Infections in Non-HIV Immunocompromised Host Fredrick M. Abrahamian, D.O., FACEP Associate Professor of Medicine UCLA School of Medicine Director of Education Department of Emergency Medicine Olive View-UCLA Medical Center Sylmar, California

Special Populations Discussed Diabetes mellitus Neutropenia Solid-organ transplant recipients Bone marrow transplant recipients Chronic corticosteroid use = Important points

= Pitfalls

Diabetes & Immune System Alters several aspects of immune system Impairs neutrophil & lymphocyte function  Exaggerated with concomitant acidosis Control of hyperglycemia:  Normalizes neutrophil function  Some evidence reduces incidence of infection Walrand S, et al. J Leukoc Biol. 2004;766:1104-1110. [Insulin & neurophil function] Van den Berghe G, et al. N Engl J Med. 2001;345:1359-1367. [SICU & insulin therapy]

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Diabetes Mellitus & Risk of Infection DM as risk factor for community-acquired infections  7417 DM vs. 18,911 control patients with HTN  Increased risk for LRTIs, SSTIs, UTIs Infections strongly associated with DM:  Emphysematous pyelonephritis  Malignant otitis externa  Mucormycosis (zygomycosis)  Emphysematous cholecystitis Muller LMAJ, et al. Clin Infect Dis. 2005;41:281-288. [Risk of infection & DM]

Diabetes & Microorganisms Group B Streptococcus  37% in 1998 44% in 2007  Bacteremia without focus, SSTIs, & pneumonia Klebsiella: Bacteremia, liver abscess Tuberculosis  4 x more frequent than in general population  Aggressive, lower lobes, with pleural effusion Candida species  Oropharynx, perineum, cutaneous (intertriginous) Skoff TH, et al. Clin Infect Dis. 2009;49:85-92. [Group B strep & DM in adults] Broxmeyer L. Med Hypotheses. 2005;65:433-439. [DM & TB relationship]

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Diabetic Foot Infections Pseudomonas & MRSA not common culprits Specimen collection for culture:  Best from debrided base by curettage or biopsy  Superficial wound swab not preferred Consider osteomyelitis when:  Ulcer does not heal after 6 weeks of therapy  Bone visible or palpable with a probe Treat concomitant fungal infections Citron DM, et al. J Clin Micrbiol. 2007;45:2819-2828. [DFI microbiology] Lipsky BA, et al. Clin Infect Dis. 2004;39:885-910. [IDSA guidelines on DFI] Grayson ML, et al. JAMA. 1995;273:721-723. [Probing bone & osteomyelitis]

Diabetes Mellitus & UTI Higher incidence of asymptomatic bacteriuria in ♀  Pyuria commonly present  Dx based on culture  Treatment not recommended 7 day Tx recommended for symptomatic cystitis Poor response / persistent fever think complications  Abscess, necrosis, & emphysematous infections ≥ 48 hrs Tx + no clinical improvement = CT scan Nicolle LE, et al. Clin Infect Dis. 2005;40:643-654. [IDSA guidelines on ASB] Hoepelman AI, et al. Int J Antimicrob Agents. 2003; 22:S35-S43. [Cystitis & diabetes]

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Emphysematous Pyelonephritis Life-threatening, suppurative, necrotizing infection E. coli most common cause CT scan imaging modality of choice Differentiate emphysematous pyelonephritis:  Emphysematous pyelitis  Emphysematous cystitis Broad-spectrum antibiotics (cover Pseudomonas) Immediate surgical consultation Huang JJ, et al. Arch Intern Med. 2000;160:797-805. [Emphysematous pyelo; prognosis] Abdul-Halim H, et al. Urol Int. 2005;75:123-128. [Emphysematous pyelo; management]

Malignant Otitis Externa

Habif TP. Clinical Dermatology. 1996.

