella mix-ELISA (Danish mix- final bodyweight, feed intake, and mortal- each of seven blocks. A total of 42 pens ELISA procedure performed by ity differed significantly between the Con- were included in the study, with 26 pigs Boehringer Ingelheim Vetmedica), trol and the two treatment groups, but not per pen for an initial stocking density of • Lawsonia intracellularis indirect- between the Pulse and Continuous groups,

Table 1: Study timeline

Week Treatment 12345678901112131415161 Continuous – TCTCCTCCTCCT––– Pulse – T – T ––T ––T ––T ––– Control ––––––––––––––––

T Tiamulin + CTC C CTC 100 – No treatment 66 Swine Health and Production — March and April, 2000 we compared the average of the two treat- Figure 1: Comparison of production parameters by treatment ment groups to the nonmedicated control, P but did not compare between different 300 aa<.0001 2.0 aaP=.02 255.9 255.2 248.1b 1.7 1.69 b antibiotic regimes. Accordingly, ﬁnal 1.55 1.5 bodyweight, feed intake, and mortality 200 were included in an economic model con- 1.0 sistent with the study design, which as-

100 ADG (lb) sumed constant growth over a 16-week 0.5

period, such that: Final weights (lb) 0 0 Net benefit or loss per group = Continuous Pulse Control Continuous Pulse Control (increase in lb of hogs marketed × a market price of hogs) – a 4.95 P=.004 4.98 4.73b × 4 P=.02 5 (increase in lb of feed consumed cost of feed) – aab 2.94 2.93 3.05 treatment cost 3 4 3 Dividing this sum by the initial number of 2 animals in the group yields the quantity F:G 2 net benefit or loss per head. Although the 1 1 treatment costs in the Continuous group 0 Feed intake (lb) 0 were higher than those in the Pulse group Continuous Pulse Control Continuous Pulse Control because the Continuous group received 7 additional weeks of chlortetracycline at 100 a, b Control is significantly different from Continuous/Pulse g per ton, we used an average treatment cost for both groups of $2.30 per head for Figure 2: Mortality by treatment the economic analysis. (Continuous = 754 g [1.66 lb] per day, Pulse = 732 kg [1.61 lb] per day) compared The outcome of partial budget analysis P<.001 to the Control group (695 g [1.53 lb] per 6% b depends greatly on both the local cost 5.22% day) during the first 2 weeks on trial, even 5% structure of the operation under study and though treated pigs received medicated 4% the prevailing market conditions.13 How- feed only during week 2. Average daily gain 3% a ever, sensitivity analysis15,17 provides a 1.92% was greater for both medicated groups 2% means to systematically vary uncertain fac- Mortality a compared to controls for the overall study 1% 0.55% tors in the analysis. Therefore we created a period (P <.0001; Figure 1). 0% matrix wherein both feed cost and market Continuous Pulse Control hog price were varied, and the net benefit Feed intake and feed efficiency or loss associated with antibiotic inclusion a, b Control is significantly different Both medicated groups had significantly treatment was assessed over a wide range of from Continuous/Pulse improved overall feed intake (P =.004) and financial scenarios. feed conversion efficiency (P =.02) compared to Controls. There were no signifi- All tested animals had seroconverted to Results cant differences in feed intake or feed con- PRRSV by week 4. PRRSV ELISA titers Allotment and final body weights version efficiency between the Pulse and peaked 6 weeks into the study (Figure 3). Body weights did not differ among treat- Continuous groups (Figure 1). There were no differences in serocon- ment groups at allotment (63 lb; 28.6 kg). version to PRRSV detected among Pigs in the Control group (P <.0001) had Mortality treatments. significantly lower final weights (i.e., at Both medicated groups had significantly Low and declining titers to SIV were week 16) than those in the Continuous lower mortality rates than the Control present at the beginning of the study in all and Pulse groups (Figure 1), but body- group (P <.001; Figure 2). There was no treatment groups. A significant rise in SIV weights did not differ significantly between significant difference in mortality rate be- titers occurred at 12 weeks in all three the Continuous and Pulse groups. Final tween the Pulse and Continuous groups. treatment groups (Figure 4). No differences weight (Continuous = 116.3 kg [255.9 lb], in seroconversion to SIV were detected Pulse = 116.0 kg [255.2 lb]) differences Serologic response among the study groups. were significant (P <.0001) between each Pigs were seronegative to PRRSV at the of the seven blocks at the beginning and initiation of the study, with a sampling fre- Fourteen percent of the pigs tested were end of the study. No interaction was de- quency (42) adequate to detect a 10% seropositive (S:P ratio breakpoint of 0.25) tected between treatment and block. prevalence rate with a 99% degree of con- to M. hyopneumoniae at the initiation of fidence. Seroconversion to PRRSV was the study, with positive animals present in Growth rate evident after 2 weeks, with 43% of the ani- each of the treatment groups. A significant Average daily gain (ADG) was significantly mals testing positive (based upon an S:P rise in M. hyopneumoniae titers occurred (P =.02) greater in both medicated groups ratio breakpoint of 0.4) on the ELISA test. beginning at 12 weeks in both the Pulse Swine Health and Production — Volume 8, Number 2 67 and the Control groups, and at 16 weeks Figure 3: PRRSV ELISA antibody response for the Continuous group (Figures 5 and 6). 2.5

