Slov Vet Res 2009; 46 (1): 29-41 UDC 636.4.09:616.2:615.281:303.7 Original Research Paper PORCINE RESPIRATORY DISEASE COMPLEX (PRDC) - A META-ANALYSIS AND SYSTEMATIC REVIEw OF THE EFFICACY OF ENROFLOXACIN Leon Ščuka1*, Irena Golinar Oven2, Zdravko Valenčak2 1Krka d.d., Šmarješka cesta 6, 8501 Novo mesto; 2Veterinary Faculty, Gerbičeva 60, 1000 Ljubljana, Slovenia Corresponding author, E-mail: leon.scuka@krka.biz Summary: Porcine respiratory disease complex (PRDC) is an economically significant disorder characterised by slow growth, decreased feed efficiency, lethargy, anorexia, fever, cough and dyspnea. A meta-analysis is a method of surveying and combining results of several independent clinical trials. Systematic reviews are concise summaries of the best available evidence that address sharply defined questions; they seek to assemble and examine all the high quality evidence on any given subject. This includes a comprehensive search of all potentially relevant articles and the use of explicit, reproducible criteria in the selection of articles for review. Enrofloxacin is a fluoroquinolone chemotherapeutic that was developed exclusively for use in veterinary medicine. The overall result of meta-analysis indicates a high efficacy of enrofloxacin (P < 0.001) in treating PRDC. The mortality rate was lower in the groups which used enrofloxacin (P = 0.037). Low resistance of all bacteria that cause respiratory tract infections was characterized from 0 to 7,6 %. The high efficacy of enrofloxacin in PRDC and its beneficial economic effect has been confirmed by meta-analysis and systematic review. Key words: fluoroquinolones; meta-analysis; pigs; porcine respiratory disease complex Introduction The aim of the study is examining the effectivness of enrofloxacin in treatment of PRDC. Efficacy of treatment, influence on mortality and susceptibility of pathogens were the main criteria for assessment. Porcine respiratory disease complex (PRDC) is a multi-factorial respiratory syndrome and is economically significant for pork producers throughout the world. PRDC is characterised clinically by slow growth, decreased feed efficiency, lethargy, anorexia, fever, cough and dyspnea and is common in pigs around 10 to 20 weeks of age. Because PRDC is not caused by a single organism the pathogens isolated from pigs vary between and within production units (1). Most commonly porcine reproductive and respiratory syndrome virus (PRRSV), swine influenza virus (SIV), porcine circovirus type 2 (PCV2), pseu-dorabies virus (PRV), Mycoplasma hyopneumoniae, Received: 15 January 2009 Accepted for publication: 15 March 2009 Bordetella bronchiseptica, Actinobacillus pleurop-neumoniae, Pasteurella multocida, Streptococcus suis and Haemophilus parasuis are evidenced in PRDC incidences (2). Beside pathogens also environmental factors, new technologies (early weaning, multisite and age segregated systems), tendency to increase the size of finishing units and their numbers of sourcing farms, lower weaning age are contributors for PRDC (3). A number of tests can be used to determine when these infections are occurring: post-mortem examination with organism identification, serological profiling, polymerase chain reaction (PCR) (4). Control of PRDC is first based on the proper management of production imports such as the environment, nutrition, biosecurity and husbandry procedures (4). In addition is recommended other management strategies that help to limit the impact of MH what include a balanced and stable sow herd with fewer than 30% replacement gilts, closing the herd or minimizing the number of sources to procure pigs, mul- 30 L. Scuka, I. Golinar-Oven, Z. Valencak tisite production, biosecurity to prevent the spread and introduction of disease, reduction of stress on pigs, optimal stocking density, and adequate ventilation, air quality and room temperature (5). Antibiotic therapy is often used to control PRDC. Feed, water and injectable medications are available. Treatment programs to eliminate infection within a group of pigs or pulse medication are procedures that is reducing clinical disease (4). The successful use of combination therapies with antibiotics has also been reported (6). Vaccination is a common control method for PRDC control (4). The economic benefit of MH vaccination has been demonstrated (7). Vaccination programs for PCV 2, PRRS, SIV and PRV are implemented in countries