Biology of Pathogenic Actinobacteria

Chapter 15

Biology of Pathogenic Actinobacteria: Nocardia and Allied Genera Kiran Chawla and Peralam Y. Prakash Kasturba Medical College, Manipal University, Manipal, Karnataka, India

15.1

INTRODUCTION

The present chapter deals with pathogenic actinobacteria of the genus Nocardia and allied genera with involvement in human infections. The genus Nocardia is mainly an opportunistic pathogen, causing infections in immunocompromised individuals such as patients with acquired immunodeficiency syndrome (AIDS), transplant recipients, and patients with long term steroid use (Georghiou and Blacklock, 1992; Van Burik et al., 1997). The term Nocardia was coined by Trevisan for Edmund Nocard, who in 1888, first described it as an aerobic actinomycetes from bovine farcy, a lymphatic disease of cattle caused by Nocardia farcinia. Later in 1890 Eppinger first described nocardiosis in humans in a report of a pulmonary disease with “pseudotuberculosis” of the lungs (McNeil and Brown, 1994; Brown-Elliott et al., 2006).

15.2

TAXONOMY, ECOLOGY, STRUCTURE

The taxonomy of Nocardia has undergone many revisions (McNeil and Brown, 1994; Brown-Elliott et al., 2006). The Nocardia genus belongs to the family Nocardiaceae and the order Actinomycetales. Since nocardiaceae branch into filaments, they were earlier misclassified as fungi. Nocardia contain tuberculostearic acids such as mycobacteria and they also possess short-chain (40 60 carbons) mycolic acids, which discriminates them from the latter (Goodfellow and Pirouz, 1982). Currently, over 50 species of Nocardia have been isolated from clinical infections. The most important pathogenic species in humans include Nocardia abscessus, Nocardia brevicatena/paucivorans complex, Nocardia nova complex, Nocardia transvalensis complex, Nocardia farcinica, Nocardia cyriacigeorgica, Nocardia otitidiscaviarum (Ramamoorthi et al., 2011), Nocardia veterana, Nocardia brasiliensis, Nocardia pseudobrasiliensis, and Nocardia africana (McNeil and Brown, 1994; Brown-Elliott et al., 2006; Mordarska et al., 1972). Recently, few newer species of Nocardia had been reported in the literature, viz., pulmonary infection due to Nocardia wallacei (Gonza´lez-Nava et al., 2016), Nocardia amamiensis (Martinez-Gamboa et al., 2017), and disseminated Nocardiosis by Nocardia elegans (Nakamura et al., 2017). Nocardia is a genus of aerobic gram positive modified acid fast stain positive bacteria widely distributed in dust, soil, water, and decaying organic plant matter. Pulmonary and systemic infections occur by inhalation of organisms through the respiratory tract, whereas cutaneous disease occurs following traumatic injury through the soil contaminated objects (McNeil and Brown, 1994; Brown-Elliott et al., 2006).

15.3

CLINICAL SPECTRUM

Clinical manifestation of disease may vary from fever, cough, pleural pain (Gowrinath et al., 2009b), anorexia, corneal ulcer, and pneumonia, to buccal space (Beena et al., 2014), mycetoma (Banashankari et al., 2013), and encephalitis (Beaman and Beaman, 1994). Disseminated nocardiosis may involve any organ, but lesions on the brain or meninges are the most common. Nocardiosis is found to be more common in males than in females. All age groups are

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susceptible and more cases are reported between 21 to 50 years of age. Disease has a high mortality, which ranges from 45% to 85%. Approximately 60% of cases of nocardiosis are associated with pre-existing immune compromise (Ambrosioni et al., 2010).

