Clinical Grand Rounds Allison Liddell, MD March 10th, 2004.

Clinical Grand RoundsClinical Grand Rounds

Allison Liddell, MDAllison Liddell, MD

March 10th, 2004March 10th, 2004

Case PresentationCase Presentation

51 yo WM w/widely metastatic 51 yo WM w/widely metastatic esophageal CA to lung, abdomen esophageal CA to lung, abdomen and brain and brain

Admit 12/7/03 SOB, cough Admit 12/7/03 SOB, cough productive of yellow sputum for 1 productive of yellow sputum for 1 weekweek

No fever, rash, palpable nodes, No fever, rash, palpable nodes, neurologic symptomsneurologic symptoms

Case PresentationCase Presentation

PMHPMH– Esoph CA dx July 2002; s/p radiation/XRT, Esoph CA dx July 2002; s/p radiation/XRT,

then taxol/carboplatin stopped in October then taxol/carboplatin stopped in October ’03 due to progression of disease. Isolated ’03 due to progression of disease. Isolated brain met resected 3/03.brain met resected 3/03.

– CCK, appy, MVA w/ankle fracture requiring CCK, appy, MVA w/ankle fracture requiring hardware and bilateral THRhardware and bilateral THR

– FH multiple malignanciesFH multiple malignancies– Remote smoker, occasional ETOH, mechanic, Remote smoker, occasional ETOH, mechanic,

married with adult children, lives in Mabankmarried with adult children, lives in Mabank

Case PresentationCase Presentation

Medications: Medications: – DexamethasoneDexamethasone– VicodinVicodin– AtivanAtivan– AmbienAmbien– TessalonTessalon– AdvairAdvair– CombiventCombivent

Case PresentationCase Presentation

PE notable for Cushingoid faces, no PE notable for Cushingoid faces, no fever, fever, BP 113/80, P 100, O2 saturation is 92% on 2L/min NC, bilateral crackles bilateral crackles with dullness in baseswith dullness in bases

CXR bilateral lower lobe infiltratesCXR bilateral lower lobe infiltrates Chest CT dense lingular infiltrate, new Chest CT dense lingular infiltrate, new

cavitary lesion, new bilateral cavitary cavitary lesion, new bilateral cavitary lesionslesions

Case PresentationCase Presentation

Initial Rx cefepimeInitial Rx cefepime Discharged on levaquin plus Discharged on levaquin plus

Bactrim for PCP prophylaxisBactrim for PCP prophylaxis

Case PresentationCase Presentation

12/18 (day 8) Sputum growing Gram + 12/18 (day 8) Sputum growing Gram + beaded filamentous bacterium-Bactrim beaded filamentous bacterium-Bactrim increasedincreased

Readmit 12/20 with continued cough, Readmit 12/20 with continued cough, SOB, marked malaise and N/VSOB, marked malaise and N/V

CXR increased bibasilar infiltratesCXR increased bibasilar infiltrates Chest CT “Chest CT “increasing pulmonary

infiltrates and pulmonary nodules, particularly in the left lung”

Case PresentationCase Presentation

Rx High dose iv Bactrim and ceftriaxoneRx High dose iv Bactrim and ceftriaxone Continued severe N/V directly attributed to Continued severe N/V directly attributed to

infusion of iv Bactriminfusion of iv Bactrim Changed Bactrim to amikacinChanged Bactrim to amikacin Discharged to complete initial 4 weeks iv dual Discharged to complete initial 4 weeks iv dual

therapy while awaiting susceptibilities of therapy while awaiting susceptibilities of Nocardia asteroides complexNocardia asteroides complex

12/21 sputum had few branching G variable 12/21 sputum had few branching G variable rods on Gram stainrods on Gram stain

NocardiaNocardiaepidemiologyepidemiology

Aerobic bacteria-Aerobic bacteria-actinomycetales actinomycetales orderorder

ubiquitous, soil-ubiquitous, soil-borneborne

500-1000 cases/yr 500-1000 cases/yr in U.S. (1976)in U.S. (1976)

