A male with relapsing community-acquired pneumonia (CAP)

1. A male with relapsing community-acquired pneumonia (CAP)

2. Case presentation • In November 2005, a 20-year-old male from Torino (Turin), Italy presented with fever, dyspnoea and cough • Vital signs: axillary temperature 38.5°C, heart rate 125/min, sat O2 98%, respiratory rate 22 breaths/min, blood pressure 120/80 mmHg • Physical examination: no cyanosis; no orthopnoea; no signs of respiratory distress • Signs of left-sided consolidation • Laboratory findings: white blood cell (WBC) count 10.2 x 109/L (10200/µL) (neutrophils 75%), normal liver and renal function, haemoglobin (Hb) 6.7 mmol/L (10.8 g/dL)

3. Past medical history • No chronic heart or lung diseases; no diabetes • Non-smoker and never treated with steroids • He had neither travelled recently nor had contact with sick children • No known exposure to infectious diseases • Not known to be an intravenous (IV) drug user • He had a tonsillectomy 12 years previously • He receives chronic treatment with valproic acid for seizures (last seizure was 4 years ago)

4. Chest X-ray (November 2005)

5. How would you treat this patient? • Admission to hospital for parenteral therapy • Parenteral therapy on an outpatient basis • Oral therapy on an outpatient basis

6. Outpatient treatment • The patient was treated empirically with 500 mg qd IV levofloxacin • He was switched to oral therapy on Day 4

7. CAP: treatment options for non-hospitalised patients Azithromycin Clarithromycin Clarithromycin ER Doxycycline Azithromycin or clarithromycin + amoxicillin or AM/CL Gati-, gemi-, levo- or moxifloxacin Azithromycin Clarithromycin Clarithromycin ER Telithromycin Introduced in 2005:750 mg qd levofloxacin No comorbidity Comorbidity + If antibiotics received in the previous 3 months: Amoxicillin or AM/CL or cefdinir or cefpodoxime or cefprozil Gilbert et al. The Sanford Guide to Antimicrobial Therapy. 35th Edn (2005) AM/CL, amoxicillin–clavulanate; ER, extended release

8. Clinical evolution • The patient was treated with levofloxacin for 10 days • No fever on Day 3; WBC count back to normal on Day 4 • Cough persisted after treatment was completed

9. Patient relapses... • One month after his first visit, the patient was admitted with fever, cough and dyspnoea • The patient is pale and appears unwell • Persisting signs of left-sided consolidation • Laboratory findings: ESR 64 mm/h, C-reactive protein 1.8 mg/L (normal <0.5 mg/L), WBC count 10.6 x 109/L (10620/µL), Hb 6.6 mmol/L (10.7 g/dL) • Serology: negative for HCV and HIV, anti-HBsAg positive (vaccinated), negative IgM for Mycoplasma spp. • Urinary antigen test negative for Legionella spp. ESR, erythrocyte sedimentation rate

10. Chest X-ray (1 month after initial presentation)

11. What do you think is the current aetiology? • Fluoroquinolone-resistant Pneumococcus spp. • Pseudomonas aeruginosa • Fungal pneumonia • Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) • Legionella spp. • Other

12. Action taken • The patient was then hospitalised on a general medical ward • A CT scan was performed • Treatment with piperacillin/tazobactam, clindamycin and azithromycin was started

13. Lung CT scan

14. Lung CT scan

15. What would you do? • Send sputum for analysis • Bronchoscopy and bronchoalveolar lavage (BAL) ± protected specimen brush • Open lung biopsy • No investigations; empiric therapy only

16. Treatment and follow-up • After 4 days of treatment with piperacillin/tazobactam, clindamycin and azithromycin, there was no change in the fever pattern • The patient then underwent bronchoscopy and BAL

17. BAL results • No neoplastic cells, plenty of neutrophils, rare macrophages (histiocytes) • Gram stain: no bacteria observed • Ziehl–Nielsen: positive for acid-fast bacilli • Samples sent to the laboratory for culture

18. Follow-up • Relapsing pneumonia in a previously healthy young man, without any risk factors for chronic lung disease and without overt epidemiological risk factors for tuberculosis (TB) • The patient was referred to an infectious diseases (ID) specialist and then transferred to the ID Unit

19. Treatment • The patient was started on a 4-drug combination regimen with isoniazid, rifampin, ethambutol and pyrazinamide PLUS moxifloxacin • Sensitivity test ordered on the Mycobacterium tuberculosis strain grown in culture • Despite treatment, the patient experienced only a transient improvement in symptoms • Fever persisted for >2 weeks

20. Is there any rationale for moxifloxacin here? • Yes • No • Don’t know

21. Why moxifloxacin? • The patient’s story is consistent with an initial satisfactory response to a fluoroquinolone, which may also suggest that pathogens other than M. tuberculosis contributed to some extent to the original infection • The patient had some degree of respiratory failure • The first ID consultant approaching this patient decided to administer moxifloxacin in order to cover conventional pneumonia pathogens possibly co-existing with M. tuberculosis

