Pulmonary nocardiosis is an uncommon bacterial infection that can be difficult to diagnose and treat and most commonly occurs in immunocompromised hosts. We present a case of multiple drug-resistant pulmonary nocardiosis in an immunocompetent host, treated successfully with moxifloxacin and minocycline.
A 67-year-old Filipino woman, with a history of severe chronic airflow limitation, presented with shortness of breath, purulent sputum, and fever. She was not taking regular oral or inhaled corticosteroids. She was significantly hypoxic with resting partial pressure of arterial oxygen of 8.7 kPa breathing air.
Chest x-ray showed bilateral consolidation, and a chest computed tomography (CT) scan confirmed extensive bilateral dense consolidation, with bronchiectasis in the lingula and right middle lobe (Fig. 1). The radiological appearances were nonspecific but were consistent with an atypical pneumonia, organizing pneumonitis, or aspiration pneumonia. Her initial total white blood count was elevated (37.4) with a neutrophil predominance. Her inflammatory markers were elevated (erythrocyte sedimentation rate, 136 mm/h; C-reactive protein, 436 mg/L). Serum immunoglobulins were normal, and HIV serology was negative. There was no clinical or radiological evidence of malignancy. Sputum culture grew oropharyngeal flora only. Antimicrobial therapy was commenced with intravenous gentamicin and cefuroxime.
When fever persisted despite antimicrobial treatment, she proceeded to bronchoscopy, which showed bilateral mucopurulent secretions that contained branching filamentous organisms suggestive of an actinomycete. Percutaneous fine-needle aspirate from an area of consolidation showed fibrosis and active chronic inflammation. Nocardiosis was suspected, and treatment was changed to intravenous cotrimoxazole.
Three weeks after initial presentation, bronchial washings grew a gram-positive, filamentous, beaded, branching organism which demonstrated partial acid-fastness by Kinyoun stain. The isolate hydrolyzed hypoxanthine (confirming it was not Nocardia asteroides complex), but it did not hydrolyze tyrosine, xanthine, adenine, and casein. Resistance to lysozyme was determined. The isolate was tentatively identified as a Nocardia transvalensis complex, and the identity was confirmed with 16S ribosomal RNA sequencing, which showed a 99% match compared with GenBank database reference strains.
The organism was resistant to cotrimoxazole (E-test minimum inhibitory concentration [MIC], 4 mg/L). Susceptibility testing by disk diffusion confirmed sensitivity to amoxicillin/clavulanic acid, and treatment was changed to this intravenously for 3 weeks with resolution of fever. There was no evidence of disease outside the respiratory tract, and a CT scan of the head was normal. Oral amoxicillin/clavulanic acid was continued with an intended treatment duration of 9 months. There was a good clinical response during treatment, and inflammatory markers had improved (erythrocyte sedimentation rate, 40 mm/h; C-reactive protein, 4.1 mg/L) when the patient returned to the Philippines 3 months after starting treatment.
There was no further contact with the patient until 2 years later when she returned to New Zealand and represented with worsening shortness of breath, fevers, and cough productive of half a cup of purulent sputum per day. She had lost 7 kg and now weighed 40 kg with a body mass index of 18 kg/m2. Oxygenation had deteriorated with a resting partial pressure of arterial oxygen of 7.1 kPa breathing air.
Her chest x-ray showed bilateral infiltrate, and a high-resolution CT scan showed deterioration in large airways disease with widespread bronchiectasis and persisting consolidation on a background of significant functional small airways disease as demonstrated by decreased attenuation (Fig. 2). Spirometry confirmed severe airflow limitation with an forced expiratory volume in 1 second of 0.52 (33% predicted) and forced vital capacity of 0.79 (41% predicted). Her inflammatory markers were elevated with an erythrocyte sedimentation rate of 77mm/h and C-reactive protein of 216 mg/L, and initial sputum culture grew mucoid Pseudomonas aeruginosa. Despite intravenous ceftazidime and standard airways therapy, she became progressively moribund with severe hypoxia and cor pulmonale. Ten days after admission, N. transvalensis complex was isolated from bronchoscopy washings.
