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
• hypoxiaintubated
• 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 7 pm 3 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/
• r immunocompromise

Epithelial cell barrier

• Infections require pre-existing epithelial cell injury

and/or immunocompromise

• Propagate the wounded state
• P. aeruginosa is an opportunistic pathogen
• Normal hosts do not get disease despite constant exposure

Apocalypse now: P. aeruginosa destroys injured epithelium

No bacteria + bacteria

PA has extensive arsenal of virulence factors

Alginate Type IV fimbriae Flagellum LPS

Extracellular Toxins / Enzymes

• tissue destruction
• evade host defenses

Associated with acute infections

Chronic (and acute infections) associated with biofilm formation -> antibiotic resistance

Acute Infections

Burn & wound infections Corneal ulcers associated with contact lenses Bladder infections Sepsis (neutropenic pts) Endocarditis, meningitis Nosocomial pneumonia VAP Ecthyma gangrenosum

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 (include AG) 16 (4%) 44% 0.03 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
• 1st and 2nd 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):
• nce daily unless contra-indications

• P. aeruginosa is commonly antibiotic resistant
• Intrinsic resistance
• Acquired resistance

Multiple mechanisms

• ß-lactamases (3rd generation

cephalosporins, aztreonam, penems)

• AmpC: chromosomal cephalasporinase
• Loss of permeability to aminoglycosides
• r modification of aminoglycosides
• Loss of Outer Membrane Protein D

(OprD) channel

• Cannot import penams
• Topoisomerase mutations: quinolones

Livermore D M Clin Infect Dis. 2002;34:634-640; Poole, K., Frontiers Microbiol, 2011

• 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
• f infection, critical illness

• 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 (include AG) 16 (4%) 44% 0.03 Appropriate 368 (96%) 21% Combination Rx 23% NS Monotherapy 20% NS

One or two antibiotics for P. aeruginosa infections?

*It’s a bad disease…

• Pena et al, CID, 2013
• 593 pts +BC PA
• Mortality within 48 hrs: 17%
• 30 D mortality 30%

Therapy # Pts relative risk of death P 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

One or two antibiotics for P. aeruginosa infections?

What are risk factors for developing drug resistance to PA?

• C. Van delden,CID 2001. 33:1859
• Case control study of 267 episodes of PA bacteremia.
• 25% of episodes preceded by exposure to anti-PA abx
• Multivariate analysis: monotherapy w/anti-PA abx was risk

factor for subsequent abx resistance

• TAKE HOME MESSAGE: avoid re-administering prev

prescribed abx when initiating empiric therapies for serious PA infections

General treatment guidelines

JAC 64:229, 2009

• Empiric Rx for serious infections: start w/2 anti-

pseudomonas abx of different classes until sensitivities known, then pare back to 1 effective abx

• Delay in effective treatment correlates with poor
• utcome
• ? prevent development of resistance
• Choice of empiric abx depends on local resistance

patterns and prior abx rx

• If choice exisits, quinolone before cephalosporin/

zosyn before penem

• Monotherapy with aminoglycosides not

recommended for pneumonia

• poor lung penetration
• For other infections, can change to monotherapy

when abx sensitivities known

• 3 controlled studies suggest that resistance to

penems develops more frequently than for ceftz, cipro, or piperacillin

• Ertapenam assoc w/incr risk of carbapenamR

General treatment guidelines

JAC 64:229, 2009

Which of these scenarios is appropriate?

• 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 meropenem and

cefepime and pare back to one active abx when sensitivities are known

Which of these scenarios is appropriate?

• 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 meropenem and

cipro and pare back to one active abx when sensitivities are known

• 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.

Ecthyma gangrenosum

• Perivascular bacterial invasion->ischemic

necrosis

• Painless: rapid progression macules-> nodules-

>vesicles->ulcerative

• P. aeruginosa nosocomial

pneumonia

• Leading cause of nosocomial

and ventilator-associated pneumonia (40% VAP)

• Higher colonization rate in

intubated patients (up to 70%)

• Attributable mortality of 40%
• Only 50% of failures assoc w/

antibiotic resistance

Guidelines for choosing effective rx

• Infxns usually occur w/colonizing strain
• Routine endotracheal aspirates (1-2/wk) may be

helpful in predicting abx susceptibility in VAP

• Chest 2005. 127; 589-97
• Intensive Care Med 2009. 35:101-107
• Prior abx history useful in determining empiric rx
• Local resistance patterns

Start w/2 drugs; narrow to 1 drug once abx sens known & pt responding to rx

• Garnacho-Montero: Observational study of 183 episodes of

PA VAP, use of 2 abx decr failure and incr survival; narrowing to monotherapy did not affect mortality, length of stay, development of resistance, recurrences (Crit Care Med 2007)

• Arts et al: Meta-analysis, monotherapy not inferior to

combination therapy (Crit Care Med 2008. 36:108)

• Heyland et al: 740 pts w/VAP combination Rx (Mero/Cipro vs

Mero). Overall monotherapy as good as combination rx. But for MDR GNR (PA, acinetobacter), higher freq of initial inadeq rx (84% vs 19%) & higher microbiological eradication (64% vs 30%). No difference in clinical outcomes (Critical Care Med

• 2008. 36:737)

How long to treat VAP?

JAMA 2003. 290:2588

• Rx for 8-14 d
• PA VAP was assoc

w/higher recurrence in 8 d rx though no effect on mortality

• If shorter Rx,

consider f/u mini-BAL to assess efficacy of rx.

