PREVENTION OF INFECTION IN THE COMPROMISED HOST

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PREVENTION OF INFECTION IN THE COMPROMISED HOST

• David Jay Weber, M.D., M.P.H.
• Professor of Medicine, Pediatrics Epidemiology
• University of North Carolina at Chapel Hill

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COMPROMISED HOST

• Topics
• Incidence of immunocompromised patients
• Caveats of infectious disease management of the
  immunocompromised host
• Changing paradigms in the past decade
• Evaluation of the febrile neutropenic patients
• IDSA guideline for treatment of febrile
  neutropenic patients

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CANCER INCIDENCE DEATHS, 2000
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TRANSPLANTATION, US, 2001 (UNOS)
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TRANSPLANTATION, US, 1988-2001
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IMMUNOCOMPROMISED HOSTS

• Caveats
• The risk of developing infection is a result of
  the interaction between the patients
  epidemiologic exposures and his/her NET state of
  immunosuppression
• Increased spectrum of infectious agents capable
  of causing serious disease
• Clinical and microbiologic diagnosis of infection
  difficult
• Prevention superior to treatment

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IMMUNOCOMPROMISED HOSTS

• The risk of developing infection is a result of
  the interaction between the patients
  epidemiologic exposures and his/her NET state of
  immunosuppression
• Underlying disease(s)
• Immunosuppressive medications (including
  steroids)
• Presence or absence of granulocytopenia
• Presence or absence of injury to host defense
  barriers to infection (e.g., intact mucocutaneous
  surfaces)
• Immunomodulating effects of certain infectious
  agents (e.g., CMV, EBV, HIV)

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TIME AS A FACTOR IN INFECTION
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DOSE AS A FACTOR IN INFECTION
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IMMUNOCOMPROMISED HOSTS

• Increased spectrum of infectious agents capable
  of causing serious disease
• Increased incidence of infection
• Increased severity of disease, if infected
• More rapid progression of disease
• Chronic disease possible (e.g., EBV, MAI)

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IMMUNOCOMPROMISED HOSTS

• The clinical presentation of infection usually
  occult, with the extent of disease at the time of
  diagnosis often far out of proportion to the
  severity of symptoms
• Infections are less responsive to therapy
• Successful therapy is dependent upon the rapidity
  of specific diagnosis and initiation of specific
  therapy
• Therapy is often rendered difficult by the side
  effects associated with currently available
  agents
• Prevention is better than treatment

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NEUTROPENIA

• Diseases associated with short term neutropenia
• Chemotherapy for cancer
• Solid-tumor chemotherapy
• Acute leukemia induction or remission
  chemotherapy
• Allogeneic autologous peripheral blood
  stem-cell transplant
• Factors related to infection risk
• Degree of neutropenia
• Duration of neutropenia (fungal disease)

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NEUTROPENIA
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CHANGING PARADIGMS

• Shift from infections due to Gram-positive to
  Gram-negative pathogens
• New Gram-positive pathogens
• NewGram-negative pathogens
• Increased importance of fungi, especially Candida
  sp.
• Increasing incidence of resistant pathogens
  (ORSA, VRE, Candida)

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CHANGING PARADIGMS

• Availability of G-CSF and GM-CSF
• Development of broad spectrum antimicrobials
• Early use of empiric antimicrobial therapy
• Improved infection control
• Use of prophylactic antimicrobial therapy
  (controversial)

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SHIFT TO GRAM-POSITIVE PATHOGENS

• Reasons for increasing prevalence of
  Gram-positive pathogens
• Oral mucositis due to increasingly potent
  chemotherapy protocols
• Profound and prolonged neutropenia
• Increasing use of indwelling vascular catheters
• Fluoroquinolone and TMP-SMX prophylaxis
• Increasing resistance among Gram-positive
  pathogens

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MUCOSITIS
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NOSOCOMIAL PATHOGENS, UNC 1980-99
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NEW GRAM-POSITIVE PATHOGENS