15.3.1

Pulmonary Manifestations

Pulmonary nocardiosis remain the most common manifestation which present as sub-acute or chronic, often with necrotizing pneumonia and associated cavitation. Clinical features that are non-specific may include anorexia, weight loss, productive cough, pleural pain, dyspnoea, and occasionally haemoptysis (Chawla et al., 2009). Empyema may present in 25% cases. Radiographic findings show fluffy infiltrates, irregular densities, sub-pleural plaques, single or scattered regular or irregular nodules or masses (often cavitated), single or multiple abscesses (Chawla et al., 2010), and even simple alveolar or interstitial reticular or reticulonodular infiltrates which may not be conclusive for specific diagnosis. The presence of cavitiary pulmonary lesions and vasculitic skin lesions may lead to false diagnosis of Wegener’s granulomatosis. Further presence of thick walled cavities and endobranchial lesions may confuse for malignancy (BrownElliott et al., 2006). In few cases, miliary lesions and respiratory distress syndrome may be seen. In rare cases, “Fungus ball” may be seen, resulting from invasion of pre-existing lung cavities by the Nocardia species (Brown-Elliott et al., 2006; Yildiz and Doganay, 2006). Tissues usually exhibit a mixed cellular response with polymorphonuclear leukocytes, macrophages, and lymphocytes infiltration; granulamatous response may be seen occasionally mimicking tuberculosis or histoplasmosis in tissue with central necrosis and calcification. In adequately treated patients, progressive fibrosis may occur with a chronic course similar to tuberculosis. Pulmonary infections may further lead to complications such as pleural effusion, empyema, pericarditis (Ramanathan and Rahimi, 2000), mediastinitis, and, rarely, local chest wall and neck abscesses.

15.3.2

Primary Cutaneous or Subcutaneous Infections

This entity represents 25% of cases and ensues following implantation. The manifestation of Nocardia includes classic mycetoma, a chronic, deep, penetrating, progressively destructive infection of skin, subcutaneous tissue, fascia, bone and muscles following localized trauma producing a localized swelling containing suppurative granulomas and multiple sinus tracts extruding white yellow granules which are only associated with mycetoma (McNeil and Brown, 1994; Brown-Elliott et al., 2006; Mahgoub, 1995) (Fig. 15.1). Further manifestations include cellulitis, pustules, pyoderma, paronychia, or localized abscesses that resmble pyogenic bacterial infections. It can also produce lymphangitis with subcutaneous nodules mimicking sporotrichosis, and is thus called the sporotrichoid nocardiosis. Most reported cases of lymphocutaneous nocardiosis are due to N. brasiliensis, but some are mimicked by Nocardia asteroides and N. otitidiscaviarum; both normal and compromised hosts may be involved. At least half of the mycetomas are caused by aerobic actinomycetes, mostly Nocardia species. Nocardia brasiliensis is the most frequently recognized cause of Nocardia induced mycetomas (Table 15.1). Cases with etiological involvement of N. asteroides, N. otitidiscaviarum, and N. transvalensis in mycetoma are also reported.

15.3.3

Systemic Infections

The systemic or disseminated Nocardia disease may be defined as presence of Nocardia lesions in two or more organs of the body. The most common sites for disseminated nocardiosis are the central nervous system (CNS), skin, and subcutaneous tissues, kidneys, joints, bones, heart, and eyes, which may get infected from a primary lesion either pulmonary or cutaneous, via the haematogenous route. Early systemic infection of Nocardia is similar to pyogenic infections, with neutrophils dominating the host immune response. As the infection advances to the chronic phase, the immune response involves macrophages and lymphocytes. As a result of progressive tissue invasion by nocardial filaments, the abscesses enlarge and remain progressive until treatment is started. Peritonitis, epididymo-orchitis, iliopsoas and perirectal abscesses, septic arthritis, pericarditis, endocarditis, osteomyelitis, and peritonitis in cases of chronic peritoneal dialysis and renal transplants have also been reported in some patients in the past (Peterson et al., 1982; Arduino and Johnson, 1993). In a study by Beaman & Beaman, the most common sites for infection in AIDS patients were lung (51.3%) and brain (11.7%). Further cases of Nocardia pericarditis and cardiac tamponade caused by Nocardia asteroids have also been reported in HIV infected individuals (Rivero

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FIGURE 15.1 Actinomycotic mycetoma of lower limb with tumefaciens, and multiple draining sinuses.