where vaccines are available. Once we understood what is circulating, then control programs can be in place (vaccination, medication) to try to avoid clinical outbreak. A meta-analysis is a method of surveying and combining results of several independent clinical trials. The term meta-analysis was first used by Glass in 1976, who, with his associate Mary Lee Smith, statistically compiled the results of 375 studies dealing with the efficacy of psychotherapy. The most frequently used definition is the one by Huque: meta-analysis refers to a statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be combinable (8). Besides quantitative integration, a meta-analysis vastly improves the potential for uncovering and studying any differences in the available scientific material and provides a basis for plausible explanations of them. It can also lead to new discoveries. A brief summary of the procedures involved in a me-ta-analysis would comprise the following logical steps: 1. the definition of the problem and the inclusion criteria for the studies; 2. positioning, classifying and coding the characteristics of individual studies and the quantitative measurement of their characteristics; 3. the integration of the results and a comparison with the characteristics of the studies (analysis and explication of results); and 4. reporting of the results (9). Systematic reviews are concise summaries ofthe best available evidence that address sharply defined questions; they seek to assemble and examine all the high quality evidence on any given subject. This includes a comprehensive search of all potentially relevant articles and the use of explicit, reproducible criteria in the selection of articles for review. When the results of primary studies are summarized but not statistically combined, the review may be called a qualitative systematic review. A quantitative systematic review, or meta-analysis, is a systematic review that uses statistical methods to combine the results of two or more studies (10). This analytical method is of particular importance in the assessment of therapeutic efficacy when individual studies do not provide an overview over all studies on a topic. As their samples are too small, individual studies cannot provide a quantitative evaluation of the effect of treatment, nor can they test null hypothesis. Prior to meta-analysis, the traditional method was a narrative discourse on previous findings, which, however, could be misleading and subjective. In the past few years, meta-analysis has been increasingly used in all fields of science. This is particularly evident for the medical science, as shown in graph 1. Graph 1: Number of publications 1975-2003 that used meta-analysis (modificated after Petitti (11)) Porcine respiratory disease complex (PRDC) - A meta-analysis and systematic review of the efficacy of enrofloxacin 31 Investigating the efficacy of certain drugs can be done in several ways: by in vitro susceptibility profiling of certain bacteria, by clinical trials or by using meta-analyses or systematic reviews. Enrofloxacin is a fluoroquinolone chemothera-peutic that was developed exclusively for use in veterinary medicine. Shortly after its administration, extremely low concentrations have a bactericidal effect against most Gram-negative and Gram-positive bacteria and will also act against mycoplasmata. It acts against both bacteria in the multiplication phase and dormant microorganisms. It is effective in the presence of oxygen and, owing to this phenomenon, it does not damage beneficial anaerobic intestinal microflora. The efficacy of fluoroquinolones is related to both the maximum concentration and the time above their MIC value. In vitro pharmacokinetic models have shown that maximum concentrations of active substances, 8 times in excess of their MIC, have been able to reduce the number of bacteria by up to 99 % and inhibit their growth for up to 24 hours. The intensity of exposure may be quantified as the ratio between the area under the time-concentration curve (AUC) and the minimum inhibitory concentrations for the causative pathogens (MIC); a short term for this ratio is AIUC - area under the inhibitory plasma concentration curve. For example, if in an enrofloxacin therapy the AIUC is higher than 125, the probability of a clinical and microbiological cure is above 80 %, otherwise it is only 42 % or 26 % in respect of a microbiological