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When The Top Gun Fails

CCM Inter-hospital Grand Round 19 th July, 2011 Queen Mary Hospital Presented by Dr. Czarina Leung Chairman: Dr. Wallace Ngai Supervisor: Dr. Wai Ming Chan. When The Top Gun Fails. 46/F Office worker NSND PMH: Known SLE with glomerulonephritis

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When The Top Gun Fails

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  1. CCM Inter-hospital Grand Round 19th July, 2011 Queen Mary Hospital Presented by Dr. Czarina Leung Chairman: Dr. Wallace Ngai Supervisor: Dr. Wai Ming Chan When The Top Gun Fails

  2. 46/F Office worker NSND PMH: Known SLE with glomerulonephritis Class IV GN in 92, Class V in 97, flare up Class V+IV 5/10 Chronic renal impairment (baseline Cr ~180) On prednisolone 15mg and Mycofenolic acid 360mg tds Smear +vepTB -> on anti-TB tx since 4 months ago Menorrhagia 2o uterine fibroid with anemia

  3. History 2 week history of progressive dyspnoea on exertion Cough with minimal non-blood stained sputum Low grade fever and chills No chest pain No GI/Urinary sx TOCC-ve

  4. Physical Examination Fever ~390C Sinus tachycardia HR ~102 BP 97/53 SaO2 97% on room air RR 18 JVP<-> No ankle edema Dual heart sounds, no murmur Chest: clear Abd/Neuro/Skin &Jt exam unremarkable

  5. Investigations ECG: sinus tachy, AR 102, normal p,QRS, PR, QT, ST/T Hb 8 MCV 81.3 PLT 163 WBC 5.11 ANC 4.79 Lym 0.1 RFT: Cr 230 (Baseline ~180) Urea 24.4 Na 136 K 4.5 LDH 420 Raised LFT unremarkable RG 6.4 CK 86 TnI 0.02 ABG on RA: pH 7.4 pO2 10.2 pCO2 3.2 HCO3 16 BE-7

  6. Further Ix • NPA –ve • Sputum: AFB smear –ve, WBC –ve culture: commensals • Serum: respiratory virus and atypical pneumonia serology non-diagnostic • Echo: LVH, LVEF 70%, mild MR, valves normal, RV nad, no pericardial effusion • USG urinary system: chronic renal parenchymal ds

  7. Management Timentin started after admission Anti-TB medication (HLE) continued Chest physiotherapy Swinging fever Increasing SOBOE, cough Doxyclycline was added Antibiotic upgraded to Meropenem

  8. Radiological Ix -CT

  9. Further Management + Empirical PCP tx: iv trimthoprim-sulfamethoxazone + Hydrocortisone 50mg q8h iv x4/7  100mg q8h Bronchoscopy: no endobronchial lesion BAL : PCP +ve Bac/legionella/AFB sm/TB PCR/Resp virus/HSV/CMV -ve

  10. Progress after 5 days of IV TMX-SMX Escalating oxygen demand and respiratory distress SaO2 80% on 6L/min O2 RR 25, AR 110 BP 100/60 Swinging fever 38-39C Minimal sputum ABG on 50% O2:pH 7.37 pO29.6 pCO2 3.5 HCO3 18 BE-5 A-a gradient 250mmHg • Deteriorating Severe Pneumocystis jiroveci Pneumonia with Type I Respiratory Failure Despite iv TMP-SMX

  11. Transferred to ICU Swinging fever Sinus tachycardia HR ~110. BP maintained CPAP: FiO2 0.8 10cm H20 to keep SaO2>90% Exertionaldesaturation, RR 25 On Day 5 IV TMX-SMX Steroid changed to Methylprednisolone Failure to respond to 5 days of IV TMP + SMX

  12. Question 1 Patient fails to clinically improve after 5 days of iv TMP-SMX, what is the next choice? • Increase dose of TMP-SMX • Change to Clindamycin + Primaquine • Change to iv Pentamidine • Others

  13. 2nd line PCP Tx:Clindamycin +Primaquine(G6PD status normal) Progress of our patient: Respiratory distress Intolerant to oral treatment Continued Methylprednisolone

  14. Question 2 Patient is intolerant to Clindamycin and Primaquine, what is the next best treatment? • Switch back to TMP-SMX • Change to iv Pentamidine • Change to iv Caspofungin • Others