Pigs were seropositive to TGEV at the 2.0 initiation of the study with signiﬁcant in- creases in titers at 4 weeks in all three treat- 1.5 ment groups. TGEV seroconversion coin- Continuous cided with an observed increase in diarrhea 1.0

throughout the barn. No differences in Mean S:P ratio Pulse TGEV titers were detected among 0.5 treatments. Control 0 There was minimal seroconversion to 0 2 4 6 8 10 12 14 16 Lawsonia intracellularis and Salmonella at Study week weeks 0 and 16, with no significant differences between groups. Figure 4: SIV hemagglutination inhibition antibody response 1.6 Cost:benefit analysis 1.4 Continuous Assuming a fixed growth period, the eco- 1.2

nomic advantage to using in-feed medica- 10 Pulse tions (due to additional pork produced 1.0 [greater weight gain and reduced mortal- 0.8 Control ity]) more than offset the cost of medica- 0.6 tion under most of the feed cost and mar- 0.4 Mean SIV Log HI ket hog price scenarios we modeled for this 0.2 herd (Table 2). As an example, the use of 0 feed medication was projected to be profit- 0246810121416 able when finishing feed costs were $0.06 Study week per lb and market hog prices were >$22 per cwt. The sensitivity analysis constructed Figure 5: Mycoplasma hyopneumoniae TWEEN 20 antibody response from this trial resulted in a net benefit of $1-$5 per head with live animal market 0.4 Continuous Control prices of $30-$50 per cwt for this herd. Pulse 0.3 Discussion Because antibiotics do not affect viruses, 0.2 the similar serologic response to the three viruses tested—PRRSV, SIV, and TGEV— Mean S:P ratio 0.1 in all three treatment groups was not unex- pected. The serologic profile we observed 0 for PRRSV was similar to those generated 0 2 4 6 8 10 12 14 16 in controlled exposure studies with naïve Study week animals,18 although we observed a slower decline in titers at 12–16 weeks. The checks or necropsy symptomatic pigs to the pigs in the Control and Pulse groups PRRSV serology suggests that pigs were confirm the presence of mycoplasma-asso- received adequate natural exposure to M. exposed to PRRSV soon after being placed ciated respiratory disease, seroconversion to hyopneumoniae during the nonmedicated in the study facility, with additional expo- M. hyopneumoniae has been shown to be period(s) to generate an active immune sure occurring 10–14 weeks post-place- associated with the development of gross response. The Continuous group, although ment. The serologic profile for SIV is con- lesions of mycoplasmal pneumonia and housed in the same airspace with the other sistent with waning maternal immunity at clinical signs typical of the disease.19–21 groups and continuously exposed to M. placement and exposure 8–12 weeks post hyopneumoniae, apparently received inad- Results suggest that adequate exposure to placement. The progression of exposure to equate M. hyopneumoniae exposure to M. hyopneumoniae for detectable changes the viruses tested was: TGEV prior to ar- stimulate an immune response until the in serologic response occurred between rival, PRRSV at 0–2 weeks, and SIV at 8– continuous medication was withdrawn late weeks 8–12 for the Pulse and Control 12 weeks post placement, with no differ- in the study (weeks 14–16). It is unlikely groups, but was delayed in the Continuous ences in exposure detected among that the penicillin derivatives with which group until weeks 14–16, when continuous treatment groups. we injected affected pigs during the period medication had been withdrawn. This dif- of seroconversion to M. hyopneumoniae Although we did not perform slaughter ference in serologic response suggests that functioned as a confounder in this study, 68 Swine Health and Production — March and April, 2000 Figure 6: Mycoplasma hyopneumoniae TWEEN 20 statistical process control serological analysis. Highlighted areas indicate timeframe of significant M. hyopneumoniae seroconversion.