cure. Resistance to fluoroquinolones is also reduced to a minimum if these parameters are taken into consideration - C /MIC ~ max' ratio is at least 8-10 and AUC/MIC at least 100-125 (12, 13). Material and methods Table 1: Short survey of studies included in meta-analysis and systematic review Author, year of publication, number of animals included Meta-analysis and systematic review parameters Comparative control group 1. Altrock 1998 (14) - lesions - incidence of bacteria - in vitro susceptibility testing of P. multocida, B. bronchiseptica, A. pleuropneumoniae, H. parasuis, B-haemolytical streptococci - 23 antimicrobial agents (in vitro susceptibility) 2. Köfer et al. 1992 (15) - lesions - incidence of bacteria - in vitro susceptibility testing of P. multocida, B. bronchiseptica, A. pleuropneumoniae, H. parasuis, P. haemolytica, Streptococcus spp. - 8 antimicrobial agents (in vitro susceptibility) 3. Rose et al. 1996 (16); n = 551 - clinical efficacy - mortality - comparative control group (cefquinome, amoxicillin) 4. Kobish et al. 1990 (17); n = 69 - clinical efficacy - mortality - negative control group - positive control group 5. Awad-Masalmeh and Schuh 1990 (18); n = 129 - clinical efficacy - in vitro susceptibility testing of P. multocida, B. bronchiseptica, A. pleuropneumoniae, M. hyopnemoniae - economic parameters - autogenous vaccines - 4 antimicrobial agents (in vitro susceptibility) 32 L. Scuka, I. Golinar-Oven, Z. Valencak 6. Ganter et al. 1995 (19); n = 64 - in vitro susceptibility testing of P. multocida, B. bronchiseptica, A. pleuropneumonias, H. parasuis, S. suis 2 - 10 antimicrobial agents (in vitro susceptibility) 7. Pommier et al. 1998 (20); n = 326 - clinical efficacy - economic parameters - comparative control group (spiramycin) 8. Flaghoff 1996 (21); n = 40 - susceptibility testing of a-hemolytic streptococci, P. multocida, B. bronchiseptica - 8 antimicrobial agents 9. Wu et al. 1997 (22) - in vitro susceptibility testing of Mycoplasma hyopneuminiae and M. hyosynoviae - 11 antimicrobial agents 10. Hannan et al. 1997 (23) - in vitro susceptibility testing of Mycoplasma hyopneuminiae - 2 antimicrobial agents 11. Kobayashi 1996 (24); n = 92 - in vitro susceptibility testing of Mycoplasma hyosynoviae and M. hyorhinis 12 antimicrobial agents 12. Herrerias et al. 1995 (25); n = 150 - clinical efficacy - control groups (norfloxacin, trimetoprim-sulfametoksazol) 13. Asawa et al. 1995 (26) - in vitro susceptibility testing of A. pleuropneumoniae 19 antimicrobial agents 14. Dom et al. 1994 (27) - in vitro susceptibility testing of A. pleuropneumoniae 9 antimicrobial agents 15. Yeh and Park 1996 (28) - in vitro susceptibility testing of A. pleuropneumoniae 16. Salmon et al. 1995 (29) - in vitro susceptibility testing of A. Pleuropneumoniae, P. multocida, S. typhimurium, S. cholerae-suis, E. coli, S. suis, ß- hemolytic streptococci - 8 antimicrobial agents 17. Hornedo et al. 1988 (30); n = 6 - clinical efficacy - negative control (untreated animal) 18. Gutierrez et al. 1993 (31) - in vitro susceptibility testing of A. pleuropneumoniae - 41 antimicrobial agents 19. Wallgren et al. 1998 (32); n = 64 Parenteral aplication - clinical efficacy - lesions - re-isolation of A. pleuropneumoniae - economic parameters - control (uninfected animals, infected untreated animals) - treatment (penicillin, danofloxacin, ceftiofur, tiamulin) 20. Wallgren et al. 1998 (33); n = 112 Peroral aplication - clinical efficacy - lesions - re-isolation of A. pleuropneumoniae - economic parameters - control (uninfected animals, infected untreated animals) - treatment (, penicillin, chlortetracycline, florfenicol, tilmicosin, tiamulin) Porcine respiratory disease complex (PRDC) - A meta-analysis and systematic review of the efficacy of enrofloxacin 33 21. Pijpers et al. 1998 (34); n = 21 - elinieal effieaey - lesions - re-isolation of A. pleuropneumonias - eeonomie parameters - inoeulation with A. pleuropneumonias - negative eontrol (untreated animal) - treatment (oxytetraeyeline) 22. Chung and Yeh 1993 (35); n = 25 - lesions - eeonomie parameters - negative eontrol - treatment (eeftiofur, oxytetraeyeline) 23. Gutierrez Martin and Rodriguez Ferri 1993 (36) - in vitro suseeptibility testing of Pasteurella multocida subspeeies multocida - 41 antimierobial agents 24. Ikoma et al. 1994 (37); n = 155 - elinieal signs - eomparative treatment (danofloxaein) 25. Heinen et al. 1998 (38); n = 8 - pharmaeokinetie study and in vitro suseeptibility (P. multocida, A. pleuropneumoniae, M. hyopneumoniae) 26. Stipkovits et al. 1994 (39) - in vitro suseeptibility testing of 7 baeteria - 3 eombinations of antimierobial agents 27. Kolodziejezyk et al. 1999 (40); n = 2065 - elinieal effieeney - in vitro suseeptibility testing of 7 baeteria - negative eontrol groups 28. Ganter and Amtsberg 1996 (41) - in vitro suseeptibility testing of Pasteurella multocida and Streptoccocus suis - 10 antimierobial agents 29. Silva et al. 1999 (42); n = 84 - in vitro suseeptibility testing of P. multocida, A. pleuropneumoniae, B. bronchiseptica - 7 antimierobial agents 30. Smith et al. 1991 (43); n = 64 - elinieal effieaey - lesions - infeeted eontrol groups - uninfeeted eontrol groups 31. Madsen and Larsen 1996 (44); n = 350 - treatment (attempt to eradieate pleuropneumonia and enzootie pneumonia) - treatment - eontrol after treatment 32. Larsen et al. 1998 (45); n = 135 - treatment (attempt to eradieate pleuropneumonia and enzootie pneumonia) - lesions - elinieal effieaey - vaeeination against A. pleuropneumoniae - disinfeetion 33. Hofmo and Luim 1998 (46); n = 51 - treatment (attempt to eradieate pleuropneumonia and enzootie pneumonia) - serology - 2 antimierobial agents (tiamulin, benzilpenieillin) - vaeeination 34 L. Scuka, I. Golinar-Oven, Z. Valencak 34. Bada et al. 1995 (47) - in vitro susceptibility testing of A. pleuropneumoniae - 10 antimicrobial agents 35. Habrun et al. 1997 (48) - in vitro susceptibility testing of A. pleuropneumoniae, P. multocida 36. Friis and Szancer 1994 (49) - in vitro susceptibility testing of M. hyopneumoniae and M. hyosynovie - 4 antimicrobial agents 37. Molnar 1992 (50) - in vitro susceptibility testing of A. pleuropneumoniae 38. Scheer at al. 1996 (51) - in vitro susceptibility testing of A. pleuropneumoniae, P. multocida - 8 antimicrobial agents 39. Flores et al. 1998 (52) - in vitro susceptibility testing of A. pleuropneumoniae - 6 antimicrobial agents 40. Stephano et al. 1988 (53); n = 20 - treatment - clinical efficacy - positive control group - negative control group 41. Aarestrup et al. 2000 (54) - in vitro susceptibility testing of A. pleuropneumoniae 42. Simon et al. 1990 (55); n = 60 - clinical efficacy - economic parameters - control group - tiamulin 43. Semjen et al. 1988 (56); n = 280 - clinical efficacy - economic parameters - 2 antimicrobial agents (tiamulin, tilozin) 44. Laak et al. 1991 (57) - in vitro susceptibility testing of M. hyopneumoniae, M. hyosynovie and M. flocculare - 17 antimicrobial agents 45. Glaswisching et al. 1989 (58) n = 190 - clinical efficacy - untreated control group 46. Friis et al. 1994 (59) - in vitro susceptibility testing of M. hyopneumoniae and M. hyosynovie - 4 antimicrobial agents 47. Chou et al. 1995 (60) - in vitro susceptibility testing of P. multocida - 3 antimicrobial agents 48. Awad-Masalmeh et al. 1994 (61) - in vitro susceptibility testing of P. multocida - 7 antimicrobial agents 49. Trolldenier 1996 (62) - in vitro susceptibility testing of P. multocida and M. haemolytica - 14 antimicrobial agents 50. Bole-Hribovsek and Zdovc 2002 (63) - in vitro susceptibility testing of P. multocida 51. Ikoma 1994 (64); n = 78 - clinical efficacy - lesions - control group - kanamicin Porcine respiratory disease complex (PRDC) - A meta-analysis and systematic review of the efficacy of enrofloxacin 35 52. Udovicic et al. 1996 (65); n = 77 - treatment - clinical efficacy - vaccination 53. Werner-Tutschu et al. 1997 (66) - in vitro susceptibility testing of P. multocida and B. bronchiseptica - 19 antimicrobial agents 54. Shin et al. 2004 (67) - in vitro susceptibility testing of A. pleuropneumonias, P. multocida and B. bronchiseptica - 8 antimicrobial agents 55. Aaerestrup and Jensen 1999 (68) In vitro susceptibility testing of A. pleuropneumoniae (7 antimicrobial agents) - determination of MIC It is evident from the table 1 that 55 studies were included in the survey (references from 14 - 67): 19 examined the usage of enrofloxacin in mixed respiratory infections, 14 studies of pleuropneumonia, 9 for enzootic pneumonia, 6 for pasteurellosis and 3 for atrophic rhinitis. There are 3 studies which dealt with pleuropneumonia and enzootic pneumonia. Eleven clinical studies were included in two metaanalyses (efficacy and mortality), other studies provided a review of susceptibility status