22. First unexpected finding • This is a multidrug-resistant (MDR) M. tuberculosis isolate • Since no prior anti-TB treatment was administered to the patient, the case is classifiable as primary MDR-TB

23. Microbiology Sensitivity of M. tuberculosis grown from first samples: • Rifampin R • Isoniazid R • Pyrazinamide R • Ethambutol R • Amikacin S • Ciprofloxacin S • Ethionamide R • Para-aminosalicylic acid (PAS) R

24. Antibiotic treatment • The patient was still undergoing treatment with isoniazid, rifampin, pyrazinamide and ethambutol WITH moxifloxacin when the results of the sensitivity test became available

25. Second-line treatment • The patient started on linezolid, moxifloxacin, amikacin, ethionamide, PAS and cycloserine • After 4–6 weeks of linezolid treatment, cultures were persistently negative • A chest CT scan performed in March 2006 showed a significant improvement in the signs of pneumonia. Small areas of bronchiectasis were reported in the left lung • The only recognisable risk factor for TB was that the patient was a student in an evening class, which was also attended by immigrants from Eastern Europe

26. Chest CT scan (March 2006)

27. Chest CT scan (March 2006)

28. Follow-up (1) • The patient was discharged on 13 March 2005 and readmitted on 7 April for nausea, vomiting, thrombocytopenia (platelets 73 x 109/L [73,000/µL]) and anaemia (Hb 4.8 mmol/L [7.8 g/dL]) • Treatment was withdrawn • The patient was discharged on 18 April • He was treated with high-dose B-vitamin complex; second-line treatment with linezolid, amikacin and levofloxacin was started 3 weeks later

29. Microbiology Anti-TB virtual monotherapy with moxifloxacin selected for fluoroquinolone resistance Sensitivity of M. tuberculosis at the start of second-line treatment • Rifampin R • Isoniazid R • Pyrazinamide R • Ethambutol R • Amikacin S • Ciprofloxacin R • Ethionamide R • PAS R

30. Linezolid and TB (1) • 55 M. tuberculosis isolates studied: 42 susceptible, 3 isoniazid-resistant and 10 isoniazid- and rifampin-resistant); 1 Mycobacterium bovis and 2 MDR M. bovis • Methods: standard 7H10 agar proportion and ESP Culture System II methods • Similar MIC90 values of 0.5 mg/L with both methods • No differences were observed between susceptible and resistant isolates with an MIC range of 0.12–0.5 mg/L • Potential role for linezolid in the treatment of TB Tato, et al. Int J Antimicrob Agents 2006;28:75–78

31. Linezolid and TB (2) • 5 patients with MDR-TB • 2 patients had MDR M. bovis, with resistance to 12 anti-TB agents • 3 patients had MDR M. tuberculosis, with resistance to all first-line drugs and other second-line drugs • Linezolid was given with thiacetazone, clofazimine or AM/CL • MIC values were <0.5 mg/L • In all cases, cultures were sterile after 6 weeks of therapy • 4 patients developed anaemia • Needed blood transfusions • In 2 patients, linezolid daily dose was reduced by 50% (300 mg twice daily) to decrease toxicity while maintaining efficacy •  Linezolid effective but frequently associated with toxicity (mainly anaemia and peripheral neuropathy) Fortun, et al. J Antimicrob Chemother 2005;56:180–185

32. Follow-up (2) • Transient elevation of lactic acid during linezolid treatment • No more thrombocytopenia • Needed multiple red blood cell transfusions for anaemia • Treatment interrupted indefinitively in June 2006 after achievement of clinical recovery and substantial improvement of radiological findings; this decision was taken after considering the worsening of peripheral neuropathy • Progressive recovery from peripheral neuropathy following treatment interruption

33. Chest CT scan (June 2006)

34. Chest CT scan (June 2006)

35. Second unexpected finding • This is an MDR M. tuberculosis isolate belonging to the Beijing family • M. tuberculosis Beijing is characterised by an unexpectedly high attack rate. In normal circumstances, 10% of exposed individuals will eventually develop active TB; however, in the case of Beijing strains, the rate may be as high as 60%

36. Key learning points • TB is on the increase worldwide; consider TB even in low-risk patients • MDR-TB is a growing reality that makes sensitivity testing highly advisable in all TB cases • Fluoroquinolones are an additional therapeutic weapon against M. tuberculosis;fluoroquinolones should be used in the treatment of CAP when the probability of TB can be reasonably excluded in order to avoid TB monotherapy and resistance selection • Further investigations regarding the potential role of linezolid in TB therapy are warranted

37. AIM core principles Patient outcomes • Select the most appropriate antibiotic depending on the patient, risk factors, suspected infection and resistance Antibiotic choice • Administer antibiotics at the right dose for the appropriate duration • If appropriate, change antibiotic dosage or therapy based on resistance and pathogen information