Do antimicrobial mass medications work? A systematic review and meta-analysis of randomised clinical trials investigating antimicrobial prophylaxis or metaphylaxis against naturally occurring bovine respiratory disease

Abstract

A distinct difference between veterinary and human medicine is the routine use of antimicrobial mass medications (prophylaxis, metaphylaxis) to healthy individuals. The need for antimicrobial mass medications is based on beliefs that group/s of animals will contract a bacterial disease (i.e. morbidity) and/or die (i.e. mortality). Bovine respiratory disease (BRD) represents the major indication for cattle antimicrobials worldwide. The objectives were to perform a systematic review and meta-analysis of randomised controlled clinical trials (RCTs) for naturally occurring BRD investigating antimicrobial prophylaxis/metaphylaxis to prevent morbidity/mortality. In total, 58 publications met the inclusion criteria summarizing 169 individual RCTs, spanning 50 years (1966-2016). Antimicrobial prophylaxis and metaphylaxis demonstrated moderate, yet highly variable relative risk reductions in BRD morbidity. These were dependent on the antimicrobial classes used, dependent on metaphylaxis definition, BRD attack rates and duration of the RCTs. Best relative risk reductions were from broad-spectrum critically important antimicrobials, or combinations. BRD prophylaxis/metaphylaxis represents major antimicrobial consumption for highly variable short-term gains in absolute risk reduction of morbidity/mortality. Despite widespread use of prevention products, the need for antimicrobial mass medications should be re-evaluated since the underlying problem is more likely the segmented infrastructure of the feedlot and veal calf industries compared to the disease itself.

Keywords: antimicrobial; bovine; metaphylaxis; prophylaxis.

Figure 1.

Forest plot of prophylaxis RCTs morbidity data sorted by antimicrobial class and control group attack rates. Random-effects meta-regression model RR predictions represented as shaded grey and black diamonds. AttRate—control group attack rate % (CER%); antimicrobials investigated included macrolides (tylosin, tilmicosin, tulathromycin, gamithromycin, tildipirosin), tetracyclines (oxytetracyline, chlortetracycline, doxycycline), amphenicols (florfenicol), cephalosporins (ceftiofur), sulfonamides (sulfadimethoxine, sulfamethazine, trimethoprim sulphonamide), and fluoroquinolones (enrofloxacin), tetracycline combinations (oxytetracyline and/or chlortetracycline + neomycin, or sulfadimethoxine and/or sulfamethazine).

Figure 2.

Forest plot of metaphylaxis RCTs morbidity data sorted by metaphylaxis definition. Random-effects meta-regression model RR predictions represented as shaded grey and black diamonds. ‘>10% Morbidity’—group medication of cattle when the BRD morbidity within the group ≥10%. ‘Fever’—group medication of cattle with pyrexia and no other symptoms. ‘In contact’—group medication of cattle in contact with clinical BRD cattle.

Figure 3.

Funnel plots of the morbidity data from RCTs. The upper panels show all morbidity data without (left) and with (right) Duval and Tweedie trim and fill to correct for potential publication bias (test for heterogeneity: Q (df = 168) = 1061.977, P-value < 0.0001). Published studies are represented with filled circles, where the added (fill) studies are shown with open circles. The lower panels show separate plots for prophylaxis studies (left) (test for heterogeneity: Q (df = 121) = 824.153, P-value < 0.0001) and metaphylaxis studies (right) (test for heterogeneity: Q (df = 46) = 195.687, P-value < 0.0001).

Figure 4.

NNT plot of all morbidity data from RCTs involving either antimicrobial prophylaxis (red circles) or metaphylaxis (black circles). Size of the circles reflects the sample size of the RCT (see the legend). Bolded circles are blinded RCTs. Green line represents the overall NNT median value = 7.27. The curve represents the expected NNT as a function of CER assuming a uniform RR (=0.52) across all values of CER. NNT, number needed to treat; ARR, absolute risk reduction; RCT, randomised clinical trial.

Figure 5.

Plot of absolute risk reductions in (a) morbidity or (b) mortality for each RCT versus the duration of the RCT. For publications stating a range of duration days for RCTs, then the average value was calculated. RCTs involving either antimicrobial prophylaxis (red circles) or metaphylaxis (black circles). Size of the circles reflects the sample size of the RCT (see the legend). Bolded circles are blinded RCTs. For the purpose of visualisation of the wide range of ARR values for the mortality data, the y-values in (b) are shown on a modified log-scale (sign(y)*log₁₀(10*y+ 1)). Labels at the tick marks are the original ARR values.