• Viridans streptococci
• Leuconostoc species
• Enterococcus species, esp. vancomycin-resistant
• Corynebacterium jeikeium, C. urealyticum
• Rhodococcus equi

• Bacillus cereus
• Stomatococcus mucilaginosus
• Lactobacillus rhamnosus
• Clostridium septicum, C. tertium
• Zinner S. CID 199929490

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NEW GRAM-NEGATIVE PATHOGENS

• Stenotrophomonous maltophilia
• Alteromonas putrefaciens
• Legionella pneumophilia, L. micdadei
• Vibrio parahemolyticus
• Capnocytophaga species
• Alcaligenes xylosoxidans

• Chrysebacterium meningosepticum
• Burkholderia cepacia
• Fusobacterium nucleatum
• Leptotrichia buccalis
• Methylobacterium species
• Moraxella-like organisms
• Zinner S. CID 199929490

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PREVENTION OF INFECTION

• Immunization
• Appropriate infection control
• Engineering controls
• Selected screening for latent infection with
  appropriate treatment and/or suppression
• Prophylaxis

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IMMUNOCOMPROMISED PERSONS

• Caveats in immunization
• Immunization is associated with a reduced
  frequency of developing protective antibody
• Immunization is associated with lower geometric
  mean titers of antibody
• Inactivated vaccines are safe
• Live virus vaccines may be hazardous
• Immunization is a valuable adjunctive therapy

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PREVENTING ANTIBIOTIC RESISTANCE

• Proper Infection control
• Proper antibiotic utilization

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ENGINEERING CONTROLS

• Aspergillus prevention
• Filtered hospital air
• Barrier protection during renovation or
  construction
• Protective isolation (HEPA filtered) for
  hematopoietic stem cell transplants
• Provide respiratory protection when patients must
  leave PE
• Legionella prevention
• Prohibit showers (use sponge baths)
• Implement surveillance for Legionella cases
• Monitor water supply if Legionella present
  initiate decontamination (controversial)

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PROCEDURES DURING CONSTRUCTION RENOVATION

• Seal hospital construction areas behind
  impervious barriers
• Clean construction area daily (i.e., remove dust
  with HEPA vacuum)
• Assure that ventilation system does not transport
  dust from inside construction area to other
  locations
• Move immunocompromised patients from adjacent
  areas
• Thoroughly clean construction area prior to
  patient use
• Conduct surveillance for airborne fungal
  infections
• Assess airborne fungal levels adjacent to
  construction
• Avoid transporting construction material through
  patient areas
• Assess compliance with infection control
  guidelines

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ISOLATION PRECAUTIONS

• Contact isolation
• Patients with MRSA, VRE, multi-drug resistant
  pathogens
• Protective precautions
• Neutropenia, organ transplant, immunosuppression
• Private room, positive air pressure, no fresh
  vegetables or non-peelable fruits, no flowers,
  limited visitors, exclusion of ill visitors/staff

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NEUTROPENIA

• Strategies for the prevention of infection
• Protective environment
• Laminar airflow of limited use in short term
  neutropenia (prevents Aspergillus)
• Private room (positive air pressure), limited
  visitors
• Mask (N-95) when leaving room healthcare setting
• Careful handwashing by healthcare workers using
  antimicrobial agent

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NEUTROPENIA

• Strategies for the prevention of infection
• Clean food and sterile water
• Omit nonpeelable fruits and fresh vegetables
• Use sterile water for drinking (avoids P.
  aeruginosa, S. maltophilia, Legionella)
• Avoid showers, use sponge baths (Legionella)
• Follow CDC guidelines for placement and
  management of intravascular devices

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NEUTROPENIA

• Strategies for the prevention of infection
• Other
• Avoid rectal temperatures
• Careful skin care (use sterile bandage materials)
• Soft toothbrushes
• Clean with rooms damp mop (not brush)
• The efficacy and effectiveness of these measures
  has not been evaluated in appropriate studies