IDU asso. in HIVIDU asso. in HIV Pulmonary entry Pulmonary entry

most commonmost common

often opportunisticoften opportunistic– solid organ recipientssolid organ recipients– AIDSAIDS– BMT BMT – pulmonary diseasepulmonary disease– corticosteroid therapycorticosteroid therapy– many othersmany others

association with association with invasive fungal invasive fungal infectioninfection

NocardiaNocardiataxonomytaxonomy

N. brasiliensisN. brasiliensis N. otitidiscaviarum (T/S resis)N. otitidiscaviarum (T/S resis) N. transvalensisN. transvalensis N. asteroidesN. asteroides complex complex

– N. asteroides sensu strictoN. asteroides sensu stricto– N. farcinica (virulent)N. farcinica (virulent)– N. novaN. nova

NocardiaNocardiaMicrobiologyMicrobiology

Variably acid-Variably acid-fastfast

Gram Gram positivepositive

filamentousfilamentous beadingbeading grow in 2-4 grow in 2-4

weeksweeks

NocardiaNocardiapathogenesispathogenesis

Facultative intracellular pathogensFacultative intracellular pathogens Complex cell wall glycolipids Complex cell wall glycolipids

protect against oxidative burstprotect against oxidative burst Inhibits phagocyte functionsInhibits phagocyte functions predilection for CNSpredilection for CNS

NocardiosisNocardiosisClinical presentationClinical presentation

FeverFever productive coughproductive cough weight lossweight loss dyspneadyspnea pleuritic chest pleuritic chest

painpain hemoptysishemoptysis soft tissue massessoft tissue masses

LymphadenopathyLymphadenopathy cutaneous ulcerationcutaneous ulceration neurologic deficitsneurologic deficits

NO pathognomonic clinical NO pathognomonic clinical feature, radiographic feature, radiographic feature or lab resultfeature or lab result

Uttamchandani et al CID 1994;18 (HIV)

Pulmonary nocardiosisPulmonary nocardiosis

Acute, subacute or chronicAcute, subacute or chronic Pneumonia, abscess, empyema (25%)Pneumonia, abscess, empyema (25%) Variable nonspecific symptomsVariable nonspecific symptoms Radiographic findings widely variable-Radiographic findings widely variable-

alveolar, interstitial, cavitaryalveolar, interstitial, cavitary Path: mixed cellular response, Path: mixed cellular response,

sometimes granulomas +/- necrosissometimes granulomas +/- necrosis Other- sinusitis, tracheitis, bronchitis, Other- sinusitis, tracheitis, bronchitis,

pleuropulmonary fistula, mediastinitispleuropulmonary fistula, mediastinitis

Figure 244-2 Chest radiograph (A) and computed tomography scan (B) from a heavily immunosuppressed patient with systemic lupus erythematosus, demonstrating multiple pulmonary abscesses due to Nocardia farcinica.

Skin/Soft tissue Skin/Soft tissue nocardiosisnocardiosis

Cutaneous/subcut nodules after trauma Cutaneous/subcut nodules after trauma or due to hematogenous spread.or due to hematogenous spread.

CellulitisCellulitis abscessesabscesses paronychiaparonychia sporotrichoid formsporotrichoid form Keratitis/endophthalmitisKeratitis/endophthalmitis Wound infections (outbreak post-Wound infections (outbreak post-

transplant Germany)transplant Germany)

N. brasiliensisN. brasiliensis

Responsible for most progressive or invasive Responsible for most progressive or invasive skin infectionsskin infections

Southern USSouthern US Invasive diseaseInvasive disease

– ?new taxon based on different antimicrobial ?new taxon based on different antimicrobial susceptibilitysusceptibility

MycetomaMycetoma– Chronic, destructive infection of skin, subQ, fascia, Chronic, destructive infection of skin, subQ, fascia,

bone, muscle after local traumabone, muscle after local trauma– Suppurative granulomas and sinus tractsSuppurative granulomas and sinus tracts– Eumycetoma (fungi) or aerobic actinomycetes Eumycetoma (fungi) or aerobic actinomycetes

(Nocardia, Actinomadura, Streptomyces)(Nocardia, Actinomadura, Streptomyces)

Figure 82-2 A, Nocardia actinomycetoma of the foot. B, Hemisection of the foot showing advanced destruction of the bones. (Courtesy of the Armed Forces Institute of Pathology, Photograph Neg. No. N-77646.)