  15. Progress Switched to iv Pentamdine + Caspofungin • Imp: Pentamidine-related Hyperamylasemia

  16. Clinical condition improving, tolerating oral intake Switched back to iv Clindamycin + poPrimaquine Continued Methylprednisolone 32mg q24h iv Primaquine-related Methaemoglobinemia  Switched back to IV Septrin

  17. … patient’s condition responded to TMP-SMX afterall

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  19. Clinically improved on iv Septrin, Caspofungin, Methylpred Improved oxygenation SaO2 98% on 2L O2 Afebrile No more desaturation and dyspnoea on exertion LDH 1844  444 RFT  baseline ~170 Amylase  normalized Caspofungin 14d course Switched to oral TMP-SMX Tailed down steroid TMP-SMX Prophylaxis

  20. FOOD for THOUGHT • Did this patient have true TMX-SMX failure? • Poor initial response due to inadequate steroid? • For mod-severe PCP (PaO2 <70mmHg on RA), give adequate steroid as soon as possible, especially within 72hr of start of PCP tx improves survival and prevents acute respiratory failure (Bozette et al, Montaner et al, 1990)

  21. 1st line Treatment Failure inPneumocystis jiroveci Pneumnonia HAS THE TOP GUN FAILED?

  22. 1st Line PCP Treatment Mild to Moderate PCP (PaO2 >70mmHg on RA) • Oral Trimethoprim-sulfamethoxazole *** • Clindamycin & Primiquine (Similar efficacy as TMX-SMX) • Dapsone-TMP (Similar efficacy as TMX-SMX) • Atovaquone (Not as effective; Huges et al NEJM 1993) Severe PCP (PaO2<70mmHg on RA or A-a grad>35mmHg on RA) • IV Trimethoprim-sulfamethoxazole (TMP-SMX) • IV Pentamadine(71% develop adverse effects) • Corticosteroid begin within 72hr of PCP tx (AI) Duration: 14 day for non-HIV infected PCP, 21 d for HIV+

  23. Treatment Failure Wait at least 4–8 days for clinical improvement before considering change in therapy(BIII) – initial reversible deterioration due to inflammatory response ***FIRST rule out: • Co-infection: e.g. CMV, Mycobacteria, fungi, bacteria • Non-infectious: Pulmonary edema, Kaposi sarcoma, non-Hodgkin’s lymphoma

  24. Treatment Failure Dx Criteria: (Smergo et al) After 4-8d of 1st line treatment: • Progressive clinical deterioration, i.e. inability to maintain a stable PaO2 despite an increase in FiO2 • Progressive deterioration of vital signs with requirement to increase FiO2

  25. Failure to Respond • PCP cannot be cultured  No antibiotic susceptibility test • Rely on clinical response to determine if tx failure • Clinical deterioration  multifactorial: • Severity of PCP • Co-morbidities, co-infection • Degree of immunosupression, burden of infection • Initial inflammatory response/immune restitution • Inadequate steroid use • Treatment toxicity • Drug resistance

  26. SEPTRIN FAILURE? • TMP-SMX Proven efficacy as 1st and 2nd Line Tx • Higher intolerance to TMX-SMZ in HIV-infected • 25% stop TMP-SMX due to failure to respond or intolerance ( Benfile et al, 2008) • Survival : Tx failure: TMP-SMX 46%, Pentamidine 56% Vs Tx Intolerance: TMP-SMX 97%, Pentamidine 94% (Klein et al) • Concurrent use of leucovorin increases TMX-SMX failure (Safrin et al 1994)

  27. 2nd Line Treatment Recommendation In HIV-infected PCP pts, 2nd line Treatement Response Rate NIH study (Benfield et al) Meta-analysis of 29 studies( 2009): • Includes only 1st line failure(TMP-SMX, Pentamidine), exclude toxicity TMX-SMZ (73%) (OR 2.1) *Top choice, if not failed in 1st line Clindamycin-primiquine (68%) (OR 2.7) Pentamidine (44%)(OR 0.8) -↑ 3mo mortality(adjusted RR 12.4) Kim et al systemic review 2009: HIV and Non-HIV-rel PCP - Only TMP-SMX cases. Includes tx failure & toxcity; HIV & Non-HIV case Clindamycin– Primaquine(64%) vs Pentamidine (11%) (p 0.03)

  28. Salvage Therapy-Caspofungin • Caspofungin  Inhibits β-1,3-glucan synthesis in Pneumocystiscyst cell wall killing the reservoir Synergistic with TMX-SMZ, which kills trophozoites  clearing both forms of the life cycles of Pneumocystis Solid organ transplant recipients with severe PCP, Caspofungin with TMX-SMZ  rapid improvement & resolution of infection (Utili et al)

