Treatment and Management of Feline Mycobacteriosis

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TREATMENT AND MANAGEMENT OF FELINE MYCOBACTERIOSIS

Author : DANIÈLLE GUNN-MOORE

Categories : Vets

Date : July 28, 2014

DANIÈLLE GUNN-MOORE BSc, BVM&S, PhD, FHEA, MACVSc, MRCVS presents the final part on her article, having previously covered epidemiology, pathogenesis, predisposition and clinical signs (VT44.10), and diagnosis (VT44.23)

MANY cases present with a single skin lesion, which is removed and sent for histopathology. It is only when the pathology report comes back suggesting a mycobacterial infection that this differential diagnosis is considered and the veterinary surgeon has to discuss treatment options with the owner.

The decision to treat a case of feline mycobacteriosis is difficult for many reasons. Most importantly, until the species has been identified it is not usually possible to tell whether the infection is tuberculosis, feline leprosy syndrome (FLS) or non-tuberculous mycobacteriosis (NTM).

In Great Britain, tuberculosis is likely in 34 per cent of cases, with any particular case having an approximately 15 per cent chance of being caused by Mycobacterium bovis (Table 1), although this does depend on where the cat lives (Gunn-Moore et al, 2011a). M bovis-infected cats are found in the south-west of England (coincident with the areas where cattle, badger, mice and other small rodents are infected with M bovis), while Mycobacterium microti-infected cats are found in the south-east of England, the north of England and the south of Scotland (where M microti-infected rodents have been detected; Gunn-Moore et al, 2011a).

Treating a case of suspected feline tuberculosis is contentious because of the potential zoonotic

1 / 16 risk; the need to use drugs that some people feel should be kept for use only in human tuberculosis; and the potential for generating drug-resistant mycobacteria (Masur, 1993).

Before undertaking treatment it is important to consider the following points.

• There is a potential zoonotic risk – the disease may be caused by a member of the tuberculosis complex (such as M bovis or M microti).

All members of the affected cat’s household must be considered. It is important to determine if there is anyone with potential immunosuppression, for example, HIV infection, or undergoing chemotherapy or organ transplantation. We strongly advise against treatment where such individuals may be exposed to an infected cat. We also advise against treatment if the affected cat has generalised disease, significant respiratory tract involvement, or extensive draining cutaneous lesions as these may increase the risk of transmission.

• Treatment is almost always long term and can be difficult to maintain considering patient non- compliance, the inherent toxicity of some of the drugs and the financial costs involved.

In some cases the drugs may, at best, suppress disease and indefinite treatment may be required. Uncomplicated cutaneous cases carry the most favourable prognosis (Greene and Gunn-Moore, 2012).

• Tailoring treatment is difficult:

? Sensitivity testing is recommended as drug sensitivities can vary between different isolates of the same organism (Horne and Kunkle, 2009); however, in vitro findings do not always correlate with in vivo results.

? Multiples of drugs are recommended to improve the chance of successful treatment and reduce the risk of generating resistant clones. However, when multiples of drugs are used, interaction is likely, and while some combinations are synergistic others are antagonistic. Unfortunately, the effects can be difficult to predict, even when using the same combination of drugs (Choi et al, 2012). It can vary

• between the species of mycobacteria involved and even the geographical strain of the species;

• whether treating intracellular or extracellular bacteria (the location of the bacteria is influenced by the type of pathology present – tuberculous verses lepromatous verses panniculitis with lipid droplets); and

• even with the species of host.

2 / 16 Unfortunately, as yet, we do not know the best drug combinations to use in cats, so treatment advice is likely to change with time.

? The drugs need to be effective in the face of an inadequate host immune response (defective innate ± adaptive immunity; Malik et al, 2013).

? Drugs used to treat humans with M tuberculous may be needed, for example, rifampicin, and discussion is needed in the veterinary profession as to the appropriateness of using these drugs if there is a risk of producing resistant clones. That said, rifampicin appears to be essential for the successful treatment of many cases of feline mycobacterial infection.

