I. INTRODUCTION

Doxycycline is an antibiotic commonly used in veterinary medicine for the treatment of bacterial and mycoplasma infections. In farm animals, it is indicated for ruminants, pigs, chickens and turkeys, but should not be used in layers during the productive stage or in lactating ruminants.

It is a semi-synthetic antibiotic of the tetracycline family derived from oxytetracycline. It is a bacteriostatic antibiotic, since it inhibits protein synthesis, but it can also alter the permeability of the cytoplasmic membrane in susceptible organisms.

It has a broad spectrum of action including gram-negative and gram-positive bacteria, Chlamydia, Rickettsia, mycoplasmas, Leptospira, Anaplasma and spirochetes. In addition, as it is more soluble than other tetracyclines, it can get to areas such as the joints (synovial fluid), the central nervous system and the eyes.

II. SPECTRUM OF ACTION

List of microorganisms sensitive to doxycycline:

1. Gram-negative Bacteria

• Acinetobacter spp.*

• Bartonella bacilliformis

• Brucella spp.

• Campylobacter*

• Enterobacter aerogenes

• Escherichia coli*

• Francisella tularensis

• Haemophilus spp.

• Klebsiella spp.*

• Moraxella

• Neisseria gonorrhoeae

• Pasteurella multocida

• Salmonella*

• Shigella spp.*

• Staphylococcus

• Vibrio spp.

• Yersinia pestis

2. Parasites

• Balantidium coli

3. Gram-positive Bacteria

• Bacillus anthracis

• Streptococcus spp.*

4. Anaerobic microorganisms

• Clostridium spp.*

• Fusobacterium fusiforme

• Propionibacterium acnés

5. Other bacteria

• Nocardiae y otros Actinomyces

• Borrelia recurrentis

• Brachyspira spp.

• Chlamydophila spp.

• Chlamydia spp.

• Fusobacterium

• Mycoplasma pneumoniae

• Rickettsiae

• Spirocheta

• Treponema spp.

• Ureaplasma urealyticum

Some strains of the microorganisms marked with (*) show intermediate sensitivity or resistance to doxycycline. Therefore, especially in gram positive and gram negative bacteria, it is important to perform an antibiogram prior to administration of the antibiotic.

III. SENSITIVITY MICROORGANISMS OF ANIMAL ORIGIN

The sensitivity of different animal-based microbes to doxycycline has been evaluated in multiple studies, some of which are cited below.

III.1. Sensitive Microorganisms

a) Mycoplasma spp.

M. synoviae is responsible for infectious synovitis in chickens and turkeys and causes considerable economic losses to the poultry industry. It is also associated with respiratory tract infections and seizures by aerosaculitis, in addition to causing subclinical infections.

Doxycycline is effective in killing Mycoplasma spp. thanks to its high penetration capacity (liposolubility). This is corroborated by a study carried out in the Netherlands, where doxycycline was effective in eradicating M. synoviae in a broiler farm [1].

b) Brucella

Brucellosis is a contagious disease of livestock that has significant economic consequences. It is characterized by the existence of abortions or lack of reproduction.

In a study carried out in Iran with different species of the genus Brucella, it was observed that all the microbial samples collected from ruminants were sensitive to doxycycline. These results indicate that doxycycline was the most effective antibiotic against Brucella [2].

Despite the demonstrated efficacy of the antibiotic, treatment of brucellosis in animals is not recommended due to the need to eradicate the disease [3].

c) Pasteurella multocida

It is the bacterium responsible for avian cholera, atrophic rhinitis in pigs and hemorrhagic septicemia in cattle.

In a study carried out in Hungary with isolates of P. multocida obtained from birds (20) and pigs (36) it was observed that P. multocida is susceptible to doxycycline, since only 3% of the strains obtained from pigs showed resistance (See Table 1) [4].

Antimicrobial agent	% of strains of birds			% of strains of pigs
	S	I	R	S	I	R
Doxycycline	95	5	–	97	–	3
TABLE 1. S = sensitive; I = Intermediate sensitivity; R = Resistant. (Sellyei et al. 2009)

The results differ from those obtained in a trial conducted in India with P. multocida of birds with avian cholera, as 56.91% of the strains proved to be susceptible to the antibiotic (see Table 2) [5].

Antimicrobial agent	Concentration (mcg/disco)	Nº of resistant (%)	Nº of Intermediates (%)	Nº of sensitive (%)
Doxycycline-HCl	10	21 (25.20)	22 (17.89)	70 (56.91)
TABLE 2. (Shivachandra et al. 2004)

Doxycycline can be combined with tiamulin to obtain a synergistic effect against P. multocida and Mycoplasma [6].