  29. When Clinical Treatment Failure Occurs Despite advances in anti-HIV medication and PCP prophylaxis as well as multiple 1st line treatment options, mortality is high: • Non-HIV-infected is 20-30%; • HIV-infected patients 10-15% Treatment failure remains a challenge • Ruling out non-response due to co-infections/co-morbidities • Adjuvant therapies e.g. Caspofungin, corticosteroid should be considered where appropriate • Currently, there is limited study on salvage management for multiple therapeutic failure

  30. Conclusion • Treatment failure ↑ mortality • Non-HIV-infected immunocompromization↑ mortality • High mortality despite treatment options and ICU care • Future study: Prospective multicenter study on rate of true treatment failure and risk factors associated + most effective salvage treatment/pathway warranted

  31. Take messages Remember: Top Gun Is Still The Best! Think twice before declaring failure

  32. Thank you!

  33. Reference • Kim T, Kim SH, Park KH, Cho OH, Sung H , Kim MN, Choi SH , Jeong JY , Woo JH, Kim YS , Lee SO; Clindamycin-primaquine versus pentamidine for second-line treatment of Pneumocystis pneumonia; J. of Infect Chemother (2009) 15:343-346 • Benfield B, Atzoria C, Miller R, Helweg-Larsen J. Second-line salvage treatment of AIDS-associated PneumocystisjiroveciiPneumonia. J Acqui Immune DeficSyndr. Vol 48, Number 1, May 1, 2008 • Helweg-Larsen, Benfield T, Atzori C, Miller R. Clinical efficacy of first and second-line treatments for HIV-associated Pneumocystisjirovecii pneumonia: a tri-centre cohort study. Journal of Antimicrobial Chemotherapy (2009). 64, 1282-1290 • Helweg-Larsen, Benfield T, Atzori C, Miller R. Second-line salvage treatment of AIDS-associated Pneumocystisjirovecii pneumonia: a case series and systematic review .CRD summary (NIH Center for Reviews and Dissemination – • Helweg-Larsen, Benfield T, Eugen-Olsen J. Effects of mutations in Pnuemocystiscariniidihydropteroatesynthase gene on outcome of AIDS-associated Pnuemocystiscarinii Pneumonia. Lancet. 1999; 354(9187): 1347-1351 • Takahashi T, Hosoya N, Endo T, Nakamura T, Sakashita H, Kimura K, Ohnishi K, Nakamura Y, Iwamoto A. Relationship between Mutations in DihydropteroateSynthase of Pneuomocystiscariniiif. sp. hominis isolates in Japan and resistance to sulfonamid therapy. Journal of Clinical Microbiology, Sept 2000, p 3161-3164 • Huang L,, Crothers K, Atzori C, Benfield T, Miller R, Rabodonirina M, Helweg-Larsen J. DihydropteroateSynthase Gene nutations in Pneumocystisand sulfa resistance. Emerging Infectious Disease. Vol 10. No 10. Oct 2004 • Bozzette SA, Sattler FR, Chiu J, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystiscarinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med. Nov 22 1990;323(21):1451-7

  34. Reference • Kovascs J., Masur H. Evolving Health Effects of PneumocystisOne hundred years of progress in diagnosis and treatment. JAMA, June 24, 2009. Vol 301, No 24 • Transplant 84: 685, 2007 • Smergo R., Nagar S., Maloba B., Popara M., Meta-analysis of Salvage Therapy for PneumocystiscariniiPneumonia. Arch Intern Med. Vol 161, June 25, 2001. pg 1529-153 • Utili R, Durant-Mangoni-E, Basilico Cr., Mattei A., Ragone E., Grossi P. Efficacy of Caspofungin Addition to Trimethoprim-Sulfamethoxazole Treatment for Severe Pneumocystis Pneumonia in Solid Orga Transplant Recipients. Transplant 84: 685, 2007 • Bonfanti P, Pusterla L, Parazzini F et al. The effectiveness of desensitization versus rechallenge treatment in HIV-positive patients with previous hypersensitivity to TMP-SMX.: a randomized multicenter study. C.I.S.A.I group. Biomed Pharmacother 2000; 54:45 • Leong GS, Stanford JF, et al. Trimethoprim-sulfamethoxazole dose escalation versus direct rechallengefoPnumocystiscarinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMX. J infect dis 2001;184:992 • S. Safrin, B.L. Lee and M.A. Sande, Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death, J. Infect. Dis. 170 (1994), pp. 912–917.

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