TABLE 15.1 Characteristic Features of Actinomycotic Mycetoma Characteristic Features

Actinomycetoma

Tumefaction

Tumor mass

Multiple and III-defined

Extent

More extensive and often osteolytic

General

Early onset and profuse

Opening

Raised with flared margins

Flap of opening

Easy to remove

Nature of discharge

Purulent

Characters

Color

Size (mm)

Etiology

White Yellow

2

Actinomadura madurae

Pink Red

0.5

Actinomadura pelleteri

Pale Yellow White

,0.5

Nocardia brasiliensis

White Yellow

,0.5

Nocardia caviae; Nocardia asteroides

Cream

,0.5

Nocardiopsis dasonvilli

Yellowish White

1

Streptomyces somaliensis

Sinuses

Grains

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et al., 2000; Chandrashekar et al., 2009). Eye involvement includes endophthalmitis and retinitis. Keratoconjunctivitis has been found as a consequence of traumatic inoculation.

15.3.4

CNS Involvement

Approximately 45% of patients with systemic nocardiosis have CNS infections (Munoz et al., 2007). Signs and symptoms of nocardial brain infection are highly variable as infectious foci may be silent and discovered only at autopsy, or may mimic tumors or present as classical abscesses or meningitis. Infection is often insidious thus difficult to diagnose and treat. Neurological impairment sometimes results in psychiatric disorders such as depression, schizophrenia, dyslexia, amnesia, and palilalia. Neurological presentations include hemiparesis, Parkinsonian features, seizure, coma, and ataxia (Beaman et al., 1992). Patients with minimal neurologic symptoms can be treated with antibiotics only; however, in most cases, surgical excision is required due to multilocation of abscesses. The abscesses can involve parietal, frontal, or occipital cortex, basal ganglia, and cerebellum. A large number of brain abscesses cases reported involve N. asteroides, although other species have been reported. Studies suggest that CNS infections are more destructive and rapidly progressive in compromised hosts as compared to normal hosts. Further studies showed that the mortality rate in patients with multiple abscesses is twice of that among patients with solitary abscesses.

15.4

APPROACHES FOR IDENTIFICATION

Presumptive genus level identification is possible by colony morphology, staining attributes, stereomicroscopic examination of aerial hyphae, and growth in lysozyme broth (Emmons et al., 1977). The members of non-Mycobaterium tuberculosis, Gordonia exhibit similar characteristics and more conclusive discrimination is thus warranted. Conventional modalities for identification commonly employ morphology, physiology, growth requirements, and biochemical methods using identification schema and algorithms (McNeil and Brown, 1994; Brown-Elliott et al., 2006). Accurate identification of a larger group of pathogenic Nocardia is possible by employing molecular methods (McNeil and Brown, 1994; Brown-Elliott et al., 2006). Further, members of the genus Nocardia exhibit susceptibility profiles aiding identification (Glupczynski et al., 2006; McNeil and Brown, 1994; Brown-Elliott et al., 2006) (Figs. 15.2 15.6).

FIGURE 15.2 Colony morphology of commonly encountered pathogenic actinobacteria with characteristic dry, wrinkled colonies.

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FIGURE 15.3 Streptomyces somaliensis on 5% sheep blood agar with no hemolysis.

FIGURE 15.4 Nocardia asteroides on skimmed milk agar with typical pale orange pigmentation.

FIGURE 15.5 Nocardia gram staining 1003 showing slender, branching, gram positive filaments.

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FIGURE 15.6 Nocardia modified kinyoun 1003 showing slender, branching, acid fast filaments.