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LATENT INFECTIONS

• Who to screen
• HIV
• Cancer chemotherapy
• Organ transplant
• Screening protocols may differ among above groups
• Why screen
• Early identification and treatment
• Provide therapy to suppress infection

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LATENT PATHOGENS

• Viral
• Cytomegalovirus (CMV)
• Epstein-Barr (EBV)
• Hepatitis (HBV, HCV)
• Herpes simplex (HSV I II)
• HIV
• Varicella-zoster (VZV)

• Bacterial
• Syphilis
• Tuberculosis

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LATENT PATHOGENS

• Fungal
• Cryptococcus neoformans
• Histoplasma capsulatum
• Blastomyces dermatitidis
• Coccidioides immitis

• Parasitic
• Pneumocystis carinii
• Toxoplasma gondii
• Strongyloides

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MANAGEMENT OF NEUTROPENIC FEVER

• Optimal care
• Meticulous attention to detail
• Repeated exams
• Thoughtful consideration of microbiologic data
• Understanding of institutional pathogens and
  local resistance patterns

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EVALUATION OF FEVER PE

• Teeth and periodontum
• Pharynx
• Chest (lungs)
• Perineum, including anus
• Skin (lesions)
• Bone marrow aspiration and vascular access sites
• Eye (fundoscopic)
• Tissue around nails

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EVALUATION OF FEVER LABS

• Blood cultures (peripheral) CVC?
• Quantitative cultures not necessary
• Inflamed catheter entry site Gram stain
  culture
• Diarrheal stools C. difficile, rotavirus for
  outpatient onset add bacterial cultures and OP
  (Cryptosporidia)
• CBC, LFTs, electrolytes, urinalysis culture
• Chest radiograph
• If indicated skin biopsy, LP, abdominal CT or MRI

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UTILITY OF BLOOD CULTURES

• EORTC Trials VIII and IX
• Microbiologically defined
• Bacteremia 24
• Bacterial-nonbacteremic 5
• Viral 1
• Fungal 2
• Mixed 0.5
• Clinically defined 26
• Unexplained fever 38
• Fever not related to infection 3.5

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COMMON SITES OF INFECTION

• Vascular access sites
• Endocarditis
• Skin (cellulitis, soft tissue infection)
• Lungs (pneumonia)
• GI (enterocolitis, typhlitis)
• Periodontum
• Perirectal area

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MANAGEMENT OF FEVER ISSUES

• Success of determining etiology of fever
• Trigger for initiating therapy
• Monotherapy versus multiple agents
• Duration of therapy
• Site of infection and pathogen known vs site of
  infection and pathogen unknown
• Response to therapy vs no response to therapy
• Recovery of WBC count vs continued neutropenia
• When to broaden therapy (antibacterial agents,
  antifungal agents)

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MANAGEMENT OF THE FEBRILE NEUTROPENIC PATIENTS

• Guideline
• Infectious Disease Society of America
• Hughes et al. Clin Infect Dis 200234730-751

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PROPHYLAXIS

• Antibiotics TMP-SMX, quinolones, selective
  decontamination, nonabsorbable antibiotics
• Antivirals Acyclovir, ganciclovir, amantadine
• Antifungals Nystatin, imidazoles or azoles
• Anti-Pneumocystis TMP-SMX, dapsone, atovaquone,
  aerosolized pentamadine
• Other RSV immune globulin

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IDSA PROPHYLAXIS

• Antibiotic prophylaxis in afebrile neutropenic
  patients
• Not routine, except for Pneumocystis prophylaxis
  (TMP-SMX)
• Quinolones
• Prophylaxis not associated with reduction in
  bacteremia due to Gram positive pathogens or
  fungi
• Quinolone resistant GNRs may emerge
• Increased MRSA may be seen