0.40

0.30 Upper control limit

0.20

Mean S:P ratio 0.10 Lower control limit 0 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16 Continuous Pulse Control Study week 1.50 1.00 Upper range limit Lower range limit 0.50 0 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16 Individual S:P range Study week Table 2: Economic analysis of treatment of respiratory disease prevalence of seroconversion to Lawsonia Feed cost per pound intracellularis in experimentally infected Pig price per cwt 00.045 05.05 00.05 05.06 00.06 0.07 pigs.24 The lack of a difference in growth 04.20 -70.0 -00.1 -30.3 -60.4 -90.5 -0.6 performance we observed between the 0.22 0.31 0.17 09.04 -20.0 -50.2 -0.3 Pulse and Continuous groups suggests that 0.24 0.65 0.52 0.39 0.26 01.13 -0.0 pulse dosing is adequate to protect growth 0.26 0.99 0.86 0.73 0.60 0.47 0.34 performance while permitting an active 0.28 1.34 1.21 1.08 0.95 0.81 0.68 immune response, which may potentially 0.30 1.68 1.55 1.42 1.29 1.16 1.03 provide long-term protection against en- 0.35 2.54 2.41 2.28 2.15 2.02 1.89 demic disease. 0.40 3.40 3.27 3.14 3.01 2.88 2.75 0.45 4.26 4.13 4.00 3.87 3.74 3.61 The nomenclature of human medicine 0.50 5.12 4.99 4.86 4.73 4.60 4.47 with regard to “pulse,” “intermittent,” or 0.55 5.98 5.85 5.72 5.59 5.46 5.33 “discontinuous” dosing differs somewhat 0.60 6.84 6.71 6.58 6.45 6.32 6.19 from that of veterinary medicine. In human medicine, these terms refer primarily since penicillin is ineffective against M. pigs. This is well past the age when mater- to once-daily dosing with antibiotics rather hyopneumoniae.22 nal immunity would have declined to an than the multiple daily doses that are typi- undetectable degree, indicating cally prescribed.25,26 In swine veterinary Seroconversion to M. hyopneumoniae using seroconversion was due to natural expo- practice, the duration of medication pulses a monoclonal blocking ELISA assay has sure. Protective immunity develops in as well as the duration of the nonmedicated been shown to occur as early as 8 days swine recovering from mycoplasmal pneu- intervals are usually on the order of days or post-infection in an experimental M. hyop- monia.22 Therefore, seroconversion due to weeks.6–8 neumoniae aerosol challenge study.20 Sero- natural exposure in the Control and Pulse- conversion was detected as early as 9 days Mechanisms that contribute to the repor- medicated pigs in the present study sug- post-intratracheal challenge using a Tween- ted success of pulse dosing in human gests that protective, active immunity de- 20 ELISA assay.23 When exposed to these medical practice include the post-antibiotic veloped in those groups. intratracheally challenged pigs, in-contact effect (PAE),26,27 post-antibiotic sub-mini- controls seroconverted using the Tween 20 Continuous medication improved growth mum inhibitory concentration (MIC) ELISA assay as early as 7 days post-expo- performance but may have prevented effect (PA SME),27 delayed tissue antibiotic sure.23 ELISA seroconversion to M. hyo- stimulation of active immunity against my- depletion kinetics,28 post-antibiotic leuko- pneumoniae is a reliable indicator of the coplasmal pneumonia, leaving animals im- cyte enhancement (PALE),29,30 and adhe- presence of antibody, which may be due to munologically naïve and potentially sus- sion inhibition.31 Some of these effects are passive maternal transfer, vaccination, or ceptible to subsequent re-exposure to M. relatively short-lived32 and it is not known natural exposure. In the present study sero- hyopneumoniae when medication was with- whether they would contribute signiﬁ- conversion to M. hyopneumoniae occurred drawn. Continuous feed antibiotic medica- cantly to the outcome of veterinary pulse in mid-to-late ﬁnishing in unvaccinated tion has also been shown to decrease the dosing as described herein. However the