for PRDC pathogens to enrofloxacin and other comparable antibacterials. Mortality was reported in three studies only, however actual causes of deaths were not reported. The total number of animals included in the metaanalysis (efficacy), was 3954, of which 1745 were from the enrofloxacin-treated groups of different studies and 2209 from their control or alternative treatment groups; and 668 (mortality), out of which 218 were from the enrofloxacin-treated groups and 450 from their control or alternative treatment groups. A lot of studies examined the susceptibility profile of respiratory pathogens; all were comparative, except for two by Aaerestrup et al. (54). In total, there were 7866 strains of respiratory pathogens examined for their susceptibility to enrofloxacin. Some of the studies also dealt with the economic parameters and the pathoanatomical signs (e.g. lesions) in respiratory organs and their changes. Evaluation method The results of meta-analyses are presented graphically. The graphs show compiled data on authors of individual studies, the year of study publication or performance, a numerical comparison between the treated and the control group (shown as effect, expressed as odds ratios) and the mean values of effect size with 95% confidence intervals. The odds ratio (OR) was used as a scale of magnitude for the effect size. Characteristic of OR is that a value of 1.0 means that a certain therapy has no effect; values below 1.0 indicate that the tested therapy (in our case the use of enrofloxacin) is better than that of the control or the comparator therapy group. Values above 1.0 indicate the advantage of the control or comparator therapy over the tested therapy. When in a graph the study presentation with its mean value and the two lines for the confidence interval does not intersect the value of 1.0, we speak about statistical significance at different levels, e.g. in 95-percent confidence intervals the P level of statistical significance equals 0.05; in 99-percent intervals it equals 0.01, etc. In cases, however, where mean values with confidence intervals intersect the 1.0 value line, we cannot speak about statistical significance. The total effect size is always conditioned by weights of individual studies; therefore, in a meta-analysis we speak about a weighted total value of the effect size which, the same as for individual study is presented by mean value and confidence intervals. In the graph the weights for individual studies are shown as bigger or smaller full circles (•). This means that studies with smaller weights have smaller circles and those with larger weights have larger circles. The total effect size is shown as a full square (■). We also reviewed in vitro susceptibility of individual microbes to enrofloxacin as well to other antimicriobial substances and evaluated the MIC values. The Comprehensive Meta-Analysis (69) computer programme was used for statistical analysis. 36 L. Scuka, I. Golinar-Oven, Z. Valencak Results Graf 2: Respiratory tract infections - efficacy of enrofloxacin treatment comparing with control group. Author rear Weight Effect (%) Glaswisching et al(58) 19 89 0.8 0.01 Heirerias et al. (25) 1995 12.2 0.60 Homedo et al. (30) 1988 0.4 0.03 Ikoma et al. (37) 1994 6.3 0.39 Koblsch et al. (17) 1990 1 .4 0.01 Kolodziejczyk et al .(40) 1999 38.5 0.21 Pommier et al. (20) 1998 19.1 0.50 Rose et al. (16) 1996 12.0 0.83 Smith et al.(43) 1991 3.5 0.11 l/Vallgreen oral (33) 1998 5.0 0.07 l/Vallgreen parent. (32) 1998 0.8 0.02 Total-fixed model (11) 0.29 Total-random model (11) 0.19 0,01 0,1 1 10 100 enrofloxacin control Homogeneity testing: Q = 43.1, d.f. (Q) = 10, P = 0.0003 Q.....heterogeneity value (x2 distribution); d.f.....degrees of freedom ; P.... probability It is evident from the graph that in the comparison of efficacy there is a statistically significant difference between the groups (P < 0.001). Author Year Weight Effect (%) Kobisch et al (17) 339 3 0.03 Pommier et al (20) 21 2 1.59 Rose et al (16) 3 9 5 9.20 Total (3) 0.14 0,01 0,1 10 Enrofloxacin Control 1 Graph 3: Respiratory tract infections - comparison of mortality between enrofloxacin and control group. The mortality rate was lower in the groups which used enrofloxacin (P = 0.037) than in the comparative control groups Homogeneity testing: Q = 2.62, d.f. (Q) = 2, P = 0.27 Porcine respiratory disease complex (PRDC) - A meta-analysis and systematic