At the first presentation, MICs were obtained using E-test methodology (AB Biodisk, Solna, Sweden) performed in accordance with published methods.1 Repeat testing of the original isolate and testing of the subsequent isolate by broth microdilution showed no change in antimicrobial susceptibility (Table 1).2
Combination therapy was started with minocycline 100 mg twice daily and moxifloxacin 400 mg daily, which was chosen on the basis of gatifloxacin susceptibility and was readily available, and was continued for a 12-month period. At completion of therapy, she remained clinically, physiologically, and radiologically stable in chronic respiratory failure on long-term oxygen therapy with resting oxygen saturation of 95% on 1 L/min of oxygen. The patient died 6 months after cessation of therapy from respiratory failure because of severe bronchiectasis. Postmortem cultures did not grow Nocardia.
The diagnosis of pulmonary nocardiosis is frequently delayed because of the difficulty of culturing Nocardia species.3 Initial therapy had included cefuroxime, and this may have contributed to the difficulty in isolating the organism on routine sputum culture.
Nocardia infection has associations with chronic obstructive pulmonary disease, and immunosuppression caused by either corticosteroid therapy or infection with human immunodeficiency virus.4 N. transvalensis complex infection is usually associated with significant host immunosuppression.5 In the case presented, there was no evidence of malignancy or significant immunodeficiency, but it represents an opportunistic infection in the setting of significant chronic lung disease.
N. transvalensis complex is a less common pathogen than other Nocardia species5 and is seen with higher frequency in Southeast Asia. It tends to be associated with noncutaneous disease.5 Although N. transvalensis complex is usually resistant to amikacin, identification of our isolate was confirmed by 16S ribosomal RNA sequencing which showed a 99% match.
Despite prolonged initial therapy and subsequent clinical improvement with amoxicillin/clavulanic acid, the patient relapsed. Although in vitro testing suggests that Nocardia species are often susceptible to β-lactams, the poor penetration of these drugs into macrophages may result in suboptimal outcomes. The development of new antimicrobial agents has led to alternative treatment approaches. However, information regarding their clinical efficacy and the role of combination therapy is limited. Oxazolidiones have good in vitro activity against Nocardia species, and linezolid has been reported to be successful in the treatment of nocardiosis.6,7
Quinolones have been shown to have activity against Nocardia isolates, but there is considerable variation in MIC between species.8 Quinolones have good oral bioavailability, eliminating the need for intravenous administration. Nocardia brasiliensis and N. transvalensis complex have been shown to be most susceptible to quinolones.9 In vitro testing of gatifloxacin and moxifloxacin against N. brasiliensis species show high activity with MICs even lower than those for amikacin.10 There is limited clinical data on the role of fluroquinolones in the treatment of N. transvalensis complex.
Therapy was initiated with moxifloxacin and minocycline. There is a lack of information as to whether combination therapy improves outcome of patients with Nocardia infections. Minocycline was included in the regimen despite reduced susceptibility to this agent. Six months of therapy is usually considered adequate for pulmonary nocardiosis.11 Longer duration of therapy is usually reserved for disseminated disease or immunocompromised hosts. Due to the large burden of disease in our case, therapy was continued for 12 months. A shorter duration may have been adequate.
This case demonstrates the difficulties in the treatment of Nocardia infection and shows success with prolonged therapy with moxifloxacin and minocycline after failure with prolonged amoxicillin/clavulanic acid treatment. There is evidence that, in a similar case, linezolid may be an appropriate alternative, but in this case of severe pulmonary nocardiosis with a large burden of disease, there was clinical response with moxifloxacin and minocycline.
The authors thank Wendy McKinney and Tracy Bathgate from LabPlus, Auckland District Health Board, for their contribution.
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