Nocardia

Nocardia is a Gram positive, rod shaped bacteria which can cause multiple illnesses and also disseminated (or invasive disease), known as Nocardiosis. Nocardia is found in the soil where its function is to degrade organic matter. It is found worldwide and some strains are pathogenic to humans.

• Nocardia is mostly an opportunistic organism and illness is more severe in the immunocompromised.
• Nocardia is interesting because it releases virulence factors which allows it to evade the normal human defence mechanisms. Examples of the virulence factors include release of cord factor which prevents nocardia from being phagocytosed by macrophages and catalase production which inactivates oxygen metabolites which would normally be toxic to bacteria.¹

90% of human infections are caused by N. asteroides and there are three subtypes:

• N. asteroides complex
• N. farcinica
• N. nova.

The remaining 10% of infections are caused by N. brasiliensis, N.otitidis-caviarum and N. transvalensis.
N. brasiliensis is found in the tropics and causes skin infection and 30% of cases are in the immunocompetent.

• Nocardia infections are rare in the United Kingdom but their prevalence is increasing in the United States and countries such as Africa and India. This may in part be due to improved detection techniques.
• Nocardia infections are usually acquired by:
  • Inhalation of the bacteria with either lung infection and/or haematological spread (this accounts for 90% of human cases)
  • Direct inoculation via traumatised skin.
• Adults are most commonly affected, especially males. There is no seasonality and outbreaks are rare.

Risk of infection with Nocardia is increased in the immunocompromised including:

• Pre-existing lung disease e.g. COPD, alveolar proteinosis¹
• Chronic steroid use or use of azathioprine and methotrexate²
• Transplant recipients e.g. kidney transplant³
• HIV/AIDS.

Nocardia can affect any organ in the body but mostly leads to 5 types of illnesses:

1. Pneumonia
2. Involvement of the skin
3. Disseminated nocardiosis
4. Involvement of the central nervous system
5. Involvement of the eyes.

Pneumonia

Pneumonia caused by Nocardia may be indistinguishable from other pneumonias. It is usually subacute developing over weeks but may be acute in the very immunocompromised.⁴Nocardia should be suspected in any prolonged pneumonia that does not respond to empirical antibiotics.⁵
The features of a Nocardia pneumonia can include:

• Cough
• Fever, malaise and anorexia
• Night sweats
• Weight loss
• Haemoptysis, chest pain and difficulty in breathing may also be present but are usually less prominent.

Chest X-ray may show infiltrates or nodules which may be multiple and can be mistaken for pulmonary metastases. In fact, some cases of Nocardia lung disease have appeared as an endobronchial mass rather than pneumonia.⁶ 30% of patients may also have a pleural effusion which is usually an empyema.

There may be local spread from the pneumonia e.g. pericarditis or mediastinitis.

It has been noted that some patients with chronic lung disorders may have positive sputum cultures for Nocardia although they do not display any other clinical features to suggest active infection.
Nocardia can also cause tracheitis, laryngitis and sinusitis but these are more rare.

Skin

Nocardia infection of the skin can present in any of the following ways:

• Ulcers
• Nodules
• Actinomycetoma or Mycetoma - this is a mass that consists of granulomas which continues to progress with eventual fibrosis and necrosis. It is commonly seen on the hands and feet but may also affect the neck, head and back. The mycetoma can lead to sinus and fistula formation which can discharge pus. These lesions may continue to be infected for months and can lead to deformity or involve deeper structures that may even be fatal, especially if the original mycetoma is on the head or neck. Mycetoma are common in Mexico, central and South America and Africa. N. brasiliensis is the most common pathogen, other species implicated are N. transvalensis. It is a serious illness as infection can pass on to surrounding or deeper structures e.g. bone, joints and muscles.
• Lymphocutaneous disease - this presents with a lesion at the inoculation site which develops a central ulcer that drains pus. There may also be enlargement of local lymph nodes.
• Cellulitis - this can take up to 1 month to develop and is clinically indistinguishable from other causes of cellulitis. Dissemination is usually rare but patients need to be reviewed for signs of local spread e.g. in to the muscle. The commonest Nocardia involved are N. brasiliensis and N. asteroides.
• Subcutaneous abscesses
• Madura foot - this is seen in N. Africa, Sudan and India in inhabitants who walk bare foot. It has also been described in Australia.⁷ It is a chronic infection and like mycetoma the infection can pass to other structures. Madura foot usually results in gross deformity of the foot.