15.5 MANAGEMENT OF NOCARDIA AND OTHER ACTINOBACTERIA ASSOCIATED INFECTIONS Due to the lack of prospective controlled trials, optimal antimicrobial treatment regimens for Nocardia have not been firmly established. Nocardia displays variable in vitro antimicrobial susceptibility patterns, and management of nocardial infections must be individualized. In the past 50 years, sulfonamides, including sulfadiazine and sulfisoxazole, have been the drug of choice for treating nocardiosis even though in vitro activity of sulfonamides is often less impressive when compared with that of other antimicrobial agents patients have been successfully treated. Sulfadiazine can induce oliguria, azotemia, and crystalluria in patients who fail to maintain a high fluid intake, which can be overcome by urine alkalinisation with oral sodium bicarbonate. Sulfisoxazole is equally effective and much less likely to cause oliguria. Trisulfapyrimidine combinations should be as effective and less toxic. In adults with normal renal function, the recommended dosing schedule (6 12 g in 4 6 divided oral doses, after a loading dose of 4 g) should lead to a serum level of 100 150 µg/mL 2 hours after administration of a dose.

15.5.1

Therapeutic Choices and Consideration

Trimethoprim-sulfamethoxazole (TMP-SMX) is the most commonly used sulfonamide preparation. Divided doses of 5 10 mg/kg per day of the trimethoprim component (or 25 50 mg/kg per day of sulfamethoxazole) are recommended to produce sulfonamide serum concentrations between 100 and 150 µg/mL. Adverse reactions to high-dose TMP-SMX therapy are frequent and include myelosuppression, hepatoxicity, and renal insufficiency. Trimethoprimsulfamethoxazole is active against most Nocardia species. It is found that N. otitidiscaviarum, N. nova, and N. farcinica are occasionally resistant to TMP-SMX (Brown-Elliott et al., 2006; Chawla et al., 2012). In HIV infected patients TMP-SMX combination, manifests as severe hypersensitivity reactions, hepatotoxicity and prolonged myelosuppression. In organ transplantation patients treated with the antirejection medication cyclosporine, TMP-SMX may lead to cyclosporine-induced nephrotoxicity. This is a reversible condition. Alternative antimicrobial agents with activity against Nocardia include amikacin, imipenem (Gombert and Aulicino, 1983), meropenem, amoxicillin clavulanic acid, ceftriaxone, cefotaxime, minocycline, moxifloxacin (Hoogkamp-Korstanje and Roelofs-Willemse, 2000), levofloxacin, linezolid (Moylett et al., 2003), and tigecycline. Imipenem is found to have better activity in contrast to a combination of meropenem or ertapenem against most Nocardia species (McNeil et al., 1995; Cercenado et al., 2007). Minocycline (100 200 mg twice a day) used as a substitute for sulfonamides is effective particularly in pulmonary nocardiosis; it was also found effective in treating a brain abscess. Nocardia transvalensis isolates are significantly resistant to minocycline. Amikacin displays impressive in vitro activity against 90% 95% of all tested strains, except N. transvalensis. Clinical experiences, particularly with compromised patients, have also been encouraging. Amikacin reduced mortality convincingly in a murine intraperitoneal infection model. Imipenem is also consistently active in vitro, although 18% 36% of N. farcinica strains are not susceptible and 70% of N. brasiliensis strains are resistant