Abstract: Sensitive microorganisms

• Doxycycline has proved to be effective against Mycoplasma spp. of avian origin.

• Doxycycline has proved to be effective against Brucella isolated in ruminants.

• There are variations in the prevalence of doxycycline resistance in P. multocida of avian origin.

III.2. Microorganisms that have shown marked resistance

a) Salmonella

Salmonella, apart from being a bacterium that causes food-borne zoonoses in humans, is one of the responsible for infectious toxic avian hepatitis.

According to a study carried out in China in 2008 with samples from birds in incubators, farms and slaughterhouses, there are multiple strains resistant to doxycycline (see Figure 1, source: [7]).

Graph 1.

The percentage of S. enteritidis resistant strains is lower than in S. indiana (56.9% and 97.85%, respectively). No significant differences were observed in microorganisms obtained from different sources (farm, incubators or slaughterhouse).

b) Streptococcus gallolyticus

Streptococcus species cause opportunistic infections in birds. Signs vary by species, but common presentations include septicemia, peritonitis, salpingitis, and endocarditis.

There is a high prevalence of resistance to doxycycline in strains of S. gallolyticus obtained from birds, even in healthy birds, probably due to the administration of this antibiotic to animals that do not show signs of disease (see Figure 2) [8].

Graph 2.

c) Clostridium perfringens

It is responsible for necrotic enteritis, one of the most important enteric diseases in broilers. It has demonstrated high levels of resistance to doxycycline (98%) in broiler isolates [9].

e) Escherichia coli

It is the cause of a very important poultry disease that is one of the main causes of disease, mortality and economic losses in poultry farms. Also in porciculture causes severe diarrhea after weaning and in newborn piglets.

The susceptibility of E. coli to doxycycline depends highly on the strain. The results of various studies of prevalence of resistance in E. coli isolated in birds vary widely: 70.12% [10]; 58.3% [11]; 16.98% [12]; so it is necessary to perform an antibiogram prior to administration of the antibiotic (see graph 3).

On the other hand, doxycycline has been able to eradicate an outbreak of colisepticemia in a broiler farm [13].

Graph 3.

f) Brachyspira hyodysenteriae

It is the causative agent of swine dysentery, a disease of great importance in the whole world.

80.9% of the isolates in pigs showed intermediate sensitivity to B. hyodysenteriae in samples obtained from clinical cases in Sweden [14]. These data corroborate the results of a study conducted in Poland, where a prevalence of intermediate-resistance sensitivity of 90.5% was observed [15].

Graph 4. Distribution of the minimum inhibitory concentration (MIC) of different species of Brachyspira (Mirajkar, Davies, and Gebhart 2016).

In contrast, in microorganisms isolated from laying hens no resistance to doxycycline was observed [17].

Summary: Microorganisms that have shown marked resistance

• Multiple strains of Salmonella enteritidis and S. indiana obtained from birds demonstrate a high prevalence of resistance to doxycycline, the percentage of resistant microorganisms varies according to the serogroup.

• The prevalence of resistance to doxycycline, even in healthy birds, is high. Despite this, the sensitivity in S. gallolyticus isolated from healthy mammals is high.

• The percentage of C. perfringens of avian origin resistant to doxycycline is high.

• The percentage of E. coli resistant to doxycycline varied widely depending on the strain.

• Variation of efficacy according to the species of Brachyspira hyodysenteriae: high percentages of resistance are observed in B. hyodysenteriae of porcine origin, while those of poultry origin prove to be susceptible.

IV. CONCLUSIONS

Doxycycline is an effective antibiotic against a wide variety of infectious agents, whether gram-positive, gram-negative, aerobic or parasite.

The efficacy of this compound on bacteria and mycoplasmas of animal origin is high, as demonstrated against Mycoplasma spp., Brucella and P. multocida.

Despite this, the presence of resistance in different microorganisms (Salmonella, S. gallolyticus, Clostridium, E. coli and Brachyspira) has been observed, depending on the serogroup, strain and species of origin, so it is advisable to perform an antibiogram prior to the administration of the treatment.

V. BIBLIOGRAPHY

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[14] M. Pringle, A. Landén, H. E. Unnerstad, B. Molander, and B. Bengtsson, “Antimicrobial susceptibility of porcine Brachyspira hyodysenteriae and Brachyspira pilosicoli isolated in Sweden between 1990 and 2010,” Acta Vet. Scand., vol. 54, no. 1, p. 54, 2012.

[15] J. Zmudzki, A. Szczotka, A. Nowak, H. Stzelecka, A. Grzesiak, and Z. Pejsak, “Antimicrobial susceptibility of brachyspira hyodysenteriae isolated from 21 Polish farms,” Polish Journat Vet. Sci., vol. 15, no. 2, pp. 259–265, 2012.

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