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, neupogen, procrit

• 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 CXRRead as nl Hospital Course

• V/Q scan low probability matched defect

• 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 pm3 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

• 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. aeruginosadestroys 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 defensesAssociated with acute infections

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

Acute Infections

Burn & wound infections

Corneal ulcers associated

with contact lenses

Bladder infections

Sepsis (neutropenic pts)Endocarditis, meningitis

Nosocomial pneumoniaVAP

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

Characteristic mucoid colonies

P. aeruginosa colonization in hospitalized pts

• Normal individuals out of the hospital have low colonization rate (<5%)• Moist areas: perineum, axilla, ear• Normal hosts do not get infected (intact immune

system)

• Skin and GI tract colonization increases in the hospital• 5th most common nosocomial pathogen • ~7.5% of hospital acquired infections• Hospital reservoirs: respiratory equip, sinks,

veggies, flowers, whirlpools etc

Overall incidence of nosocomial PA infections 2009-2010

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)

General Principles of Anti-Pseudomonal Antibiotic Rx

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

• 3rd/4th generation cephalosporins• Ceftazidine (but not Ceftriaxone), Cefepime

• 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

• 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

• ß-lactamases (3rd generation cephalosporins, aztreonam, penems)

• Loss of permeability to aminoglycosides or modification of aminoglycosides

• Loss of OprD channel (resistance to penems)

• Topoisomerase mutations: quinolones

Livermore D M Clin Infect Dis. 2002;34:634-640

Efflux pumps confer resistance to multple drug classes

• Multiple efflux pumps that 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

Journal of Hospital MedicineVolume 8, Issue 10, pages 559-563, 10 SEP 2013 DOI: 10.1002/jhm.2080http://onlinelibrary.wiley.com/doi/10.1002/jhm.2080/full#jhm2080-fig-0001

Abx resistance in nosocomial P. aeruginosa infections

2009-2010

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?

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

Are 2 drugs be better than 1CID 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• 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

• 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. aeruginosainfections?

*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 30 d mortality/relative risk of death

P

Adequate empirical Rx 332 (56%)

Inadequate empirical Rx 261 (44%) 23.3%/1.7 .052

Adequate empirical combination Rx 30%/1.0 NS

Adequate empiric single Rx 26.5%/1.17 NS

Risk of death

Adequate definitive combination Rx 71 (15%) 1.0

Adequate definite single Rx 339 70%) 1.36 NS

Inadequate definitive Rx 71 (15%) 86 NS

One or two antibiotics for P. aeruginosainfections?

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 showed that previous monotherapyw/anti-PA abx was a risk factor for subsequent isolates being resistant

• TAKE HOME MESSAGE: avoid re-administering prevprescribed 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 untilsensitivities known, then pare back to 1 effective abx• Delay in effective treatment correlates with poor

outcome

• ? 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

General treatment guidelines JAC 64:229, 2009

• 2 Anti-pseudomonas drugs of different classes for Pseudomonas bacteremia in neutropenic pts, endocarditis, meningitis• ? sepsis or pneumonia

• May delay development of resistance

• Avoid double b-lactams

• Monotherapy with aminoglycosides not recommended for pneumonia• poor lung penetration

• For other infections, can change to monotherapywhen 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 abxsens 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 RxHow 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.

Case

57F who in July 2012 underwent an elective laparoscopic repair of a paraesophageal hernia - Immediately post-op had cardiac arrest, 2 more- Bowel ischemia, small bowel obstruction, TPN- Pulmonary embolus, extremity thrombi- Acute renal failure, respiratory failure- Gluteal pressure ulcers, RUE wound- Ventilator associated pneumonia

(Stenotrophomonas, treated with bactrim), UTI (Pseudomonas, treated with cipro)

Case (cont.)

Day 100 ID gets called for consult: persistent fevers and leukocytosis

• 4 days ago had a cardiac arrest, of unclear etiology possibly from hypoxemia

• Mini BAL shows >10,000 colonies of P. aeruginosais this a VAP?