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as well. A favorable clinical outcome with combination imipenem/amikacin therapy has been reported in a case of prosthetic aortic valve endocarditis. Combinations of amikacin and imipenem with cefotaxime and TMP-SMX display in vitro synergy against most strains (Gombert et al., 1986). Imipenem/cefotaxime display synergy in 92% of tests, amikacin/TMP-SMX in 83% of tests, and imipenem/TMP-SMX in 80% of tests, while imipenem/amikacin is a predominantly additive, sometimes synergistic, combination. Imipenem and amikacin were statistically superior in combination (than either alone) in reducing tissue organism counts in the brains of mice with cerebral nocardiosis (Gombert et al., 1990). Patients with severe nocardiosis may benefit from the addition of a third agent, such as linezolid (Moylett et al., 2003). Combination therapy need to be proceeded until clinical improvement. Single-drug therapy may suffice thereafter. Treatment time is extended to avoid or lower the risk of relapse. Immunocompetent patients with pulmonary or multifocal (non-CNS) nocardiosis may be treated for 6 12 months of therapy. The immunocompromised and patients with CNS disease should receive at least 12 months of antimicrobial therapy with the appropriate clinical monitoring. Linezolid, an oxazolidinone, is quite active against all pathogenic Nocardia species. It is used in the treatment of patients with disseminated and CNS nocardiosis. Its cost and significant toxicities, including myelosuppression, peripheral neuropathy, and lactic acidosis, limits its use (Moylett et al., 2003). Amoxicillin-clavulanic acid is moderately active against many strains of N. asteroids (Wallace et al., 1988), N. farcinica (Gowrinath et al., 2009a), and N. brasiliensis (Smego and Gallis, 1984), but inactive against most strains of N. nova, N. otitidiscaviarum (Gowrinath et al., 2008), and N. transvalensis. Among the Nocardia species, N. farcinica, N. brasiliensis, and N. otitidiscaviarum tend to have higher increased chances of resistance to multiple antimicrobial agents.

15.5.2

Duration of Therapy and Progression

Clinical response is evident within 7 10 days after the initiation of therapy. Parenteral therapy can be changed to an oral regimen, and high doses of TMP-SMX may be reduced after 3 6 weeks. Patients with extensive nocardiosis, those inaccessible to surgery, and slow responders may benefit from prolongation of intravenous and oral treatment. Response to early therapy may be hindered due to primary drug resistance, inadequate penetration of drugs into sites of infection, especially in abscesses, and immunocompromised status, including AIDS (Kim et al., 1991). Treatment duration is dependent on the site of the lesion, the extent, and the underlying patient immunity. Cutaneous forms are cured after 1 3 months of treatment, but prolonged therapy is required in cases of mycetoma (Partha et al., 2014). Pulmonary and systemic nocardiosis, excluding CNS involvement, should be treated for at least 6 months (Chawla et al., 2009). In non-HIV-infected patients therapy needs to be continued for 12 months or longer; depending on increase in immunosuppression, with treatment with TMP-SMX in low doses being necessary. In AIDS patients, low doses of TMP-SMX is considered for secondary treatment. Further, primary treatment in patients who are immunocompromised is not recommended, owing to the low incidence of nocardiosis. It is has been noted that the use of TMP-SMX for the treatment of other opportunistic infections is found to have a favorable effect against nocardiosis. The clinical outcome of therapy depends on the site and extent of diseases and underlying host factors; 100% cure in patients with soft tissue involvement is found. The successful treatment outcome is 90% in pleuropulmonary disease, 60% in disseminated forms, and 50% in brain abscesses. Mortality is higher among immunocompromised patients and those with multiple brain abscesses. Many of the patients have successful treatment outcome, with early initiation of treatment. Delay in diagnosis and early suspension of treatment, especially in AIDS patients, is associated with relapse and failure of treatment.

15.5.3

Surgical Treatment

The extent and site of nocardiosis dictates the role of management by surgery. In extraneural disease, indications for aspiration, drainage, or excision of abscesses are similar to those for other chronic bacterial infections. Needle aspiration is generally insufficient to have any therapeutic value in patients with thick-walled multiloculated abscesses, which contain free-flowing pus, including patients with mycetomas. In patients with brain abscesses, surgery should be performed when the abscesses are accessible and relatively large. It is required if the lesions progress despite 2 weeks of therapy with lack of reduction of abscess size. Decompression of lesions can be accomplished by stereotactic aspiration, although cure in many cases is achieved only after craniotomy and total excision. A significant reduction in mortality rate in patients with craniotomy (24%) in comparison to those who had undergone aspiration or drainage (50%) has been reported.

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15.6

CONCLUSION

The pathogenic role of actinobacteria in human infectious diseases are often misconstrued owing to the relative impediments in culture with features akin to filamentous fungal counterparts. Most often they are disregarded and their emerging involvement needs to be closely monitored by diagnostic laboratories.

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