• Surgical excision of small cutaneous lesions may be considered. However, debulking larger lesions risks wound dehiscence and local recurrence of infection.

Interim management

Pending a definitive diagnosis, interim therapy with a fluoroquinolone has been recommended. However, this should only be considered in cases of localised cutaneous infection. Pradofloxacin is recommended as it is more effective against mycobacteria than older fluoroquinolones (Govendir et al, 2011). With more extensive disease, double or triple therapy is advised (Table 2). Giving more than one drug generally gives the best chance of clinical resolution, and decreases the potential for resistance to develop. Resistant clones can be a particular problem when treating tuberculosis or Mycobacterium avium-intracellulare complex (MAC), especially when using older fluoroquinolones such as marbofloxacin or enrofloxacin. This is an important consideration since drug resistance will be detrimental, not only to the individual cat, but may also endanger human patients.

Continuing treatment

It is strongly inadvisable to continue treating a cat if M tuberculosis is identified (these cases are incredibly rare, thankfully) or if a cat has disseminated disease and M bovis is identified, UK and Scottish law dictates M bovis infection is notifiable (Defra, 2013).

M microti and M avium are also potentially zoonotic, although very few human cases have been reported, and none due to feline exposure. Unfortunately, in many cases it is not possible to culture the organisms from tissue samples even when acid fact bacteria (AFB) are present. Because of this it is essential to counsel owners carefully so they know it might not be possible to identify the causal species, making it difficult to predict potential risks and complications.

Treatment for tuberculosis

Ideally, anti-tuberculosis treatment should consist of an initial and a continuation phase.

3 / 16 The initial phase usually requires three drugs and lasts for two months, while the continuation phase requires two drugs and lasts for perhaps a further four months, depending on the extent of disease. In those cats where triple therapy is not feasible, treatment should still involve two drugs and should be given for a minimum of six to nine months (Greene and Gunn-Moore, 2012).

A combination of drugs needs to be given. First-line treatment for tuberculosis in humans consists of combinations of rifampicin, isoniazid, ethambutol, dihydrostreptomycin or pyrazinamide. However, these drugs are very toxic in cats, and all but rifampicin are reserved for resistant cases.

The newer fluoroquinolones, including pradofloxacin (or moxifloxacin), have good efficacy against most mycobacteria, and clarithromycin (a macrolide) is useful, especially when given in combination with rifampicin and/or another antibiotic as per culture and sensitivity, for example, doxycycline.

A useful once-daily alternative to clarithromycin is azithromycin.

From clinical experience gained across 15 years, we at Edinburgh currently recommend an initial phase of rifampicin-fluoroquinolone-clarithromycin/azithromycin, followed by a continuation phase of rifampicin and either fluoroquinolone or clarithromycin/azithromycin (Table 2).

While these combinations are also used when treating human mycobacterial infections, some experimental studies have shown that with M tuberculosis and MAC infection (see later), combining these new fluoroquinolones with clarithromycin (or azithromycin) or rifampicin may be at least mildly antagonistic, and combining fluoroquinolones and rifampicin may be antagonistic against extracellular, but not intracellular, AFB.

What this means for the treatment of feline cases is not yet clear.

For ease of administration, all three once-daily medications can be given as liquids and placed in a single syringe prior to oral administration, or given as tablets with all three being given together after being placed in a single gelatin capsule and administered together using a pill popper.

Where oral medication proves too difficult, an oesophagostomy tube may be placed (through which the liquid medications can be given) and left in place for the duration of the treatment. It is not recommended owners put their fingers directly in the animal’s mouth when administering medication and they must wash their hands thoroughly after the medication has been given.

Rifampicin can cause significant side effects, including hepatotoxicity. It is, therefore, sensible to monitor cases closely, and check routine haematology and serum biochemistry two weeks after starting treatment, then every few months if possible, and whenever there is any change in the cat’s demeanour and/or appetite.

4 / 16 In cases where resistance develops, a rifampicin-isoniazid-ethambutol combination may be considered, although toxicity can be severe. If necessary, ethambutol can be substituted with dihydrostreptomycin or pyrazinamide. However, M bovis is naturally resistant to pyrazinamide. Rifampicin and isoniazid are more effective and less toxic than ethambutol and dihydrostreptomycin and, consequently, are more appropriate choices if only two drugs are required.