Patient Course

D1 D96 D100

Prior:VancomycinPipercillin-Tazobactam MeropenemMetronidazoleTrimeth-Sulfa Ciprofloxacin

Vanc/pip/tazo

ID consulted

3rd cardiac arrest, has new fever and leukocytosis

Labs

LFTs wnl

UA neg, Ucx neg

Bcx 2/2 ngtd

\ 8.7 / 11 ------ 295

/ \

| | 16 /------------------

| | 0.5 \

Patient Course

D1 D96 D100

Prior:VancomycinPipercillin-Tazobactam MeropenemMetronidazoleTrimeth-Sulfa Ciprofloxacin

Vanc/pip/tazo

Respiratory status improving

3rd cardiac arrest, has new fever and leukocytosis

D101D101

Acute respiratory and HD worsening, large R lung consolidation

Initial MicroInitial abx choice?

A. Cefepime/carbapenemextended infusion

B. Cefepime/carbapenem + tobramycin

C. Cipro + tobramycin

D. Any of above + colistin

Initial therapy• Cefepime 2g IV q8h, over 3hrs

• Tobramycin 7mg/kg iv q24

Placed in contact isolation

Ucx 7/29 mBAL 9/30

Piperacillin-tazobactam

32 I >128 R

Ceftazidime 8 S >16 R

Cefepime 32 R

Imipenem >8 R

Meropenem >8 R >8 R

Aztreonam >16 R

Ciprofloxacin <=0.5 S 2 I

Levofloxacin 8 R 8 R

Gentamicin <=2 S

Tobramycin <=2 S <=2 S

Colistin

Patient Course

D1 D96 D100 D101D101

Prior:VancomycinPipercillin-Tazobactam MeropenemMetronidazoleTrimeth-Sulfa Ciprofloxacin

Vanc/pip/tazoCefepimeTobramycinMetronidazoleColistinRifampin

Respiratory status improving

D109 D112 D123

Comfort care

HD instability, worsening hypoxia

D128 D131

Worsening resp status, fever, leukocytosis, new LLL consolidation

Cdiff neg

3rd cardiac arrest, has new fever and leukocytosis

Acute respiratory and HD worsening, large R lung consolidation

Completes 14 day course

Marked improvement in respiratory status

MDR P. aeruginosa has worse outcome

• Tam et al, AAC 2010• Retrospective study of pts with PA bacteremia• Pts with MDR PA more likely to

• Receive inappropriate empirical rx• Longer hospital stay• 30 day mortality• Faster death

• Pena et al, CID, 2013• Prospective study of pts with PA bacteremia

30 d mortality P

Non-MDR 26.6%

MDR 33.2% .001

XDR 42.6% <0.001

Treatment options for MDR P. aeruginosa

Pharmacokinetic/Pharmacodynamic

Optimization

Alternate

DeliveryRoutes

Synergy

Adjunctive Agents

New uses for old abxyou 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

• 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-adminsteredw/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

MICT>MIC

(Time Dependent)

Optimizing Time>MIC with β-lactamsC

on

ce

ntr

ati

on

Time

Traditional dosing

MIC

Optimizing Time>MIC with β-lactams

Co

nc

en

tra

tio

n

Time

Continuous infusion

Traditional dosing

MIC

Alternate Delivery Routes

• Administration of antibiotics other than IV or PO routes

• Advantages• Potentially greater concentrations at site of infection

• Potentially lower systemic toxicity

• Disadvantages• Most data for prevention (CF), not treatment

• Differences in delivery methods

• Local toxicity

• Lack of activity at metastatic sites

XDR P. aeruginosa –what to do

• 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

What’s in the pipeline

• Beta-Lactamase Inhibitors• Avibactam

• In Phase III clinical trials

• Complicated intra-abdominal infections, UTIs

• Likely to be marketed in combination with existing beta-lactams

• Ceftazidime and ceftaroline

• Efficiently protects against beta-lactamases• Including ESBL, KPC, AmpC

What’s in the pipeline

• Beta-Lactams• Biapenem (RPX-2003)

