Scientia Agricultura Sinica ›› 2019, Vol. 52 ›› Issue (16): 2899-2911.doi: 10.3864/j.issn.0578-1752.2019.16.015

• ANIMAL SCIENCE·VETERINARY SCIENCE·RESOURCE INSECT • Previous Articles     Next Articles

Antibacterial Activity in Vitro and Protection of Tildipirosin Injection Against Artificially Infected Haemophilus Paracoides in Piglets

LI GuoJi1,YAN ChaoQun1,MA YuQiao1,XIE Shun1,GU Xin2,CAO Ying2,HUANG ShiXin2,HUANG XianHui1()   

  1. 1 Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642
    2 Shanghai Animal Disease Control Center, Shanghai 201103
  • Received:2018-11-12 Accepted:2019-03-29 Online:2019-08-16 Published:2019-08-21
  • Contact: XianHui HUANG E-mail:xhhuang@scau.edu.cn

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Abstract:

【Objective】The study was carried out to investigate the antibacterial activity in vitro and protection of tildipirosin injection against artificially infected Haemophilus Paracoides in piglets. 【Method】Minimal inhibitory concentration (MIC) of Tildipirosin injection against Haemophilus paracoides, Actinobacillus pleuropneumonia, Pasteurella multiflora, and Bronchial septicemic wave bacillus were determined by two-fold dilution method in vitro. In the protective effect of tildipirosin injection against Haemophilus paracoides in piglets, 0.5 mL·kg -1bw suspension of Haemophilus paracoides with a bacterial volume of 1 10 10 CFU·mL -1 was selected as the challenge dose for intraperitoneal injection to replicate the pathological model. All the therapeutic groups of pigs were medicated via intramuscular injection in single dose with tildipirosin injection (2, 4, 8 mg·kg -1bw), tulathromycin (2.5 mg·kg -1bw). In the process of isolating and identifying dead pig pathogens, isolated and purified Haemophilus paracoides colonies were selected for genomic DNA extraction. A pair of specific primers were designed for the 16s RNA sequence of Haemophilus paracoides, and the base sequence length of the target DNA fragment was tested after PCR amplification.【Result】The results of the antibacterial activity in vitro showed that MIC of Haemophilus paracoides, Septicopharynx, Actinobacillus pleuropneumoniae and Pasteurella multocida for tildipirosin injection was 0.06-8, 0.06-8, 0.25-1, and 2-32 μg·mL -1, respectively, which indicated the effect of Tildipirosin injection against Haemophilus paracoides and Septicopharynx was stronger than Actinobacillus pleuropneumoniae and Pasteurella multocida. PCR amplification results of the DNA target fragment showed that the length of the PCR amplification target fragment was consistent with the predicted band, and the specific fragment length was about 820bp, which indicated that all the dead pigs died of Haemophilus paracoides infection. The result of protective effect indicated that, in tildipirosin injection groups (2, 4, 8 mg·kg -1bw), the average gain of weight was (2.5±0.2), (2.9±0.2), (2.9±0.3) kg, respectively; the mortality rate were 40%, 0 and 0, respectively; the effective rate was 40%, 100% and 100%, respectively; the cure rate was 40%, 100% and 100%, respectively. In tulathromycin injection groups (2.5 mg·kg -1bw), the average gain of weight was (3.0±0.2) kg; the mortality rate were 10%; the effective rate was 90%; the cure rate was 80%. In infective control group, the average gain of weight was (2.1±0.1) kg; the mortality rate were 70%. The results of in vitro treatment showed that there was no significant difference between the high- and medium-dose group of tildipirosin and the tulathromycin group (P>0.05), which could alleviate the clinical symptoms rapidly and had significant therapeutic effects. The therapeutic effect of tildipirosin low-dose group was comparable to the non-administered group, and there was no significant difference (P>0.05). 【Conclusion】Through the above results, the product was recommended to be administered at a dose of 4 mg·kg -1bw, which could effectively treat respiratory diseases in pigs caused by Haemophilus Parasuis infection.

Key words: tildipirosin injection, MIC, Haemophilus Paracoides, piglet

Table 1

The groups and treatment of animals"

组别
Groups		 数量（头）
Numbers (Head)		 体重
Weights (kg)		 剂量
Dosage (mg·kg-1bw)		 给药方案
Drug regimen
健康对照组
Healthy control group		 10 12.5±0.6 — 不感染,不给药
No infection, No administration
泰地罗新注射液高剂量组
High dose group of Tildipirosin injection		 10 12.9±0.9 8.0 感染,肌注注射
Infection,im
泰地罗新注射液中剂量组
Middle dose group of Tildipirosin injection		 10 12.9±1.1 4.0 感染,肌注注射
Infection,im
泰地罗新注射液低剂量组
Low dose group of Tildipirosin injection		 10 12.7±0.9 2.0 感染,肌注注射
Infection,im
泰拉霉素注射液
Tulathromycin injection		 10 13.1±0.5 2.5 感染,肌注注射
Infection,im
感染对照组
Infective control group		 10 12.5±0.6 — 感染,不给药
Infection, No administration

