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 O 2 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 10 9 /L (10 200/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? 1.Admission to hospital for parenteral therapy 2.Parenteral therapy on an outpatient basis 3.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 Gilbert et al. The Sanford Guide to Antimicrobial Therapy. 35th Edn (2005) If antibiotics received in the previous 3 months: Amoxicillin or AM/CL or cefdinir or cefpodoxime or cefprozil No comorbidityComorbidity + Introduced in 2005: 750 mg qd levofloxacin 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 10 9 /L (10 620/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? 1. Fluoroquinolone-resistant Pneumococcus spp. 2. Pseudomonas aeruginosa 3. Fungal pneumonia 4. Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) 5. Legionella spp. 6. 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

15. What would you do? 1.Send sputum for analysis 2.Bronchoscopy and bronchoalveolar lavage (BAL) ± protected specimen brush 3.Open lung biopsy 4.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. 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 BAL results

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? 1.Yes 2.No 3.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. Sensitivity of M. tuberculosis grown from first samples: RifampinR Isoniazid R Pyrazinamide R Ethambutol R AmikacinS CiprofloxacinS EthionamideR Para-aminosalicylic acid (PAS)R Microbiology

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)

28. Follow-up (1) The patient was discharged on 13 March 2005 and readmitted on 7 April for nausea, vomiting, thrombocytopenia (platelets 73 x 10 9 /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 Sensitivity of M. tuberculosis at the start of second-line treatment RifampinR Isoniazid R PyrazinamideR Ethambutol R AmikacinS CiprofloxacinR EthionamideR PAS R Anti-TB virtual monotherapy with moxifloxacin selected for fluoroquinolone resistance

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 MIC 90 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)

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 1.TB is on the increase worldwide; consider TB even in low-risk patients 2.MDR-TB is a growing reality that makes sensitivity testing highly advisable in all TB cases 3.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 4.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