review of the efficacy of enrofloxacin 37 Table 2: In vitro susceptibility of respiratory pathogens to various antimicrobial substances (% of resistant strains) -summary of results from the reviewed articles Antibacterial A. pleuropneumoniae P. multocida B. bronchiseptica H. parasuis Gentamicin 6.4% (n = 235) 3.9% (n = 1142) 3.7% (n = 162) 9.5% (n = 42) Trimethoprim/ sulfonamide 16.5% (n = 260) 19.9% (n =1141) 68.1% (n = 207) 30.9% (n = 42) Enrofloxacin 2.3% (n = 2943) 2.8% (n = 2987) 7.6% (n = 904) 0.0% (n =124) Kanamycin 3.3% (n = 87) 6.6% (n = 872) 7.0% (n = 106) 3.1% (n = 31) Neomycin 10.3% (n = 223) 8.5% (n =1036) 3.4% (n = 148) 4.8% (n = 42) Ampicillin 14.0% (n = 205) 15.1% (n = 1408) 57.7% ( n =153) 23.3% (n = 30) 5.4% of all strains of M. haemolytica (n = 908) were resistant to enrofloxacin. Table 3: Minimal inhibitory concentrations (MICs) for respiratory pathogens (enrofloxacin) Bacteria MIC (Mg/ml) Bacteria MIC (Mg/ml) P. multocida < 0.03-0.5 M. haemolytica < 0,03-1.0 B. bronchiseptica 0.125-0.25 A. pleuropneumoniae < 0,03-0.06 Log OR Graph 4: Funnel plot standard error by effect size (odds ratio - OR) The funnel plot interprets dispersion of data. If heterogeneity is insignificant, data form a funnel with a wide opening of the funnel at the bottom of the graph and spire on the top. This way of presentation shows good agreement with the calculation of heterogeneity and funnel plot. From funnel plot (graph 4.) it is evident that the studies included in the meta-analysis were heterog-enous (P < 0.001). Discussion Graphs 2 and 3 demonstrate that enrofloxacin effectively treats respiratory tract infections in pigs (P < 0.001), and that in the enrofloxacin groups there were fewer deaths (P = 0.037). In the study of efficacy and from graph 4 (funnel plot), we established that there was a heterogeneity of included studies, therefore, the total effect size was also calculated according to the random model. The reasons for heterogeneity might probably be explained in terms of the larger number of included studies which dealt with different respiratory tract infections and were compiled in the joint meta-anal-ysis, along with different sample sizes in individual studies. The susceptibility analysis, which excluded the four studies which stood out from the rest (17, 30; 32, 58,), demonstrated that these studies were not the cause of heterogeneity. The causative pathogens are also characterized by a considerably low resistance of all bacteria that cause respiratory tract infections whereas the high efficacy of enrofloxacin is indicated by the low MICs of bacteria which are the causative pathogens of respiratory tract infections (Table 2. and 3.) 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Comprehensive meta-analysis: manual for meta-analysis. Eaglewood: Biostat, 2000. (computer programme) Porcine respiratory disease complex (PRDC) - A meta-analysis and systematic review of the efficacy of enrofloxacin 41 METAANALIZA IN SISTEMATIČNI PREGLED UČINKA ENROFLOKSACINA NA PRAŠIČJI RESPIRATORNI BOLEZENSKI SINDROM (PRDC) Ščuka L., Golinar-Oven I., Valenčak Z. Povzetek. Prašičji respiratorni bolezenski sindrom (angl.: porcine respiratory disease complex - PRDC) je ekonomsko pomembna motnja. Zanj je značilna večja smrtnost živali, manjši dnevni prirast, zmanjšan apetit, daljše pitanje živali, kašelj, težko dihanje, pljučnica. Metaanaliza je metoda pregledovanja in kombiniranja rezultatov, dobljenih v različnih neodvisnih kliničnih poskusih. Sistematični pregledi so kratki povzetki najboljših dosegljivih dognanj na natančno definirana vprašanja. Poskušajo zbrati in pregledati vse kakovostne podatke o obravnavani temi. To vključuje obširno iskanje vseh potencialno pomembnih člankov in uporabo jasno ponovljivih kriterijev pri izboru študij, uporabljenih za pregled. Enrofloksacin je fluo-rokinolonski kemoterapevtik, ki so ga razvili izključno za rabo v veterinarski medicini. Celotni rezultati metaanalize kažejo na visoko učinkovitost enrofloksacina (P < 0,001) pri zdravljenju PRDC. Smrtnost je bila manjša v skupinah, zdravljenih z enrofloksacinom (P = 0,037). Odpornost proti vsem bakterijam, ki povzročajo okužbe dihal, je bila nizka (0 % - 7,6 %). Z metaanalizo in sistematičnim pregledom smo dokazali visoko učinkovitost enrofloksacina pri PRDC in njegovo ekonomsko korist. Ključne besede: fluorokinoloni; metaanaliza; prašiči; prašičji respiratorni bolezenski kompleks