Swine Health and Production — Volume 8, Number 2 69 interaction between sub-MICs of antibiot- term immunologic protection once the improve growth performance while ics and the immune system (especially short-term ‘cover’ of medication is discon- permitting exposure to and stimula- phagocytosis) is probably of great impor- tinued. Pulse dosing also decreased the to- tion of active immunity against tance27 and the contribution of a func- tal duration of antibiotic use from 12 mycoplasmal pneumonia. tional immune system to the role of antibi- weeks to 5 weeks in this herd, a potentially • Continuous medication may improve otics in resolving infectious disease is important additional consideration in light growth performance without permit- recognized.33,34 Our observation that sero- of current concerns regarding potential ting sufficient natural exposure to and conversion to M. hyopneumoniae was in- overuse of antimicrobials in food animal stimulation of active immunity against hibited in pigs dosed with the low inclu- production. Metaphylaxis, implemented mycoplasmal pneumonia, leaving sion rate of 100 g per ton CTC (after pulse properly, may actually provide better health animals immunologically naïve and dosing with therapeutic levels of tiamulin and performance with reduced antimicro- potentially susceptible to subsequent and CTC) was somewhat surprising in bial use than traditional prophylactic or re-exposure when medication is light of the low dose administered, and therapeutic approaches. withdrawn. may possibly be due to a PA SME or It is unlikely that there will be any ‘cook related mechanism. The PA SME differs book’ metaphylactic program suitable for Acknowledgements fundamentally from the PAE and SME The authors thank Jeff Beekhuizen, Kevin every herd. Diagnostics are needed to iden- phenomena, even though its name implies Karhoff, Court Garloff, Dale Polson, Dave tify the organisms involved, their antimi- similarity. Briefly, the PAE refers to the Baum, and the Health Management Cen- crobial susceptibility profile, when they continued suppression of bacterial growth ter team of Boehringer Ingelheim infect pigs, and when clinical disease typi- after administration of the drug is discon- Vetmedica Inc. for their valuable assistance cally occurs in that production system. tinued, an effect that generally persists for in the conduct and analysis of this study. Knowledge of the spectrum of activity and <2–4 hours.27 The SME refers to decreased tissue distribution of the available antimi- expression of virulence factors (e.g., crobial options is needed to design a ratio- References - refereed adhesins, toxins, normal morphology, etc.), 1. Burch D, Jones G, Heard T, Tuck R. The syner- nal antimicrobial intervention plan not necessarily decreased bacterial growth, gistic activity of tiamulin and chlortetracycline: In- whether it is prophylactic, metaphylactic, feed treatment of bacterially complicated enzootic when an organism is exposed to sub-MIC or therapeutic in intent. Swine practitio- pneumonia in fattening pigs. Vet Rec. levels of drug.35 SMEs of tiamulin against 1986;119:108–112. ners are well equipped to provide that ser- Pasteurella multocida and Actinobacillus 8. Kavanagh N. The effect of pulse medication with vice, information, and advice to their pork pleuropneumoniae virulence factor expres- a combination of tiamulin and oxytetracycline on producing clients. the performance of fattening pigs in a herd infected sion including reduced production of cap- with enzootic