Malignant Otitis Externa Involves external auditory canal & temporal bone Pseudomonas most common culprit Fever commonly absent Confused with severe perichondritis or otitis externa Workup includes CT scan / MRI of temporal bone Initiate antipseudomonal therapy Consult ENT  Cultures to determine susceptibility  Tissue biopsy R/O epidermal carcinoma  Debridement usually required Berenholz L, et al. Laryngoscope. 2002;112:1619-1622. [Pseudomonas resistance to Cipro]

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Rhinocerebral Mucormycosis Infection involves sinuses & surrounding structures Clues to Dx:  Ulcers, black eschars on palate, nasal mucosa Dx: Biopsy & culture of necrotic tissue Workup includes CT / MRI of head & neck Initiate high-dose IV amphotericin B  Major concern nephrotoxicity  Newer lipid formulations with less toxicity Emergent surgical consultation Perfect JR. Clin Infect Dis. 2005;40:S401-S408. [Amphotericin lipid complex]

Emphysematous Cholecystitis Clinically similar to acute cholecystitis More common in males Gangrene & perforation more frequent High rate of mortality Gallstones present (50%) Dx: Abdominal CT scan Microbiology: E. coli, C. perfringens, B. fragilis Initiate broad-spectrum antibiotic therapy Emergent surgical consultation Garcia-Sancho Tellez L, et al. Hepatogastroenterology. 1999;46:2144-2148. [Case reports]

Neutropenia & Fever Neutropenia:  ANC < 500 cells/mm3 or an ANC expected to decrease to < 500 during the next 48 hours Fever:  Single oral temp ≥ 38.3°C (101°F)  Temp ≥ 38.0°C (100.4°F) for ≥ 1 hour Risk or severity of infection increases with:  Profound neutropenia (ANC ≤ 100 cells/mm3 )  Duration of neutropenia > 7 days Freifeld AG, et al. Clin Infect Dis. 2011;52:e56-e93. [IDSA guidelines neutropenic fever]

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Clinical Presentation Fever may be only feature of infection Signs & symptoms of infection may be minimal Pain despite absence of signs suspect occult infection Special attention to:  Oral cavity, perineum, toes, bone marrow aspiration site & vascular catheters Look for splenectomy scar  Higher risk of infection with S. pneumoniae, H. influenzae, & N. meningitidis

Bacterial Microbiology Majority: Gram-positive organisms  Staphylococcus & streptococcus species  Enterococcus faecalis / faecium  Corynebacterium species (PICC lines) Gram-negative organisms  Escherichia coli, Klebsiella species  Pseudomonas aeruginosa Anaerobes uncommon, unless:  Oral mucositis, perirectal, intra-abdominal source

Initial Evaluation Initial workup must include blood cultures (x 2)  One set from device lumen (if present) Gram stain & culture of exudate at catheter entry site (if present) Initiate empiric antibiotic therapy:  All febrile neutropenic patients  Afebrile neutropenic patients with new signs or symptoms suggestive of infection Freifeld AG, et al. Clin Infect Dis. 2011;52:e56-e93. [IDSA guidelines neutropenic fever]

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Neutropenic Fever: Decision-Making Process High risk Inpatient therapy

Low risk No

Outpatient therapy

Initiate empiric IV antibiotics (within 2 hrs) Decide if need to add vancomycin & metronidazole

Yes

 Involve Heme/Onc  Cipro plus amox-clav or  Cipro plus clindamycin

Freifeld AG, et al. Clin Infect Dis. 2011;52:e56-e93. [IDSA guidelines neutropenic fever]

Empiric IV Antibiotics Piperacillin-tazobactam Imipenem / Meropenem Cefepime Ceftazidime  Poor activity against many gram-positives Penicillin-allergy:  Ciprofloxacin plus clindamycin  Aztreonam plus vancomycin Freifeld AG, et al. Clin Infect Dis. 2011;52:e56-e93. [IDSA guidelines neutropenic fever]

Additional Antibiotics Add vancomycin if:  Severe sepsis / septic shock  Pneumonia  Catheter-related infection  Skin & soft-tissue infection  Known history of MRSA Add metronidazole if using cefepime/ceftazidime:  Oral mucositis  Perirectal infection  Intra-abdominal infection