Systemic NocardiosisSystemic Nocardiosis

Primary pulmonary focus may resolvePrimary pulmonary focus may resolve Progressive lesionsProgressive lesions

– CNSCNS– Skin/subQSkin/subQ– EyesEyes– KidneysKidneys– JointsJoints– BonesBones– HeartHeart

CNS NocardiosisCNS Nocardiosis

45% of systemic cases involve CNS45% of systemic cases involve CNS 1/3 of all cases involve CNS1/3 of all cases involve CNS Highly variable presentationHighly variable presentation Mimic tumor, brain abscessMimic tumor, brain abscess Rarely meningitis (usually w/abscess), Rarely meningitis (usually w/abscess),

spinal involvement, diffuse spinal involvement, diffuse involvementinvolvement

All pulm/dissem Nocardiosis patients All pulm/dissem Nocardiosis patients should have MRIshould have MRI

Case PresentationCase Presentation

Marked initial improvement in Marked initial improvement in cough/sputumcough/sputum

N/V resolved with discontinuation N/V resolved with discontinuation of Bactrimof Bactrim

Continued pain, edema, anorexiaContinued pain, edema, anorexia

Case PresentationCase Presentation

Kirby-BauerKirby-Bauer– Susc: amikacin, cefotaxime, ceftriaxone, Susc: amikacin, cefotaxime, ceftriaxone,

gentamicin, imipenem, sulfisoxazole, tobramycin gentamicin, imipenem, sulfisoxazole, tobramycin – Intermed: Augmentin, doxycycline, minocyclineIntermed: Augmentin, doxycycline, minocycline

Microdilution MICMicrodilution MIC– Susc:amikacin, ceftriaxone, imipenem, Susc:amikacin, ceftriaxone, imipenem, linezolidlinezolid, ,

meropenem, sulfamethoxazole, tobramycinmeropenem, sulfamethoxazole, tobramycin– Intermed: cefotaxime, Augmentin, gatifloxacin, Intermed: cefotaxime, Augmentin, gatifloxacin,

minocyclineminocycline– Resis: ciprofloxacin, clarithromycinResis: ciprofloxacin, clarithromycin

NocardiosisNocardiosisTreatmentTreatment

SulfonamidesSulfonamides– Trim/Sulfa 5-15mg/kg/dTrim/Sulfa 5-15mg/kg/d– SulfisoxazoleSulfisoxazole

species mattersspecies matters– asteroides highly susc to asteroides highly susc to

T/ST/S– transvalensis higher transvalensis higher

amikacin and T/S amikacin and T/S resistanceresistance

– farcinica highly resistant, farcinica highly resistant, esp to cephsesp to cephs

– ot-cav resis to T/Sot-cav resis to T/S

– nova susc to ECN and nova susc to ECN and cephs, but not cephs, but not AugmentinAugmentin

Clinical data supports Clinical data supports sulfas are superiorsulfas are superior

Experimental modelsExperimental models– Carbapenems Carbapenems

superiorsuperior– Combinations superior Combinations superior

to single agentto single agent

TreatmentTreatment

NO controlled trialsNO controlled trials Most would begin Most would begin

with 2 drugs for with 2 drugs for severe disease while severe disease while awaiting ID/suscawaiting ID/susc

Duration at least 3 Duration at least 3 months, usually 6-months, usually 6-12 months in normal 12 months in normal

