Chlamydia abortus is the causative agent of EAE and a zoonotic pathogen posing potential threat to pregnant women when in contact with infected ewes (Table 1). Globally, C. abortus is a serious cause of economic loss to the sheep production industry (Pospischil et al., 2002; Longbottom and Coulter, 2003). Treatment of early abortion and suspected EAE involves long-acting oxytetracycline (20 mg/kg) during the last month of pregnancy flock-wide (Supplementary Table 1). This administration has been shown to reduce the severity of C. abortus infections, pathological damage and eventually to increase the chances of live birth (Aitken et al., 1982; Greig et al., 1982). Usually a single dose is recommended to avoid emergence of TET resistance, however, fortnightly routine administration (oral tetracycline type product included in the feed at 400–500 mg/hd/day) until lambing seems to further suppress chlamydial shedding, which is crucial to prevent excretion of C. abortus at birth as well as on-farm spread of the infection (Rodolakis et al., 1980; Supplementary Table 1). Prophylactic use of tetracycline could potentially lead to emergence of acquired TET resistance, moreover, the use of therapy does not guarantee eradication of C. abortus infection with a small percentage of the pregnant flock still producing stillborn and weak born lambs whilst potentially carrying C. abortus post-treatment (Essig and Longbottom, 2015; Rodolakis and Laroucau, 2015; Table 1). To date tetracycline-resistant strains in C. abortus have not been isolated yet, however, relapse of infection or presence of C. abortus shedding post-treatment is suggestive of treatment failure due to the establishment of antibiotic protected reservoirs. Simultaneous detection of C. suis and C. abortus in semen of boars and conjunctiva of sows in pig production has been reported (Schautteet et al., 2010), further highlighting the potential risk of the spread of TET^R resistance to other animal chlamydiae if significant selective pressure is maintained (Suchland et al., 2009). Despite being a major veterinary pathogen of zoonotic importance, there appears to be a lack of in vitro and in vivo models/studies investigating the role of antibiotics in the treatment of C. abortus infections in humans and animals.

Chlamydia psittaci is an avian pathogen capable of causing systemic wasting disease in wild birds and production species such as chickens and ducks (Knittler and Sachse, 2015). Infection spill-over to other hosts is also a concern with C. psittaci recognized as a serious zoonotic agent of atypical pneumonia in humans (Stewardson and Grayson, 2010; Knittler and Sachse, 2015) with evidence growing for spill-over of infections and disease to other mammalian hosts as well (Van Loo et al., 2014; Jenkins et al., 2018). Human cases of psittacosis are effectively treated using orally administered doxycycline and tetracycline hydrochloride for a period of 10–14 days (Beeckman and Vanrompay, 2009; Senn et al., 2005). In patients for whom tetracycline is contra-indicated, i.e., in pregnant woman and children under the age of 8 years treatment with azithromycin and erythromycin at a dose of 250–500 mg PO qd for 7 days has proven to be the best alternative (Senn et al., 2005; Beeckman and Vanrompay, 2009). This is probably the main reason for the general decline in psittacosis cases worldwide, particularly those with fatal outcome, in the past decades. However, use of quinolones to treat chlamydia infections in humans has resulted in reports of treatment failure (Beeckman and Vanrompay, 2009).

The antibiotics of choice in veterinary medicine for the treatment of C. psittaci infections are doxycycline or other tetracyclines and the fluoroquinolone enrofloxacin administered orally (feed/drinking water) or parenterally (intramuscular or subcutaneous routes) (Flammer, 1989; Butaye et al., 1998; Supplementary Table 1). In terms of persistent infections, studies in bovine respiratory models have shown that treatment with tetracycline or rifampicin revealed evidence of clinical recovery of respiratory symptoms although re-isolation of the organism was still possible in some animals with no significant reduction in chlamydial shedding 14-days post-treatment of antibiotics (Prohl et al., 2015a,b; Table 1). In vitro studies also suggest that the development of drug-resistant C. psittaci strains is possible (Binet and Maurelli, 2005) and that C. psittaci is also capable of entering a persistent state upon treatment with penicillin G conceivably playing a role in the development of chronic infections, as well as in failure of antibiotic therapy and immunoprophylaxis (Goellner et al., 2006; Table 1). Although, TET^R seems to be a problem only in C. suis, lack of antimicrobial resistance screening in routine diagnostic testing from C. psittaci field isolates in poultry and cattle impairs the assessment of the actual situation. While treatment with doxycycline and/or azithromycin seems to be efficacious for C. psittaci infections in birds, the widespread use of tetracycline in feed and/drinking water and long periods of treatment (21–25 days) in the poultry and bird industry (Guzman et al., 2010; Krautwald-Junghanns et al., 2013) can also lead to an accumulation of sub-therapeutic drug plasma concentrations (Tell et al., 2003), supporting the emergence of drug-resistant C. psittaci strains (Supplementary Table 1). Subclinical, persistent and chronic disease and infection relapse post-treatment is also plausible suggesting that there is need for pre- and post-antimicrobial treatment surveillance of C. psittaci infections in animals.