At present, we know cats with tuberculosis are deficient in vitamin D (Lalor et al, 2012). However, as yet, we do not know if treating this deficiency will help in the successful management of the cases.

Treatment for FLS

Surgical removal of small nodules is recommended, and clarithromycin, pradofloxacin and rifampicin or clofazamine are recommended (Table 2). Dapsone is considered too toxic for use in cats, and is antagonistic to clofazamine. Treatment should be continued until lesions are completely resolved, and ideally, a further two to three months to reduce the risk of recurrence; however, some cases require life-long clarithromycin to prevent this occurring (Malik et al, 2013).

Treatment for NTM

The minimum of a fluoroquinolone is suggested while waiting for culture. The new fluoroquinolones (such as pradofloxacin or moxifloxacin) are recommended as they have an extended spectrum of activity that includes some NTM, and are even effective against MAC.

However, while these newer fluoroquinolones are more effective as sole agents, they can cause problems when combined with other drugs, where they can have unpredictable effects – for example, moxifloxacin plus azithromycin or clarithromycin is less effective than moxifloxacin alone when treating M abscessus, but more effective when treating M massiliense (Choi et al, 2012).

Treatment of choice is therefore difficult to predict and evaluation of the individual case is required. Ideally, antimicrobial therapy should be determined by culture and sensitivity (although this is often not consistent with in vivo results, particularly with MAC infections), and if disease is extensive, double or triple therapy is recommended.

MAC infections are particularly difficult to treat. Clarithromycin should be included (Baral et al, 2006) ideally in combination with rifampicin ± another antibiotic as per culture and sensitivity – for example, doxycyclin. If initial treatment consisted of a fluoroquinolone, this should be stopped once the diagnosis is made as fluoroquinolones generally have poorer efficacy for MAC, and are antagonistic against clarithromycin when treating MAC. For resistant and extensive disease consider clarithromycin, rifampicin and ethambutol or amikacin. An alternative to clarithromycin is azithromycin, although it may not be as effective.

5 / 16 Different species of NTM have differing sensitivity patterns (Table 3), but these can vary between individual isolates. Consider using double or triple therapy as for tuberculosis (Table 2). Most cases have made a significant clinical improvement within a month, but treatment should be continued at least one to two months beyond apparent clinical resolution, and extensive or systemic infections typically need six to 12 months of treatment.

Pyogranulomatous panniculitis requires long-term antibiotics and radical well-planned surgery: for example, doxycycline for several weeks, then radical surgical excision and local reconstruction plus parenteral gentamicin perioperatively for three to five days, followed by a prolonged course (three to six months) of a fluoroquinolone. Non-surgical cases may require double or triple therapy.

Prognosis

Prognosis depends on the type of mycobacteria involved, the extent and severity of the infection and whether treatment involves the appropriate drug(s) for the necessary length of time.

While many cases respond favourably to treatment (56 per cent overall in the largest study), and achieve apparent cure or long-term remission (42 per cent), the prognosis should be stated as guarded because relapses are common (64 per cent), and are often followed by pulmonary and/or systemic spread (Gunn-Moore et al, 2011b).

Cutaneous tuberculosis caused by M microti or M bovis typically responds well to treatment (even if there is pulmonary involvement). However, the prognosis should always be stated as guarded.

While some cases of FLS respond favourably to treatment, and some resolve spontaneously, some may be more complicated. Prognosis should be stated as good to poor.

Prognosis of disease due to NTM is more variable, and should be stated as poor to guarded. It is very dependent on the extent of disease and the specific mycobacteria involved. Systemic disease caused by M avium is typically difficult to treat; as is extensive granulomatous panniculitis, and the prognosis deteriorates further if there have been previous unsuccessful attempts at surgery.

