Case I ID: Pt was a 63 yo female h/o CLL S/P splenectomy admitted - PDF document

Pseudomonas aeruginosa infections Joanne Engel, M.D., Ph.D. Chief, Division of Infectious Disease Depts of Medicine and Microbiology/Immunology Case I • ID: Pt was a 63 yo female h/o CLL S/P splenectomy admitted for 3 day h/o fever, cough, and SOB • Meds on admission: Septra, ACV • PE in ER • Vitals: T 38.3, RR28, 97% RA, HR114, BP 138/74 • Labs WBC 20.4, Hb 10.3, Plts 131 • Lytes 136/4.4/105/19 BUN/Cr 34/2.3 (baseline 0.9) • LFTs AST 40, ALT24, ALK PHOS 205 • UA tr Hb, >300 protein, 11-20 WBC • Allergies: PCN (hives) but tolerates cephalosporins

Admission CXR Read as nl Hospital Course • Pt started on Doxy/Cefepime for CAP in IC pt • HD2 • � hypoxia � intubated • Hypotension � Neo, Levo, vasopressin • Vanco, Clindamycin, Voriconazole, ACV added • ARF � CVVHD • Continued hypotension, PA dissociation � chest tube placed for possible tension pneumothorax � large amt of purulent fluid released • Pt expired shortly thereafter

1 am 6 am 3 pm 7 pm Cultures • Chest tube fluid: GS GNR • Culture + P. aeruginosa (pan-sensitive) • ET aspirate: Mod RBCs, few GNR • Culture + P. aeruginosa (pan-sensitive) • Blood cultures sterile • Urine culture sterile

Gross autopsy: Necrotic lung Hemorrhage & Inflammation

Bacteria P. aeruginosa • Microbiology • Pathogenesis of infections • Spectrum of infections • Principles of abx therapy • Case studies

P. aeruginosa : bacteriology • Gram Negative Rod • Aerobic, indole+, Non- lactose fermenter • Distinguish from acinetobacter, stenotrophomonas • Produces pigments • Pyocyanin, pyoverdin • Ubiquitous • Grows on most carbon sources • Found everywhere: water, soil, plants P. aeruginosa is an opportunistic pathogen • Normal hosts do not get disease despite constant exposure • Infections require pre-existing epithelial cell injury and/ or immunocompromise Epithelial cell barrier

P. aeruginosa is an opportunistic pathogen • Normal hosts do not get disease despite constant exposure • Infections require pre-existing epithelial cell injury and/or immunocompromise • Propagate the wounded state Apocalypse now: P. aeruginosa destroys injured epithelium No bacteria + bacteria

PA has extensive arsenal of virulence factors LPS Type IV fimbriae Flagellum Alginate Extracellular Toxins / Enzymes -tissue destruction -evade host defenses Associated with acute infections Chronic (and acute infections) associated with biofilm formation -> � antibiotic resistance Acute Infections Nosocomial pneumonia Burn & wound VAP infections Sepsis (neutropenic pts) Ecthyma Corneal ulcers Endocarditis, meningitis Bladder gangrenosum associated infections with contact lenses

Chronic infections • Chronic colonization/recurrent pneumonia in Cystic Fibrosis (CF) patients • Thought to form biofilms in the resp tract-antibiotic resistant • AIDS patients mucoid colonies Biofilm

Community acquired infections • CAP: very rare except in IC and AIDs pts • Prev hospitalization, lung dz • External otitis (swimmer ’ s ear) • Ocular infxs: assoc w/contact lenses • Skin-soft tissue infections • Hot tub folliculitis • Puncture wounds/osteomyelitis (nail thru tennis shoe)

Early effective Abx Rx is important • Kang et al, AAC, 2005 • Lodise et al, AAC, 2007 • Isih et al, AAC, 2007 • Bowers et al, AAC, 2013 • 384 pts +BC PA, hospitalized ≥ 48 hrs after index culture • Excluded polymicrobial bacteremia • Overall mortality: 30.4% Therapy # Pts 30 d mortality P value Inappropriate 16 (4%) 44% 0.03 (include AG) Appropriate 368 (96%) 21%

Clinically active antibiotics • Extended spectrum B-lactams • Pip/tazobactam (Zosyn) • Clinical failures when MIC 32-64 • Ceftolazine/tazobactam (Zerbaxa) • 3rd/4th generation cephalosporins • Ceftazidine ( but not Ceftriaxone ), Cefepime, (Ceftalozone) • Quinolones • Ciprofloxacin, Levofloxacin ( not Moxifloxacin ) • Carbapenems • Imipenem, Meropenem, Doripenem (most potent) • Aminoglycosides (poor lung penetration) • Monobactam: Aztreonam (for PCN/ceph allergic pts) • Polymixins (disrupt LPS) • Colistin (but nephro- and neuro-toxic) NO activity • PCN, Ampicillin, Amoxicillin, Augmentin, Unasyn • 1 st and 2 nd generation cephalosporins, Ceftriaxone • Moxiflaxacin • Tigecylcine, Ertapenem