30 d mortality P Non-MDR 26.6% MDR 33.2% .001 XDR 42.6% <0.001 Pharmacokinetic/ Pharmacodynamic Optimization Alternate Delivery Routes Synergy Adjunctive Agents

New uses for old abx

you can teach an old drug new tricks

• Aminoglycosides (gentamycin, tobramycin,

amikacin)

• Poor permeability into lung
• Nephro (kidney) and oto (ear) toxic
• Requires close monitoring of serum levels (peak/trough)
• Once daily dosing for maximal benefit
• Can be given inhaled to increase lung concentrations

and to limit systemic toxicity

• Inhaled? (only approved for CF)
• Colistin
• No cross-resistance to other classes
• Very nephro and neurotoxic
• Resistance through modification of LPS
• Arises quickly
• Can be given inhaled to increase lung concentrations

and to limit systemic toxicity

• Synergy or beneficial effect when co-adminstered w/

2nd effective drug (carbapenam)

• Delays emergence of resistance

Optimizing ß-lactam or cephalosporin administration

• ß-lactam antimicrobial

activity predicted by time above MIC

• Max killing occurs at 4-5x

MIC, so higher conc only increase toxicity, not efficicacy

• Can give prolonged or

continuous infusion Pip/ tazo, Ceftaz, Cefepime, Penems (careful w/imi)

Cmax MIC T>MIC

(Time Dependent)

Lodise et al, CID, 2007; Kaufman et al, AJHSP, 2011; Korbila et al, Expt Rev Anti Infect Ther 2013; Falagas et al, CID, 2013

Optimizing Time>MIC with β-lactams

Concentration Time Traditional dosing MIC D

• s

e 1 D

• s

e 2 D

• s

e 3

Optimizing Time>MIC with β-lactams

Concentration Time Continuous infusion Traditional dosing MIC D

• s

e 1 D

• s

e 2 D

• s

e 3

Maiz et al, Expert Opinion Pharmacother 2013

• Contact isolation
• Call ID pharmacy
• Optimize dosing
• In vitro data (ancient and recent) for using

combinations, even with in vitro resistance

• Carbapenam+Rif+AG+Colistin (or some combination

thereof)

• Lim et al plos one 2011

Bad bugs, no drugs

Case V

• 78 yo m h/o type II DM presented w/3 mo h/o bloody

drainage R ear & severe otalgia. 2 mo PTA also noted increasing unsteadiness of gait and frequent falls or near falls. Denies f/c/ns. Long-standing h/o bilateral hearing loss of unclear etiology w/bilat hearing aids; recently stopped wearing R ear hearing aid because “it didn’t help.” Referred to UCSF after results from head CT obtained.

• ROS notable for incr hoarseness but no dysphagia; incr

SOB.

• PE: R ear w/greenish d/c visible in external canal. No

pain w/manipulation of pinna; no periauricular tenderness.

• Neuro: palate elevates asymmetrically L>R, tongue

deviates to R.

• Invasive infection of

external ear canal, mastoid, and base of skull

• infxn spreads from

external auditory canal- >Cartilagious-osseous jxn-> temporal bone- >fissures of Santorini- >mastoid->VII nerve- IX,X,XI,XII.

Malignant Otitis Externa (skull-base osteomyelitis)

Lancet Inf Dis Jan 2004

Microbiology

• P. aeruginosa most common (ignore nl skin flora

in cultures)

• Rarely S. aureus, Aspergillus, Proteus,

Klebsiella, other fungal pathogens

Risk factors

• Elderly, DM
• Immunosuppression, HIV
• Previous local damage (XRT, surgery)
• Ear irrigation
• Subacute: afebrile, non-toxic

appearing

• Nl WBC but elev ESR, CRP
• Severe, unrelenting otalgia
• Purulent otorrhea
• HA, TMJ pain
• Ext ear canal: edematous,

granulation tissue

• Cranial nerve palsies (VII>IX,

X, XI, XII>V,VI)

Clinical presentation

Diagnosis

• Clinical presentation (ear drainage, ear pain, HA,

CN palsies)

• Granulation tissue in ear canal
• Culture ear drainage-if neg for PA, may need to

do bone bx

• CT (bone involvement) & MRI (soft tissue

involvement)

Rx

• 6-10 wks PO (if Cipro/Levo sens) or IV Rx w/

single drug

• Inpatient severe disease-bx, debridement, IV rx
• 2 drugs initially (can narrow if abx sensitivities
• btained)
• Increasing quinolone resistance—only options

are IV Rx

Summary

• Serious infections: start w/2 abx, then narrow to
• ne
• Continue 2 drug Rx: neutropenic bacteremia,

meningitis, endocarditis

• If recently exposed to anti-pseud abx, use others
• Gnarly MDR bugs: extended infusion b-lactams,

aminoglycosides, colistin

Length of Rx

• UTI: pull catheter; 3-5 d rx
• Urosepsis: 10-14 d
• Pyelonephritis: 14-21 d
• Perinephric abscess: possibly longer
• Prostatitis: 6-12 wks oral quinolone
• Endocarditis: surgery + 6 wks 2 drug rx
• VAP: 8-14 d

• Meningitis: 21 d Meropenem (not Imi).
• Difficult choice for 2nd drug: Quinolones-not much

experience; AG-poor CSF penetration, requires IV or IT administration

• Ocular infxns: consult opthamologist
• Endopthalmitis: Cipro, Ceftaz, Imipenem have

reasonable intraocular levels;

• Direction injection of abx
• Otitis externa: ear drops
• Malignant otitis externa: 6-10 wks oral

quinolones or IV rx

• Hot tub folliculitis: local care, or topical polymixin

B, or 5-7 d oral quinolone

• Puncture wounds/osteo: abx w/local

debridement

• Ecthyma gangrenosum/nec fascitis: 2 drugs IV
• Burns: topical agents, early/freq debridement of

necrotis tissue

• Treat overt infxns w/2 drugs