• Phase I clinical trials underway

• Ceftolozane• Phase III clinical trials underway

• Complicated IAI, UTI

• Expect future studies in HAP/ VAP

• Less susceptible to resistance mechanisms• Efflux pumps, de-repressed AmpC

• Co-formulated with tazobactam

What’s in the pipeline

• Aminoglycosides• ACHN-975

• Phase I development

• Plazomicin• Phase II clinical trials

• Complicated UTI, acute pyelonephritis

• Less susceptible to resistance via aminoglycoside modifying enzymes

References

• Sun et al, Recent advances in chest medicine, 139:1172, 2011

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

obtained)

• Increasing quinolone resistance—only options are IV Rx

Summary

• Serious infections: start w/2 abx, then narrow to one• 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

Case VII

• 23 yo m h/o CF presents w/fever, incr sputum production, SOB, CP that has not responded to inhaled tobramycin. Chest CT shows new LLL infiltrate. Pt has h/o MDR PA

• Sputum culture: 2 morphologies• Pip/tazo-R, Ceftaz-R, Ceftaz-R, Cefepime-

RMero/Ime-R, Aztreonam-R, Tobra/Gent-R, Amik-R, Cipro-R, Colistin-S

• Pip/tazo-R, Ceftaz-MIC=4, Cefepime-S, Mero/Ime-R, Aztreonam-R, Tobra/Gent-R, Amik-R, Cipro-R, Colistin-S

100

80

60

40

20

00-1 2-5 6-10 11-17 18-24 25-34 35-44 >45

P. aeruginosa

S. aureus

H. influenzae

B. cepacia

Age years

Pe

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Cystic fibrosis: organisms isolated from the lower respiratory tract

Pseudomonas Infection in CF• Chronic Infection

• Acquired early in life• Once infected, difficult to eradicate• Therapies to suppress pseudomonas

• Azithromycin 500 mg Mon Wed Fri• TOBI® cycles of 28 days on/28 days off

• Acute Pulmonary Exacerbation• Decline in lung function inversely proportional to

amount (CFU) quantitative sputum cultures • Majority of patients have same strains of PA when ill as

when stable.• Cystic Fibrosis Foundation recommends at least one

culture annually

Managing Pseudomonas Infections in CF

• Surveillance sputum cultures • Cystic Fibrosis Foundation recommends at least one culture annually • Specific protocol for processing samples to enable detection of S.

aureus and Burkolderia species

• Preventive therapy • Mucolytics and mucus clearance for all patients with CF lung disease• Azithromycin and inhaled tobramycin are specific for the

pseudomonas infected patient• Synergy studies

• CF Referral Center for Susceptibility& Synergy Studies at Columbia University: closed 2009

• Making antibiotic treatment selections based on “synergistic combinations” of anti-pseudomonal antibiotics did alter not the course or outcome of CF pulmonary exacerbations in retrospective clinical study.

Flume et al: Am J Respir Crit Care Med, 2009, 180: 802-802

Update?

Treatment Guidelines of Pulmonary Exacerbation in CF

• 2 drug rx to enhance activity and reduce selection of resistant organisms• CF Referral Center for Susceptibility& Synergy Studies at

Columbia University: closed 2009• Making antibiotic treatment selections based on “synergistic

combinations” of anti-pseudomonal antibiotics did alter the course or outcome of CF pulmonary exacerbations retrospective clinical study.

• Dosing of antibiotics• Once daily doing of aminoglycoside is preferred.• Insufficient evidence exists to support continuous infusion of

ß-lactam antibiotics• Duration of therapy

• Variable practice among CF Centers nationwide with insufficient evidence to endorse or refute the value of shorter duration of therapy.

• 61 yo HIV+ on ARVs, quadriplegic (C3/4) trached h/o recurrent PNA and UTI’s tx’d to UCSF 12/19/09 for hypoxemia, fever, hypotension. Tx/d w/Vanco/zosyn x 14 d. Defervesced but failed to wean from ventilator• ET asp 1/2/10: >10 K PA (Mero-R, Pip-R, Cipro/Levo R,

Tobra/Gent-S,Cefepime-S (MIC=4)

• 1/5/10: Dev new fevers and higher PEEP rqt

• ID consult: Increase Cefepime to 2 G IV q12 and administer over 4 hrs

• Add Tobramycin

• Pt initially had good response (repeat mini-BAL 1/14/10 neg) though he redeveloped fevers