Disseminated Nocardiosis

• Nocardia can be inhaled and may result in pneumonia which can then be disseminated to the blood and other organs. Up to 50% of Nocardia pneumonias will disseminate.
• Alternatively, 20% of patients will inhale Nocardia and not have an ensuing lung illness but the Nocardia spreads in to the blood stream and causes illness elsewhere. Once Nocardia is in the blood the kidneys, skin, gastrointestinal tract and central nervous system can be infected.
• The pathology of the illness is usually the formation of suppurative abscesses leading to organ dysfunction. However, infection of the central nervous system is the most common organ affected in Nocardiosis.

Central nervous system

The central nervous system is affected in more than 30% of cases of Nocardia infection.
Infection usually results in abscess formation and presenting features include:

• Headache
• Fever
• Focal neurological deficits: depending on which area of the brain is affected e.g. seizures, cranial nerve palsies.⁸
• Some patients may be asymptomatic.

The abscesses are usually supratentorial and may be multiple and loculted. They can drain in to the subarachnoid space although, examination of the cerebrospinal fluid does not usually reveal Nocardia organisms.

Eyes

Nocardia infection of the eyes leading to keratitis is rare and usually follows a traumatic injury to the eye e.g. surgery.⁹ However, it is potentially reversible with treatment.

• Diagnosis is confirmed by the growth of Nocardia from tissue samples sent for staining and culture. Nocardia is a strict aerobe and on culture colonies are seen with hyphae. There may also be a mildew odour. No serological methods are presently available for diagnosis.¹
• Examples of specimens that can be sent are sputum, bronchoscopy specimens, skin or brain biopsies.
• Nocardia is very slow growing and it can take up to 4 weeks for a positive culture. The microbiology laboratory needs to be informed if Nocardia is suspected so that samples can be incubated for a longer period of time than usual.
• Nocardia is a Gram positive rod - however, the appearances on Gram staining can be misleading. For example, patients are usually treated with routine antibiotics to begin with and these can not only slow the growth of the Nocardia but also lead to wall changes meaning that the Nocardia is unable to keep the Gram stain and thus appearing as a Gram negative species.¹

• The first line treatment of Nocardia is with Sulfonamide antibiotics. An alternative is a combination of sulphamethoxazole with trimethoprim - usually reserved for those on immunosuppressants. Treatment usually lasts 6 - 12 months.
• Minocycline can be used as second line therapy in patients who are unable to tolerate sulfonamides. For parenteral treatment or refractory cases imipenem or a third generation cephalosporin can be used e.g. ceftriaxone or cefotaxime. But note that some species are resistant (see below).
• Disseminated illness may require addition of a further agent e.g. combination of imipenem and amikacin. Furthermore, some authors advocate the use of these two agents from the outset in Nocardia pneumonia as dissemination is highly likely.⁵
• Resistance within the Nocardia species has been described e.g. resistance to erythromycin and some of the third generation cephalosporins.
• Abscesses may required drainage either surgically or radiologically if appropriate. Empyemas should be drained to dryness. Good wound care management will also be needed. Keratitis has been successfully treated with cefazolin eye drops.⁹
• Patients who are at risk or who have been infected once may need long-term prophylactic therapy e.g. sulphamethoxazole with trimethoprim in HIV patients with a CD4 count less than 250 or in transplant recipients.

• Involvement of the lungs may lead to fibrosis and long-term difficulty in breathing.
• Scarring of areas of the skin that have been infected may lead to disfigurement and deformity that may lead to malfunction.
• Abscesses in the brain may lead to long-term neurological deficits.

Prognosis varies with the site of infection of Nocardia. Involvement of the central nervous system increases the mortality and morbidity. Furthermore, the presence of disseminated Nocardiosis or involvement of more than one site also carries a poorer prognosis.

• Avoid walking bare foot in high risk areas and also ensure that cuts and grazes are appropriately covered.
• A high index of suspicion is required for the detection of cases of Nocardia.

Nocardia is an interesting organism as it has many ways of evading the human immunological system. Furthermore, some species of Nocardia can produce antibiotics and enzymes e.g. converting-enzymes.¹ This versatility of Nocardia has inspired researchers to try and determine the genome of Nocardia. Thus far, research has been difficult due to practical problems e.g. finding appropriate vectors to study the gene sequence.