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IDSA PROPHYLAXIS

• Fluconazole
• Not associated with reduction of Aspergillus
• Activity limited against C. krusei and C.
  glabrata
• Itraconazole
• Associated with reduced frequency of Candida
  infections and decreased mortality rate

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DEFINITIONS

• Fever A single oral temperature of gt38.3 oC or
  gt38.0 oC over at least 1 hour
• Neutropenia Neutrophil count lt500/mm3 or
  lt1,000/mm3 with predicted decline to lt500/mm3
• Impact
• gt50 of neutropenic patients that become febrile
  have an established or occult infection
• gt20 of patients with lt100/mm3 have bacteremia

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INITIAL EVALUATION

• CBC with differential
• Chest radiography
• Cultures of blood (peripheral and catheter), skin
  lesions, and diarrheal stools
• Liver function tests (transaminases)
• Electrolytes
• Other tests as indicated

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IDSA INITIAL ANTIBIOTIC THERAPYLOW RISK
PATIENTS (adults)

• Ciprofloxacin plus
• Amoxicillin-clavulanate

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IDSA INITIAL ANTIBIOTIC THERAPYLOW RISK
PATIENTS (scientific data)

• Absolute neutrophil count gt100 cells/mm3
• Absolute monocyte count gt100 cells/mm3
• Normal CxR
• Nearly normal LFTs and renal function
• Duration of neutropenia lt7 days
• Resolution of neutropenia in lt10 days
• No IV catheter-site infection
• Evidence of bone marrow recovery

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IDSA INITIAL ANTIBIOTIC THERAPYLOW RISK
PATIENTS (scientific data)

• Malignancy in remission
• Peak temperature lt39.0 oC
• No neurologicalor mental changes
• No appearance of illness
• No abdominal pain
• No comorbidity complications

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IDSA INITIAL ANTIBIOTIC THERAPYHIGH RISK
PATIENTS

• Vancomycin is not needed
• Monotherapy
• Cefazidime/cefepime
• Imipenem/meropenem
• Duotherapy (complicated case or resistance
  expected)
• Aminoglycoside and
• Antipseudomonal ?-lactam, cefazidime/cefepime,
  or imipenem/meropenem

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IDSA INITIAL ANTIBIOTIC THERAPYOTHER
CONSIDERATIONS

• Local patterns of infection Type, frequency,
  antibiotic susceptibilities
• Drug allergies
• Drug interactions
• Organ dysfunction (renal and liver)
• Cisplatin, amphotericin B, cyclosporine,
  vancomycin, and aminoglycosides should be avoided
  in combination
• Consider need for vitamin K

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IDSA INDICATIONS FOR VANCOMYCIN

• Suspected catheter-related infection
• Colonized with MRSA or DRP
• Positive blood culture for Gram bacteria (final
  identification pending)
• Hypotension or evidence of cardiovascular
  impairment
• Substantial mucosal damage
• Quinolone prophylaxis
• Sudden increase of temperature to gt40 oC

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IDSA INITIAL ANTIBIOTIC THERAPYCR-BSI

• Follow IDSA guidelines
• Indications for catheter removal
• Tunnel infection or periport infection
• Bacillus spp., P. aeruginosa, S. maltophilia, C.
  jeikeium, VRE, Candida spp.
• ?Established infection with Acinetobacter spp.
• Supplemental therapy (controversial)
• Antibiotic impregnated catheters,
  antibiotic-containing heparin lock therapy,
  delivery via each lumen or rotation through
  multiple lumens

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IDSA MONITORING THE RESPONSE

• Non-response (fever, clinical findings)
• Emergence of secondary infections
• Adverse effects
• Development of drug-resistant organisms

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IDSA AFEBRILE WITHIN 3-5 DAYS

• If no etiology identified
• Low risk change to oral antibiotic
  (ciprofloxaxin plus cefixime children or
  amoxacillin-clavulanate adults)
• High risk continue same antibiotics
• If etiology identified adjust to most
  appropriate therapy (continue broad spectrum
  coverage)
• Continue at least 7 days, until cultures negative
  and signs and symptoms of infection resolved
• Desirable to continue until WBC gt500/mm3