Antibiotic therapy and the associated resistance reported for C. suis have been thoroughly reviewed recently (Borel et al., 2016). Briefly, C. suis is an endemic GIT pathogen of pigs. While a range of pathologies have been reported in association with C. suis infection (respiratory disease, diarrhea, conjunctivitis and reproductive disorders), the high rates of GIT positivity for this pathogen are commonly reported in the absence of disease (Schautteet and Vanrompay, 2011). Due to the endemic nature of C. suis in most pig production facilities, infections are rarely treated by antibiotics such as oxytetracycline. Quinolones (enrofloxacin) or macrolides (erythromycin) can be administered, in case of an infection with a TET^R C. suis strain (Schautteet and Vanrompay, 2011; Table 1). However, due to emergence of TET^R in C. suis, alternative treatment strategies such as the short-term treatment of C. suis infections with enrofloxacin and tiamulin was unsuccessful resulting in recurrence of C. suis infections in pigs (Reinhold et al., 2011a). The TET^R feature of this bacterium, namely that it is the first and only species of intracellular bacteria known to have genetically acquired antibiotic resistance (Sandoz and Rockey, 2010) is of significant interest. The basis of this stable TET^R phenotype is the presence of a Tet-island in the genome of C. suis, consisting of tetC gene encoding a TET efflux pump, TET repressor gene (tetR) (Dugan et al., 2004). These loci share high nucleotide sequence identity with several other Gram-negative bacterial-resistance plasmids, one of them being the fish bacteria Aeromonas salmonicida mobilizable plasmid pRAS3.2 (Dugan et al., 2004). Expanded studies of this Tet-island found that even in very distinct C. suis evolutionary lineages, this Tet island is present in the same genomic location adjacent to an rRNA operon (Seth-Smith et al., 2017). Based on studies at the herd-level, antibiotic treatment appears to promote the emergence of TET^R and further spread of this resistance cassette among Tet-sensitive C. suis strains (Hoffmann et al., 2015; Wanninger et al., 2016).

It should be noted that acquisition of Tet Island is associated with mobile genetic elements, raising concerns over the potential spread and distribution of these elements across diverse set of bacteria, particularly into C. trachomatis, the most closely related currently described chlamydial species to C. suis. This potential risk has been confirmed experimentally with studies showing that C. suis can confer TET^R to C. trachomatis in vitro (Suchland et al., 2009). Further highlighting this risk, C. suis has also been documented in ocular infections in humans with trachoma (Dean et al., 2013) and in workers in a pig production facility (De Puysseleyr et al., 2014). While most of the current risk of C. suis TET^R resistance is confined to pigs, C. suis has also been detected in other animals including livestock, horses, cats, poultry (Teankum et al., 2006; Polkinghorne et al., 2009; Pantchev et al., 2010; Szymanska-Czerwinska et al., 2013; Guo et al., 2016) and wildlife (e.g., frogs) (Blumer et al., 2007).