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Multinational Association for Supportive Care in Cancer Risk Index (MASCC ) To identify low-risk for complications in febrile neutropenic cancer patients Age > 16 years Derivation n=756 Validation n=383 Risk-index score ≥ 21  PPV 91% ; NPV 36%  Sensitivity 71%  Specificity 68%  Misclassification rate 30%

Characteristic No or mild symptoms No hypotension No COPD Solid tumor or no prior fungal infection No dehydration Moderate symptoms Outpatient status Age < 60 years

Wt. 5 5 4 4 3 3 3 2

Klastersky J, et al. J Clin Oncol. 2000;18:3038-3051. [Identifying low-risk of complications]

Other Factors Favoring Low-Risk Absolute neutrophil count ≥ 100 cells/mm3 Neutropenia < 7 days Peak temp < 39ºC & RR ≤ 24 breaths/min Normal chest X-ray No IV catheter-site infection

Disposition Decision always made with Heme-Onc Patient agreeable to plan Obtain consent Ability to care for self /or presence of a caregiver Ability to access medical care

IV Catheter-Related Infections Most common cause of catheter-related infection:  Coag-negative staph (often methicillin-resistant)  Vancomycin first line of therapy Removal indicated if :  Signs of infection (pain, erythema, purulence, induration)  Septic shock with no other source of infection In general, not emergent to remove lines in ED Always involve Hem-Onc Mermel LA, et al. Clin Infect Dis. 2009;49:1-45. [IDSA guidelines on catheter infections]

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Infections in Solid-Organ Transplant Recipients Difficult to differentiate infection from rejection Broad spectrum of potential pathogens Dx often requires invasive diagnostic procedures Predictive temporal pattern of infections:  < 1 month: Nosocomial & post-op infections  1-6 months: Opportunistic infections  > 6 months: Community-acquired infections

Fishman JA. N Engl J Med. 2007;357:2601-2614. [Infection in organ transplant recipients]

Infections in Bone Marrow Transplant Recipients Predictive temporal pattern of infections 0-30 days  Primarily involves  Profound neutropenia skin, liver, & GI tract  Bacterial infections common  Alters neutrophil 31-100 days function  Further adds to  Acute graft vs. host dz. immunosuppression  CMV infection  Increases risk of infections > 100 days  S. pneumoniae, H. influenzae

Infections & Corticosteroid Use Interferes with many aspects of immune system Chronic use predisposes to a variety of infections  Equivalent ≥ 15 mg /day prednisone ≥ 1 month Risk of infectious complications multifactorial  Underlying medical condition  Route of administration  Dose: Risk ↑ if > 10 mg/day or cumulative dose of > 700 mg of prednisone  Durations of therapy: Risk ↑ if given > 21 days Stuck AE, et al. Rev Infect Dis. 1989;11:954-963. [Risk of infections & dose of steroids]

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Infections & Corticosteroid Use Broad spectrum of potential pathogens Most infections due to pyogenic bacteria  S. aureus & streptococci  Enterobacteriaceae Tuberculosis  Often miliary or disseminated  Chronic use suppresses tuberculin reactivity  Induration ≥ 5 mm is considered positive Consider fever etiology infectious until proven otherwise CDC. MMWR. 2000;49(No. RR-6):1-51. [Tuberculin skin testing & steroid use] Rovin BH, et al. Kidney Int. 2005;68:747-759. [Fever in patients with SLE]

Take Home Points Diabetic foot infections:  Think osteo if persistent ulcer after 6 weeks of effective therapy Pyelonephritis & DM:  CT if ≥ 48 hrs of Tx & no clinical improvement Malignant otitis externa:  Needs culture & biopsy

Take Home Points Neutropenic febrile patients:  Initiate antipseudomonal therapy in all patients Solid-organ transplant patients:  Difficult to differentiate infection from rejection Chronic steroid use & tuberculin reactivity:  Induration ≥ 5 mm is considered positive

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