References

Baral R M, Metcalfe S S, Krockenberger M B, Catt M J, Barrs V R, McWhirter C, Hutson C A, Wigney D I, Martin P, Chen C A, Mitchell D H and Malik R (2006). Disseminated Mycobacterium avium infection in young cats: overrepresentation of Abyssinian cats, Journal of Feline Medicine and Surgery 8(1): 23-44. Choi G E, Min K N, Won C J, Jeon K, Shin S J and Koh W J (2012). Activities of moxifloxacin in combination with macrolides against clinical isolates of Mycobacterium abscessus and Mycobacterium massiliense, Antimicrobial Agents and Chemotherapy 56(7): 3,549-3,555.

6 / 16 Defra (2013). Defra guidance notes on tuberculosis in cats and dogs, www.defra.gov.uk/ahvla-en/files/AG-TBYP-01.pdf Greene C E and Gunn-Moore D A (2012). Mycobacterial infections. In Greene C E (ed) Infectious Diseases of the Dog and Cat (4th edn), W B Saunders, Philadelphia: 495-510. Govendir M, Norris J M, Hansen T et al (2011). Susceptibility of rapidly growing mycobacteria and Nocardia isolates from cats and dogs to pradofoxacin, Veterinary Microbiology 153(3-4): 240-245. Gunn-Moore D A, McFarland S, Brewer J, Crawshaw T, Clifton-Hadley R S, Kovalik M and Shaw D J (2011). Mycobacterial disease in cats in Great Britain: I. bacterial species, geographica distribution and clinical presentation of 339 cases, Journal of Feline Medicine and Surgery 13(12): 934-944. Gunn-Moore D A McFarland S Brewer J Crawshaw T, Clifton-Hadley R S, Schock A and Shaw D J (2011). Mycobacterial disease in a population of 339 cats in Great Britain: II. Histopathology of 225 cases, and treatment and outcome of 184 cases, Journal of Feline Medicine and Surgery 13(12): 945-952. Horne K S and Kunkle G A (2009). Clinical outcome of cutaneous rapidly growing mycobacterial infections in cats in the south-eastern United States: a review of 10 cases (1996-2006), Journal of Feline Medicine and Surgery 11(8): 627-632. Lalor S M, Mellanby R J, Friend E J, Bowlt K L, Berry J and Gunn-Moore D (2012). Domesticated cats with active Mycobacteria infections have low serum vitamin D (25(OH)D) concentrations, Transboundary and Emerging Diseases 59(3): 279-281. Malik R, Smits B, Reppas G, Laprie C, O’Brien C and Fyfe J (2013). Ulcerated and nonulcerated nontuberculous cutaneous mycobacterial granulomas in cats and dogs, Veterinary Dermatology 24(1): 146-153. Masur H (1993). Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease in patients infected with the human immunodeficiency virus. Public Health Service Task Force on prophylaxis and therapy for Mycobacterium avium complex, N Engl J Med 329(12): 898-904.

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Figure 1. Placing an oesophagostomy tube can be a helpful way to administer long-term anti- mycobacterial medication. This cat had a non-tuberculous mycobacterial infection in its “apron fat” (see Figure 2). Prior to leaving the clinic the tube was cut short to approximately 5cm so it (with the bung in place) fitted neatly below the patient’s normal collar.

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Figure 2. Pyogranulomatous panniculitis in the “apron fat” of a three-year-old, neutered, female, domestic shorthaired cat. The lesion contained Ziehl Neelsen (ZN) positive acid-fast bacteria (AFB), but no mycobacteria could be grown on culture.

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Figure 3. A low-profile percutaneously placed endoscopic gastrostomy (PEG) tube was used to administer daily anti-mycobacterial drugs to the same cat as in Figure 1 and Figure 2. Ultimately, it needed a year of treatment (and pulled out three oesophagostomy tubes when climbing trees, hence the decision to place the low-profile PEG tube).

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12 / 16 Table 1. Mycobacterial culture results

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Table 2. Potentially useful drugs for the treatment of feline mycobacterial disease* (see text for information on potential drug combinations and treatment duration)

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Table 3. More detail on potentially useful drugs for the treatment of feline non-tuberculous mycobacterial disease

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