Reasonable two drug combinations • Classical: b-lactam (or cephalosporin) +aminoglycoside ( synergy ) • Issues: nephrotoxicity of AG, poor lung penetration • (B-lactam or Ceph) +quinoline ( synergy or additive ) • Issue: increasing quinolone resistance • Avoid double b-lactams • Don ’ t do Zosyn/cefepime or cetaz/cefepime or penem/cephalosporin Dosing: HIGH • IV dosing • Assuming nl renal function • Pip/tazo 4.5 g q6 • Zerbaxa 1.5 g q 8 • Ceftaz 2 q q8 • Cefepime 2q q12 • Meropenem/Imi 1 g q6 • Cipro 400 q8 • Aminoglycosides (concentration dependent killing): once daily unless contra-indications

P. aeruginosa is commonly antibiotic resistant • Intrinsic resistance • Acquired resistance Multiple mechanisms Livermore D M Clin Infect Dis. 2002;34:634-640; Poole, K., Frontiers Microbiol, 2011 • ß-lactamases (3 rd generation cephalosporins, aztreonam, penems) • AmpC: chromosomal cephalasporinase • Loss of permeability to aminoglycosides or modification of aminoglycosides • Loss of Outer Membrane Protein D (OprD) channel • Cannot import penams • Topoisomerase mutations: quinolones

• Multiple efflux pumps, have broad substrate specificity • Simultaneous resistance to Quinolones, Pip, Ceftaz, Cefepime • Quinolones induce upregulation of efflux pump: select for resistance to these drugs • OprD and MexEF pump co-regulated: simultaneous resistance to quinolones and penems Increasing ABX resistance in P. aeruginosa

Antibiotic resistance is increasing MDR CLASBI CAUTI VAP SSI AG 10.0 10.9 11.3 6.0 Cefepime/Ceftaz 26.1 25.2 28.4 10.2 FQ (Cipro/Levo) 30.5 33.5 32.7 16.9 Carbapenam 26.1 21.3 30.2 11.0 PIP/PipTZ 17.4 16.6 19.1 5.3 MDR(>=3 classes) 15.4 14.0 17.7 5.3

Cases II & III • 63 yo f h/o AML s/p autologous SC transplant admitted with fevers, pancytopenia, peripheral blasts. Urine and 2/2 Blood cultures grow PA. • 65 yo m severe pancreatitis c/b abd abscesses. New JP drain placed in abscess; cultures grow PA.

What is the appropriate initial empiric rx and subsequent targeted rx? 1. For the neutropenic pt, start meropenem/tobramycin and pare back to one active abx when sensitivities are known 2. For the neutropenic pt, start meropenem/tobramycin and continue for 2 wks with two active antibiotics 3. For the pt with abd abscess, start cipro and mero and continue for 2 wks with two active antibiotics 4. For the pt with abd abscess, start cipro and mero and pare back to one active abx when sensitivities are known Are 2 drugs better than 1 and why? CID 2011, S33 • Inherently better coverage (synergy) • Better odds that you have at least 1 effective abx • Prevents emergence of resistance

One or two antibiotics for PA infections? • Combination is superior: • Hilf et al. Am J Med 1989; 87: 542 • Combination is not superior: • Meta-analyses: Paul et al, BMJ, 2004; Safdar et al, LID, 2004; Vardakas et al, Lancet ID, 2013 • Bodey et al. Arch Intern Med 1985; 145: 1621 • Chatzinikolaou et al. Arch Intern Med 2000; 160: 501 • Kuikka et al. Eur J Clin Microbiol Infect Dis 1998; 17:701 • Leibovici et al. Antimicrob Agents Chemother 1997; 41: 1127 • Siegman-Igra et al. Intern J Infect Dis 1998; 2: 211 • Vidal et al. Arch Intern Med 1996: 156: 2121 • Chamot et al Antimicrob Agents Chemother 2003; 47: 2756 • Micek et al. Antimicrob Agents Chemother 2005; 49: 1306 Serious flaws w/the HilF study suggesting that monotherapy is inferior • Hilf et al, AJM, 1989 • 200 consec pts w/PA bacteremia • 58% immunosuppressed • Monotherapy mortality: 47% • Combination therapy mortality: 27% • Did not separate out whether initial monotherapy was effective • PA therapy was limited (ticarcillin, aminoglycosides) • Other predictors of poor outcome: neutropenia, site of infection, critical illness

One or two antibiotics for P. aeruginosa infections? • Bowers et al, AAC, 2013 • 384 pts +BC PA, hospitalized >= 48 hrs after index culture • Excluded polymicrobial bacteremia • Overall mortality: 30.4%* Therapy # Pts 30 d mortality P Inappropriate 16 (4%) 44% 0.03 (include AG) Appropriate 368 (96%) 21% Combination Rx 23% NS Monotherapy 20% NS *It’s a bad disease… One or two antibiotics for P. aeruginosa infections? • Pena et al, CID, 2013 • 593 pts +BC PA • Mortality within 48 hrs: 17% • 30 D mortality 30% Therapy # Pts relative risk of P death Adequate empirical Rx 332 (56%) Inadequate empirical Rx 261 (44%) 1.7 .052 Adequate empirical combination Rx 1.0 NS Adequate empiric single Rx 1.17 NS Adequate definitive combination Rx 71 (15%) 1.0 Adequate definite single Rx 339( 70%) 1.34 NS Inadequate definitive Rx 71 (15%) .86 NS