Great Abx lecture!

1. INTRO TO ANTIBIOTICS:
PART II – CLINICAL PEARLS
July 28, 2016
Dr. James Cutrell
Infectious Diseases

2. Outline
• Empiric Rx for Clinical Syndromes
• Pathogen-Directed Rx
• Pharmacologic Strategies

3. Empiric Rx for Clinical Syndromes
• Community Acquired Pneumonia
• Nosocomial Pneumonia (HCAP/HAP/VAP)
• Bacterial meningitis
• Diabetic foot infection and osteomyelitis
• Cellulitis
• Neutropenic fever
• Severe sepsis / septic shock
• CAUTI / Asymptomatic Bacteriuria

4. Question #1
• A 35 yo male with no significant PMHx is admitted with 2 days of
acute onset SOB, cough, fevers, and rigors. Admission WBC is 22k
and CXR confirms a RLL lobar consolidation. Arrival BP is 85/55 and
remains low despite initial aggressive fluid resuscitation in ED.
Sputum gram stain is negative; sputum and blood Cx are pending.
• What are guideline-recommended empiric abx Rx?
1) Levofloxacin
2) Ceftriaxone + Vancomycin
3) Ceftriaxone + Azithromycin
4) Vancomycin + Piperacillin-tazobactam

5. CAP: Empiric Rx
• What are the most common pathogens in CAP?
- Strep pneumoniae - Mycoplasma
- H. influenzae - Chlamydophila
- Respiratory viruses - Legionella (severe)
“Atypicals”
Setting Empiric Rx*
Outpt, healthy w/o recent abx Macrolide or doxycycline
Outpt, comorbid disease Respiratory FQ OR
PO Beta-lactam + macrolide
Inpt, non-ICU IV Beta-lactam + macrolide OR Resp FQ
Inpt, ICU IV Beta-lactam + macrolide OR
IV Beta-lactam + Resp FQ
Without specific risk factors, MRSA or resistant GNR are rare in CAP pts
* Oral BL= amox or amox/cl; IV BL= CTX, cefotaxime, amp/sulb, ertapenem
IDSA CAP Guidelines. Clinical Infectious Diseases 2007; 44:S27–72.

6. CAP: When to consider other bugs?
• When to consider PseA or other resistant GNRs?
• Bronchiectasis or COPD + frequent steroids/antibiotics
• Chronic alcoholism
• Recent hospitalization in last 90 days (see HCAP)
• When to consider community acquired MRSA?
• Risk factors: ESRD, IVDA, recent FQ, recent or concurrent flu
• Presentation: Cavitary/necrotizing PNA or rapid pleural effusion;
Skin lesions; Gross hemoptysis; Severe, multilobar PNA in young
• CA-MRSA PNA is dramatic, not subtle, presentation
• MRSA and above GNR easily seen on adequate
sputum Gram stain and Cx
IDSA CAP Guidelines. Clinical Infectious Diseases 2007; 44:S27–72.

7. Nosocomial Pneumonia
• Hospital-acquired PNA (HAP)
• PNA beginning 48 hours after admission
• Ventilator-associated PNA (VAP)
• PNA beginning 48 hours after intubation
• Healthcare-associated PNA (HCAP)
• PNA in non-hospitalized patient with extensive HC contact and
perceived risk for MDR bacteria based on specific criteria
• Excluded from the recently published HAP/VAP guidelines
Management of Adults With HAP/VAP. Clin Infect Dis 2016. Accessed 7/14/2016.

8. New HAP/VAP Guidelines
• Major Changes
• HAP and VAP considered separate entities; removal of HCAP
• Emphasis on local antibiogram to guide empiric abx choices
• GRADE methodology for evidence basis
• Focus on evidence-based risk factors for MDR pathogens
• De-emphasis on invasive or quantitative culture techniques
• Highlight short-course therapy and abx de-escalation in most cases
Unanswered questions remain about how precisely to
operationalize these guidelines and how to manage the patients
previously falling in the “HCAP” category
Management of Adults With HAP/VAP. Clin Infect Dis 2016. Accessed 7/14/2016.

9. Risk Factors for MDR Pathogens
Management of Adults With HAP/VAP. Clin Infect Dis 2016. Accessed 7/14/2016.
Major Risk
Factor:
IV Abx use in
prior 3
months!

10. Empiric VAP Rx Algorithm
VAP Suspected
Obtain appropriate cultures (non-invasive
preferred in most cases), then start empiric
antibiotics (local antibiogram or order sets)
No
Anti-PseA Beta-Lactam:
Pip-tazo 4.5 gm q 6h
Cefepime 2 gm q 8h
Meropenem 1 gm q 8h
Imipenem 500 mg q 6h
No:
No anti-MRSA
coverage
required
Anti-Pseudomonal Abx (1 or
2 drugs)?
• > 10% GNR resistance
• Structural lung dz (e.g. CF)
• Risk factor for MDR VAP
MRSA?
• >10-20% Staph isolates MRSA
• Risk Factor for MDR VAP
Yes:
• Vancomycin
15 mg/kg IV
q8-12h
OR
• Linezolid 600
mg q12h
Yes
Anti-PseA Beta-Lactam
Plus 1 of either:
• FQ (Levo 750 q24h,
Cipro 400 q8h)
• AG (Amikacin, Gent,
Tobra)
• Polymyxin (Colistin)
Management of Adults With HAP/VAP. Clin Infect Dis 2016. Accessed 7/14/2016.