pneumonia. Irish Vet J. 1994;47:58– sular polysaccharides, iron-regulated pro- Strategic pulse dosing may be appropriate 61. teins, and hemolysins have been for conditions where: 9. Jouglar J, Borne P, Sionneau G, Bardon T, demonstrated.36 The PA SME refers to a Echlache D. Evaluation of the efficacy of the • management techniques (such as early tiamulin-oxytetracycline combination premix in the prolonged period of growth suppression (and weaning and age-segregated rearing) prevention of enzootic pneumonia in slaughter pigs. concomitant virulence factor expression) Rev Med Vet. 1993;144(12):981–988. are unable to exclude infection of all when bacteria are exposed to sub-inhibi- 10. Shewhart W. In: Statistical method from the view- piglets resulting in disease outbreaks in tory concentrations of drug after supra- point of quality control. Dover publications, Mineola later stages of production; New York, 1939 (reprinted 1986). inhibitory concentrations.27 Prolonged • vaccines may not exist or may not be 11. Wheeler D, Chambers D. In: Understanding growth suppression of M. hyopneumoniae perceived to be cost-effective for the Statistical Process Control. SPC press, Knoxville Ten- might explain the lack of seroconversion in nessee, 1992. production-limiting diseases present; the presence of natural exposure in the 12. Hoblet KH, Miller GY, Bartter NG. Economic • vaccination prior to disease exposure continuously medicated group of pigs in assessment of a pseudorabies epizootic, breeding does not occur; herd removal/repopulation, and downtime in a the present study, although a PA SME • multiple disease challenges exist, commercial swine herd. JAVMA. 1987;190(4):405– specifically for chlortetracycline against M. 409. requiring the use of a broad-spectrum hyopneumoniae has not been reported. 13. Parsons TD, Pitcher PM, Johnstone C. Eco- intervention tool; or nomic analysis of an epizootic of pseudorabies and The strategic use of pulse dosing is an ex- • continuous use of dietary antimicrobi- subsequent production following the institution of a vaccination program in a Pennsylvania swine herd. ample of ‘metaphylactic’ use of antimicro- als is unacceptable. JAVMA. 1990; 197(2):188–191. bials. Metaphylaxis can be defined as ‘early 14. Lane DM, Rendleman CM, Ott SL. Using par- treatment’ after natural exposure to en- Implications tial budgets to analyze selected management prac- demic disease organisms. With metaph- • Both Pulse and Continuous feed tices associated with reduced preweaning mortality. ylactic applications, some pathogen expo- medication strategies significantly Swine Health Prod. 1997;5(3):95–102. 15. Drum SD, Marsh WE. How to use partial bud- sure generally occurs but intervention is improved performance versus gets to predict the impact of implementing segre- initiated prior to an actual disease out- nonmedicated Controls as measured gated early weaning in a swine herd. Swine Health break. The present study provides evidence by growth rate, feed intake, feed Prod. 1999;7(1):13–18. that pulse dosing in this metaphylactic conversion efficiency, and 16. Boehlje MD, Eidman VR. Farm Management. manner may facilitate the added benefit of survivability. New York, New York: Wiley and Sons. 1984. 17. Parsons TD, Smith G, Galligan DT. Economics stimulating active immunity (via natural • Metaphylactic pulse dosing with of porcine parvovirus vaccination assessed by deci- exposure to endemic pathogens) for long- appropriate antimicrobials may sion analysis. J Prev Vet Med. 1986;4:199.