There is limited information on the efficacy of antibiotics against C. pecorum, with a single in vitro study suggesting that livestock isolates of this pathogen are susceptible to macrolides, tetracyclines and quinolones with potential recovery upon removal of the antibiotic not evaluated to further understand chlamydial latency (Pudjiatmoko et al., 1998; Table 1). In practice, treatment of C. pecorum-infected animals displaying evidence of arthritis, sporadic bovine encephalitis and conjunctivitis involves the use of intramuscular injections of long-acting oxytetracycline (300 mg/mL at a dose rate of 1 mL per 10 kg bodyweight) once a week, twice (Walker et al., 2016; Supplementary Table 1). Potential issues of chlamydial latency rather than infection clearance (Mårdh and Löwing, 1990; Smith, 2002) have been reported in association with this treatment with detectable chlamydial DNA loads as high as pre-treatment levels, three to 6 weeks post-treatment reported in some studies (Parkinson et al., 2010; Reinhold et al., 2011b; Walker, 2013; Table 1). In vitro data also suggests that penicillin G induces the chlamydial stress response (persistence) and is not bactericidal for this chlamydial species (Leonard et al., 2017; Table 1). This is of particular concern in livestock production industry where it is likely that some animals with endemic, asymptomatic C. pecorum infection are treated with both veterinary-approved and off-label antibiotics for other infections and purposes.

The treatment of C. pecorum infections is also of relevance to the veterinary treatment of the iconic Australian marsupial, the koala. Koalas infected by C. pecorum can develop ocular and urogenital tract disease that may lead to animals being admitted into wildlife hospitals for veterinary treatment (Polkinghorne et al., 2013). Treatment of clinical and subclinical koala chlamydiosis most commonly involves the administration of chloramphenicol due to its perceived safety and anecdotal effectiveness, despite a lack of information on therapeutic efficacy or pharmacokinetics in this marsupial host (Black et al., 2015; Table 1). Chloramphenicols are preferred over the efficacious first-line antichlamydials, azithromycin, or tetracyclines, as use of the latter antibiotics have been associated with gastrointestinal dysbiosis and emaciation in koalas (Osawa and Carrick, 1990). Summary of treatment regimens and associated complications of ocular, urogenital and reproductive tract disease in koalas have been reviewed in detail and can be found elsewhere (Vogelnest and Portas, 2018; Supplementary Table 1).

The discovery of new family level lineages in the order Chlamydiales such as the Parachlamydiaceae, Simkaniaceae, Criblamydiaceae, and Waddliaceae has prompted investigations into the pathogenic potential of this bacteria. Thus far, a range of studies have suggested that these bacteria may be linked to adverse pregnancy outcomes and respiratory disorders in humans and animals, with animal contact as a potential risk factor for higher prevalence (Taylor-Brown et al., 2015; Ammerdorffer et al., 2017; Borel et al., 2018; Table 1). While the pathogenic potential of these chlamydiae is yet to be fully defined, more recently described chlamydiae spread across several family-level taxonomic groups are well recognized causes of the gill disease of fish, epitheliocystis (Blandford et al., 2018).

There are very limited studies reported so far on antibiotic treatment regimens for CRBs in humans and animals with most of the knowledge of antibiotic efficacy and/or phenotypic resistance based on in vitro studies (Friedman et al., 2003; Goy and Greub, 2009; Greub, 2009; Vouga et al., 2015, 2017). These in vitro studies have revealed that most CRBs are resistant to quinolones and β-lactams with Parachlamydia and Neochlamydia spp. also demonstrating phenotypic resistance to amoxicillin, ceftriaxone and imipenem (MIC ≥32 μg/ml) (Vouga et al., 2015; Table 1). In the absence of data from animal models and from case reports, azithromycin, clarithromycin and/or doxycycline might be used therapeutically in case of Parachlamydia acanthamoebae infections (Greub, 2009). For Simkania, a single case study reported that simkania-associated pneumonia was successfully treated with a regimen of erythromycin (Lieberman et al., 1997). Oxytetracyclines have been found to be effective in treating epitheliocystis infections in several fish species, usually, mixed in the feed at a dose of 50 mg/kg/d for 3–5 consecutive days (Goodwin et al., 2005; Chang et al., 2016; Supplementary Table 1). Enrofloxacin failed to treat a leopard shark with epitheliocystis (Polkinghorne et al., 2010). Apart from the use of antibiotics in aquaculture, several alternative strategies have been used for treating epitheliocystis such as sterilization of rearing water using ultraviolet light (Miyaki et al., 1998), chemical treatments such as formalin, salt, benzalkonium chloride, potassium permanganate, and water exchange (Somridhivej et al., 2009; Blandford et al., 2018).