Table 2

PCR reaction system"

体系组分
System components		 用量
The dosage (μL)
灭菌超纯水 Sterilized ultra-pure water 12.6
10×PCR buffer 2
dNTP（2.5 mmol·L-1） 1.6
上游引物 Forward primer 0.8
下游引物 Reverse primer
模板DNA（Template DNA）		 0.8
2
rTag DNA酶 rTag DNA enzyme, 5 U·μL-1 0.2

Table 3

The results of MIC(μg/mL) of tildipirosin against four stains"

菌种
Bacterial strain		 MIC MIC50 MIC90
胸膜肺炎放线杆菌（39株）Actinobacillus pleuropneumonia（39 strains） 2-32 4 16
多杀性巴氏杆菌（25株）Pasteurella multiflora（25 strains） 0.25-1 0.5 1
支气管败血波氏杆菌（10株）Bronchial septicemic wave bacillus（10 strains） 0.06-8 2 8
副猪嗜血杆菌（74株）Haemophilus Paracoides（74 strains） 0.06-8 0.5 2

Table 4

Poison attack dose and results of 50 healthy pigs"

菌株
Bacterial strain		 日龄接种
Inoculate days		 活菌量
Living bacterium
quantity (CFU/mL)		 接种剂量
Inoculation dosage (mL·kg-1）		 数量（头）
Number
(Head)		 攻毒结果 Poison attack results
发病数量（头）
Morbidity（Head）		 死亡数量（头）
Mortality（Head）
13R 7-8周龄
7-8 weeks		 1×1010 0.3 10 5 1
1×1010 0.5 10 10 7
1×1010 0.8 10 10 10
1×1010 1 10 10 10
TSB培养基
TSB medium		 7-8周龄
7-8 weeks		 1×1010 1mL 10 0 0

Fig. 1

Temperature of each experimental group after administration"

Fig. 2

Clinical symptom observation results of piglets"

Table 5

Mean temperature and standard deviation of each experimental group after administration"

时间
Time (h)		 健康对照组
Healthy control
group		 泰地罗新注射液
高剂量组
High dose group of Tildipirosin injection		 泰地罗新注射液
中剂量组
Middle dose group of Tildipirosin injection		 泰地罗新注射液
低剂量组
Low dose group of Tildipirosin injection		 泰拉霉素注射液
Tulathromycin injection		 感染对照组
Infective control
group
0 39.2±0.18 39.4±0.19 39.1±0.22 39.2±0.20 38.9±0.22 39.3±0.31
1 39.1±0.19 40.2±0.18 40.6±0.23 40.4±0.22 40.2±0.18 40.5±0.29
3 39.2±0.22 41.2±0.21 41±0.19 41.1±0.21 41.2±0.21 41±0.22
4 38.6±0.21 40.9±0.20 40.8±0.17 41.3±0.22 41.1±0.19 41.8±0.28
6 39.3±0.20 40.4±0.19 40.4±0.16 40.7±0.24 40.7±0.23 41.2±0.17
8 39.1±0.17 40.1±0.23 40±0.21 40.5±0.18 40.3±0.21 40.8±0.19
12 38.9±0.20 39.5±0.18 39.5±0.22 40.2±0.19 39.6±0.18 40.9±0.24
24 39±0.19 39.3±0.23 39.5±0.18 40.2±0.22 39.2±0.19 40.6±0.22
36 39.2±0.23 39.4±0.25 39.1±0.19 39.5±0.22 39.4±0.27 40.5±0.28
48 38.8±0.16 39.2±0.21 39.3±0.20 39.5±0.24 39.1±0.26 40.7±0.26
60 39.1±0.21 39.2±0.20 39±0.20 39.4±0.22 38.9±0.29 40.8±0.21
72 38.9±0.22 38.9±0.17 39.4±0.22 39.3±0.22 39.2±0.19 40.6±0.27
84 39.2±0.18 39.3±0.22 39.4±0.25 38.9±0.21 39±0.18 40.5±0.30
96 39.1±0.19 38.8±0.20 38.9±0.21 39.2±0.22 39.3±0.21 40.4±0.22
108 39.3±0.20 39.1±0.24 39.2±0.19 39.1±0.19 38.9±0.21 40.5±0.22
120 38.7±0.22 39.1±0.22 39±0.17 39.4±0.22 39.2±0.22 40.4±0.24
132 39.2±0.18 39.2±0.19 39.2±0.20 38.8±0.24 39.4±0.19 40.3±0.25
144 39.1±0.21 39.2±0.21 39.3±0.20 39.2±0.21 39.1±0.21 40.4±0.21
156 39.4±0.21 39.4±0.25 39.2±0.18 39±0.22 39.2±0.18 40.3±0.24

Table 6

Weight change in each dose group during the trial ($\bar{X}$±S.D)"