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IDSA AFEBRILE WITHIN 3 DAYS

• Low risk
• No signs or symptoms of unresolved infection
• No evidence of sepsis (chills, hypotension)
• Negative cultures
• Afebrile
• WBC gt100/mm3
• Switch to oral therapy consider home intravenous
  therapy

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IDSA PERSISTANT FEVER

• Evaluate for source of persistent fever
• Noninfectious (e.g., PE) or nonbacterial etiology
• Resistant pathogen or slow response to therapy
• Emergence of second infection (overgrowth,
  superinfection, nosocomial infection)
• Inadequate serum or tissue level of antibiotic(s)
• Drug fever
• Cell wall-deficient bacteremia
• Abscess, obstruction, foreign body infection

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IDSA PERSISTANT FEVER

• Indicated reassessment
• Review all previous therapy
• Meticulous physical exam
• CxR
• Ascertaining status of vascular catheters
• Reculture of blood and specific sites of
  infection
• Diagnostic imaging of any suspected infection
  sites
• High resolution CT (especially lungs),
  ultrasonography
• Determination of antibiotic levels
  (aminoglycosides)
• Selected serologies (e.g., EBV, CMV, HSV)

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IDSA PERSISTANT FEVER

• Reassess on day 3 to 5
• If no change (especially if neutropenia likely to
  resolve within 5 days) continue antibiotics
  consider stopping vancomycin if cultures are
  negative
• If progressive disease change antibiotics
  (consider addition of vancomycin)
• If febrile on days 5-7 and resolution of
  neutropenia not immenent add amphotericin B with
  or without antibiotic changes
• 1/3 have systemic fungal infection (usually
  Candida or Aspergillus)
• Alternatives AmBisome or Abelcet (same efficacy
  as amph B)
• New alternative Itraconazole

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IDSA DURATION OF THERAPY

• Afebrile by days 3-5
• If ANC gt500/mm3 for 2 consecutive days stop
  antibiotics 48 hr after afebrile
• If absolute neutrophil count lt500/mm3 by day 7
• Low risk stop when clinically well afebrile
  for 5-7 days
• High risk (ANC lt100/mm3, mucositis, unstable
  signs) continue antibiotics

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IDSA DURATION OF THERAPY

• Persistent fever
• If absolute neutrophil count gt500/mm3 stop 4-5
  days after ANC gt 500/mm3
• If absolute neutrophil count lt500/m3 continue
  for 2 weeks, reassess and stop if no disease
  sites

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IDSA OTHER THERAPIES

• Antiviral drugs
• No indication for empirical use of antiviral
  agents
• Treat HSV or VZV lesions
• Consider acyclovir (famiciclovir or
  valacyclovir) for suppression of HSV (hematologic
  malignancy)
• BMT consider need to treat CMV with ganciclovir
  or foscarnet

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IDSA OTHER THERAPIES

• Granulocyte transfusions
• Not routine
• Consider with profound neutropenia and failure to
  control bacterial infection despite optimal
  antibiotics and G-CSF, and for severe
  uncontrollable fungal infections

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IDSA OTHER THERAPIES

• Colony-stimulating factors
• Not routine (does not alter infection
  related-mortality)
• Consider when worsening of course predicted and
  expectation of long delay in marrow recovery
  pneumonia, hypotensive episodes, severe
  cellulitis or sinusitis, systemic fungal
  infections, multiorgan dysfunction secondary to
  sepsis
• Stop when neutrophil count stabilized at
  gt500-1,000/mm3

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G-CSF
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CONCLUSIONS

• Treatment of immunocompromised patients
  (including neutropenic patients) based on
  epidemiologic exposures and NET immunosuppression
• Increasing frequency of infection due to Gram
  positive pathogens growing concern about
  resistant pathogens
• No clear benefit for any specific broad spectrum
  agent