At least 12 months At least 12 months in immunosuppin immunosupp

Duration of iv Duration of iv therapy before oral is therapy before oral is judgement calljudgement call

surgery in some surgery in some casescases

Bactrim intolerance Bactrim intolerance in at least 50%in at least 50%– hypersensitivity,

gastrointestinal toxicity, or myelotoxicity

TreatmentTreatment

Bactrim is mainstayBactrim is mainstay For severe disease, For severe disease,

combinationcombination– T/ST/S– ImipenemImipenem– Amikacin (synergy)Amikacin (synergy)

after 3-6 weeks after 3-6 weeks change to oral change to oral therapytherapy

IV alternativesIV alternatives– cephalosporinscephalosporins

Oral alternativesOral alternatives– minocin (low minocin (low

therapeutic index)therapeutic index)– Augmentin (low Augmentin (low

therapeutic index)therapeutic index)– clarithromycin clarithromycin

(nova)(nova)– flouroquinolonesflouroquinolones

LinezolidLinezolid

OxazolidinoneOxazolidinone Useful for MRSA, VREUseful for MRSA, VRE Dose 600mg po BIDDose 600mg po BID 100% oral bioavailability100% oral bioavailability Excellent CNS penetrationExcellent CNS penetration MOA interferes with translation by MOA interferes with translation by

binding 50S ribosomebinding 50S ribosome Main toxicities GI and thrombocytopeniaMain toxicities GI and thrombocytopenia

Kaplan. Pediatric Infectious Disease JournalVolume 22 • Number 9 • September 2003

LinezolidLinezolid

In vitro data confirms linezolid effective In vitro data confirms linezolid effective for multiple strains (AAC 2001:45)for multiple strains (AAC 2001:45)

Case reports (Case reports (Wallace et al CID 2003:36Wallace et al CID 2003:36))– 6 cases (3 asteroides, 2 otit., 1 brasil.)6 cases (3 asteroides, 2 otit., 1 brasil.)– CGD (2), chronic steroids (2)CGD (2), chronic steroids (2)– Ages 6-63Ages 6-63– 4 dissem, 1 pneumonia, 1 soft tissue4 dissem, 1 pneumonia, 1 soft tissue– Bactrim intolerant, resistanceBactrim intolerant, resistance– 5 cures, 1 recurrence then cure with T/S5 cures, 1 recurrence then cure with T/S– Anemia, peripheral neuropathy, lactic acidosisAnemia, peripheral neuropathy, lactic acidosis

LinezolidLinezolid

Limitations:Limitations:– Lack of data for long-term safetyLack of data for long-term safety– Cost ($35,000 for 12 months)Cost ($35,000 for 12 months)

NocardiosisNocardiosispreventionprevention

ProphylaxisProphylaxis– primary-some primary-some

recommend post-recommend post-transplant if >3% transplant if >3% incidenceincidence

– secondary-if secondary-if remains on remains on steroids, HIV, steroids, HIV, prolonged prolonged immunosuppressioimmunosuppressionn

Bactrim DS daily Bactrim DS daily (TIW not (TIW not effective)effective)

References:References:

Lerner PI. Nocardiosis. CID 1996;22:891-905Lerner PI. Nocardiosis. CID 1996;22:891-905 Moylett et al. Clinical Experience with Linezolid for Moylett et al. Clinical Experience with Linezolid for

the Treatment of Nocardia Infection. CID the Treatment of Nocardia Infection. CID 2003;36:313-82003;36:313-8

Uttamchandani et al. Nocardiosis in 30 Patients with Uttamchandani et al. Nocardiosis in 30 Patients with Advanced Human Immunodeficiency Virus Infection. Advanced Human Immunodeficiency Virus Infection. CID 1994;18:339-47CID 1994;18:339-47

Choucino et al. Nocardiosis in Bone Marrow Choucino et al. Nocardiosis in Bone Marrow Transplant Recipients. CID 1996;23:101209Transplant Recipients. CID 1996;23:101209

Multi-system Infection with Nocardia farcinica—Therapy with Linezolid and Minocycline. The Journal of Infection 2003;46(3):199-202