组别
Groups		 试验前体重
Pretrial weight (kg)		 试验后体重
Posttest weigh (kg)		 增重
Weight increment (kg)
健康对照组 Healthy control group 12.5±0.6 15.5±0.7 3.0±0.2a
泰地罗新高剂量组 High dose group of Tildipirosin injection 12.9±0.9 15.8±1.2 2.9±0.3a
泰地罗新中剂量组 Middle dose group of Tildipirosin injection 12.9±1.1 15.7±1.2 2.9±0.2a
泰地罗新低剂量组 Low dose group of Tildipirosin injection 12.7±0.9 15.2±0.9 2.5±0.2b
泰拉霉素注射液 Tulathromycin injection 13.1±0.5 16.1±0.6 3.0±0.2a
感染对照组 Infective control group 12.5±0.6 14.6±0.7 2.1±0.1c

Fig. 3

Observation results of ocular pathological changes"

Fig. 4

Observation of pathogen isolation and culture"

Fig. 5

PCR results of 16S rRNA from Haemophilus parthenosus"

Table 7

The therapy of Tildipirosin injection against Haemophilus Paracoides in pigs (Effective rate)"

编号
No.		 组别
Groups		 头数
Head		 死亡率
Mortality (%)		 有效率
Efficient (%)		 治愈率
Cure rate (%)		 与第5组 比较
（χ2检验）
Compare with group 5 (χ2 test)		 与第4组 比较
（χ2检验）
Compare with group 4 (χ2 test)		 与第3组
比较
（χ2检验）
Compare with group 3 (χ2 test)		 与第2组 比较
（χ2检验）
Compare with group 2 (χ2 test)
1 泰地罗新高剂量组
High dose group of Tildipirosin injection		 10 0（0/10） 100（10/10） 100（10/10） 20 1.053 8.571 1.053
2 泰地罗新中剂量组
Middle dose group of Tildipirosin injection		 10 0（0/10） 100（9/10） 90（9/10） 16.36 0 5.495 -
3 泰地罗新低剂量组
Low dose group of Tildipirosin injection		 10 40（4/10） 40（4/10） 30（3/10） 5 5.495 - -
4 泰拉霉素注射液
Tulathromycin injection		 10 10（1/10） 90（9/10） 80（8/10） 16.364 - - -
5 感染对照组
Infective control group		 10 70（7/10） - - - - - -
6 健康对照组
Healthy control group		 10 - - - - - - -

Table 8

The therapy of Tildipirosin injection against Haemophilus Paracoides in pigs (Cure rate)"

编号
No.		 组别
Groups		 头数
Head		 死亡率
Mortality (%)		 有效率
Efficient (%)		 治愈率
Cure rate (%)		 与第5组 比较
（χ2检验）
Compare with group 5 (χ2 test)		 与第4组 比较
（χ2检验）
Compare with group 4 (χ2 test)		 与第3组
比较
（χ2检验）
Compare with group 3 (χ2 test)		 与第2组 比较
（χ2检验）
Compare with group 2 (χ2 test)
1 泰地罗新高剂量组
High dose group of Tildipirosin injection		 10 0（0/10） 100（10/10） 100（10/10） 20 2.222 10.769 1.053
2 泰地罗新中剂量组
Middle dose group of Tildipirosin injection		 10 0（0/10） 100（9/10） 90（9/10） 16.364 0.392 7.5 -
3 泰地罗新低剂量组
Low dose group of Tildipirosin injection		 10 40（4/10） 40（4/10） 30（3/10） 3.529 5.051 - -
4 泰拉霉素注射液
Tulathromycin injection		 10 10（1/10） 90（9/10） 80（8/10） 13.333 - - -
5 感染对照组
Infective control group		 10 70（7/10） - - - - - -
6 健康对照组
Healthy control group		 10 - - - - - - -

Table 9

The therapy of Tildipirosin injection against Haemophilus Paracoides in pigs (Mortality rate)"

编号
No.		 组别
Groups		 头数
Head		 死亡率
Mortality (%)		 有效率
Efficient (%)		 治愈率
Cure rate (%)		 与第5组 比较
（χ2检验）
Compare with group 5 (χ2 test)		 与第4组 比较
（χ2检验）
Compare with group 4 (χ2 test)		 与第3组
比较
（χ2检验）
Compare with group 3 (χ2 test)		 与第2组 比较
（χ2检验）
Compare with group 2 (χ2 test)
1 泰地罗新高剂量组
High dose group of Tildipirosin injection		 10 0（0/10） 100（10/10） 100（10/10） 10.769 1.053 5 /
2 泰地罗新中剂量组
Middle dose group of Tildipirosin injection		 10 0（0/10） 100（10/10） 90（9/10） 10.769 1.053 5 -
3 泰地罗新低剂量组
Low dose group of Tildipirosin injection		 10 40（4/10） 40（4/10） 30（3/10） 1.818 2.400 - -
4 泰拉霉素注射液
Tulathromycin injection		 10 10（1/10） 90（9/10） 80（8/10） 7.500 - - -
5 感染对照组
Infective control group		 10 70（7/10） - - - - - -
6 健康对照组
Healthy control group		 10 - - - - - - -
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