70 Swine Health and Production — March and April, 2000 20. Sorensen V, Ahrens P, Barford K, Feenstra A, 31. Ofek I, Beachey E, Eisenstein B, et al. Suppres- 5. Puig J. Effects on pig performances (ADG, FCR) Feld N, Friis N, Bille-Hansen V, Jensen N, Pedersen sion of bacterial adherence by subminimal inhibi- after oral treatment with tiamutin-oxytetracycline M. Mycoplasma hyopneumoniae infection in pigs: tory concentrations of beta-lactam and combination in an enzootic pneumonia naturally Duration of the disease and evaluation of four diag- aminoglycoside antibiotics. Rev Infect Dis. infected herd. Proc IPVS. 1994:286. nostic assays. Vet Micro. 1997;54:23–34. 1981;1:832–837. 6. Walter D. An evaluation of the performance of 21. Sitjar M, Noyes E, Simon X, Pijoan C. Relation- 32. LeBel M, Spino M. Pulse dosing versus continu- tiamulin plus chlortetracycline pulse-dosed in medi- ships among seroconversion to Mycoplasma hyopneu- ous infusion of antibiotics: pharmacokinetic-phar- cated feed versus chlortetracycline alone and moniae, lung lesions, and production parameters in macodynamic considerations. Clin Pharm. tiamulin alone in commingled feeder pigs with pigs. Swine Health Prod. 1996;(4)6:273–277. 1988;14:71–95. naturally occurring disease. Proc AASP Ann Meet. 22. Ross R. Mycoplasmal diseases. In: Diseases of 33. Bakker-Woudenberg I, Roosendaal R. Impact of 1995:101–104. Swine, 7th ed, 1992;537–543. dosage regimens on the efﬁcacy of antibiotics in the 7. Scattolini E, Montanari L, Bresciani C. Field 23. Sheldrake R, Gardner I, Saunders M, Romalis L. immunocompromised host. J Antimicrob Chemother. evaluation of performance improvement in fattening Serum antibody response to Mycoplasma hyopneumo- 1988;21:145–147. pigs after strategic in feed “pulse medication” based niae measured by enzyme-linked immunosorbent 34. Roosendaal R, Bakker-Woudenberg I, van den on tiamulin and chortetracycline. Proc IPVS. assay after experimental and natural infection of Berge-van Raffe M, Michel M. Continuous versus 1994:324. pigs. Aus Vet J. 1990;67(2):39–42. intermittent administration of ceftazidime in experi- 18. Polson D, Johnston D, Karhoff K, Catlett K. 24. Schwartz K, Knittel J, Walter D, Roof M, mental Klebsiella pneumoniae pneumonia in normal Using statistical process measurement methods in Anderson M. Effect of oral tiamulin on the develop- and leukopenic rats. Antimicrob Agents Chemother. conjunction with post-vaccination antibody re- ment of porcine proliferative enteropathy in a pure- 1986;30:403–408. sponse curves to continuously measure natural culture challenge model. Swine Health Prod. 35. Lorian V, Gemmel C. Effects of low antibiotic PRRS virus exposure and compliance to PRRS vac- 1999;7(1):5–11. concentrations on bacteria. Effects on ultrastructure, cination in a pig production system. PRRS Aujeszky’s virulence and susceptibility to immunodefenses. In: Dis Proc. 1999:277–278. 25. Donaldson J, Martin G, Maltby C, Seyward E. rd The efﬁcacy of pulse-dosed antibiotic therapy in the Antibiotics of Laboratory Medicine, 3 ed. 19. Bahnson P, Marsh W, Dial G. The associations management of persistent otitis media with effusion. 1991;493–555. among serology to M. hyopneumoniae, lesions at J Otolaryng. 1990;19(3):175–178. slaughter, and a clinical index of cough in groups of growing pigs. Proc IPVS. 1994:131. 26. Kirby W, Craig W. Theory and applications of References - nonrefereed 2. Blagovic S, Bilic V. The synergistic activity of 36. Jacques M, Rioux S, Archambault M, Foiry B, pulse dosing: A summary of the symposium. Rev Inf ® Dis. 1981;3(1):1–3. tiamulin and oxytetracycline(Geoltilin ): Investiga- Galameau C, Luki N. Evaluation of the effects of tion of the sensitivity of bacteria and the possibility tiamulin and valnemulin on the growth and produc- 27. Cars O, Odenholt-Tornqvist I. The post-antibi- of preventing colibacillosis, dysentery, and pneumo- tion of virulence factors of Actinobacillus pleuropneu- otic sub-MIC effect in vitro and in vivo. J nia in pigs. Proc IPVS. 1986:144. moniae and Pasteurella multocida. Proc IPVS. Antimicrob Chemother. 1993;(31) suppl D, 159– 1998:270. 166. 3. Heard T. The control of some pneumonia prob- lems in pigs by strategic medication procedures. Proc 28. Bergan T. Pharmacokinetics of tissue penetra- IPVS. 1986:284. tion of antibiotics. Rev Infect Dis. 1981;3:45–66. 4. Morgan J, Aitken I, Collins P, Shearn M, Dalziel 29. MacDonald P, Wetherall B, Pruul H. R, Burch D, Ripley P. The efficacy of in-feed antibi- Postantibiotic leukocyte enhancement: Increased otics for the prevention of experimentally-induced susceptibility of bacteria pretreated with antibiotics Actinobacillus pleuropneumonia. Proc Euro Assoc Vet to activity of leukocytes. Rev Inf Dis. 1981;3:38–44. Pharm Tox. 1994:204. 30. Raponi G, Keller N, Overbeek B, Rosenberg- Arsak M, van Kessel K, Verhoef J. Enhanced phagocytosis of encapsulated Escherichia coli strains after exposure to sub-MICs of antibiotics is correlated to changes of the bacterial cell surface. Antimicrob Agents Chemother. 1990;34:332–336.

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