11. Empiric HAP Rx Algorithm
HAP Suspected
Obtain appropriate cultures (non-invasive
preferred in most cases), then start empiric
antibiotics (local antibiogram or order sets)
No
Anti-PseA Beta-Lactam:
Pip-tazo 4.5 gm q 6h
Cefepime 2 gm q 8h
Meropenem 1 gm q 8h
Imipenem 500 mg q 6h or
Levoflox 750 mg q24h
No:
No anti-MRSA
coverage
required
Anti-Pseudomonal Abx (1 or
2 drugs)?
• Prior IV abx last 90 days
• Structural lung dz (e.g. CF)
• Septic shock or MV need
MRSA?
• >20% Staph isolates MRSA
• Prior IV abx last 90 days
• Septic shock or MV need
Yes:
• Vancomycin
15 mg/kg IV
q8-12h
OR
• Linezolid 600
mg q12h
Yes
Anti-PseA Beta-Lactam
Plus 1 of either:
• FQ (Levo 750 q24h,
Cipro 400 q8h)
• AG (Amikacin, Gent,
Tobra)
Management of Adults With HAP/VAP. Clin Infect Dis 2016. Accessed 7/14/2016.

12. What to do about “HCAP patients”?
• For those with well-established risk factors for MDR
pathogens, manage with empiric HAP antibiotics
• IV antibiotics in last 90 days
• Hospitalization for ≥ 2 days in last 90 d
• Immunocompromised status
• Septic shock or requirement for MV at presentation
• For all others, consider managing with empiric CAP
antibiotic regimens
• Remember clues for MRSA or PseA in CAP patients

13. Bacterial Meningitis
• Empiric Rx determined by age and other host risk factors
Pt Factors Suspected
Organisms
Empiric Abx
Age 2-50 yo Strep pneumo
N. Meningitidis
Ceftriaxone 2 q12h +
Vancomycin (high dose)
Age > 50 or risk factors
(Immunosuppressed,
alcoholism, steroids)
Strep pneumo
N. Meningitidis
Listeria
Aerobic GNR
Ceftriaxone 2g q12h +
Vancomycin (high dose) +
Ampicillin 2g q4h
Nosocomial (Post-NSG,
CSF shunt)
Staph aureus
CONS
GNR (incl. PseA)
Vancomycin (high dose) +
Cefepime 2g q8h or
Meropenem 2 g q8h
Remember piperacillin-tazobactam does not achieve good penetration
into the CSF
# High dose vancomycin = Loading dose followed by 30-45 mg/kg divided in 2-3 doses
IDSA Bacterial Meningitis Guidelines. Clinical Infectious Diseases 2004; 39:1267–84.

14. Diabetic Foot Infections
Severity Empiric Rx (Representative agents) Duration #
Mild Clinda, Cephalexin, Amox-Clav, Doxy,
TMP-SMX
1-2 wks, po
Moderate* Amp-sulbactam, ertapenem, ceftriaxone,
FQ + clinda
2-3 wks, +/-
IV at start
Severe MRSA coverage (vanc, linezolid, dapto) +
GNR/anaerobic (pip-tazo or carbapenem
or cefepime/flagyl)
2-3 wks, + IV
at start
* Assess for risk factors for MRSA or PseA which may alter empiric Rx
# Presence of diabetic foot osteomyelitis will require longer duration
IDSA Diabetic Foot Infection Guidelines: CID 2012; 54(12)132-73.
If patient does not have signs of sepsis, hold abx and get deep
tissue or bone biopsy for Cx!

15. Cellulitis: Non-purulent
• Key distinction is between non-purulent (think Strep)
and purulent cellulitis (consider Staph including MRSA)
Raff A, Kroshinsky D. JAMA 2016; 316 (3):325-337.

16. Cellulitis: Purulent
Raff A, Kroshinsky D. JAMA 2016; 316 (3):325-337.

17. Neutropenic Fever
• Low-risk, outpatients: Cipro + Amox/Clav
• Inpatients: Anti-PseA beta-lactam monotherapy
• Cefepime 2 g IV q8h
• Pip-Tazo 4.5 g q6h or 3.375 g q8h Extended infusion
• Meropenem 2 g q8h or Imipenem 1 g q6h
• Do not routinely add MRSA or double PseA coverage
unless PNA or shock!
• When to add Vancomycin: PNA, suspected skin or catheter
infxn, shock; De-escalate Vanc if Cx negative at 2-3 d
• Consider addition of antifungals if persistent fever > 4 d
IDSA Neutropenic Fever Guidelines. Clinical Infectious Diseases 2011;52(4):e56–e93.

18. Severe Sepsis/Septic Shock: Principles
• Goal is “ the administration of effective IV abx within 1st hour of
recognition of septic shock (grade 1B) or severe sepsis (grade 1C).”
• Initial empiric Rx should include “one or more drugs active against all
likely pathogens with adequate penetration into tissues presumed to
be source of sepsis (grade 1B).”
• Abx should be “reassessed daily for potential de-escalation (grade 1B).”
• “Combination therapy, when used empirically for severe sepsis,
should not be continued more than 3-5 days” but de-escalate to
single-agent therapy as soon as susceptibilities are known (grade 2B).
• Source control undertaken in first 12 hours if feasible (grade 1C).
Surviving Sepsis Campaign International Guidelines: 2012 Crit Care Med Feb 2013; 41(2): 580-637.

19. Severe Sepsis/Septic Shock: Empiric Rx
• Empiric Rx depends on host factors, recent abx exposure, allergies, clinical
syndrome and likely site of infection, local antibiogram and pt’s prior
infections or colonization
• Combination therapy recommended in neutropenics with severe sepsis, those
with prior MDR pathogens, and respiratory failure or septic shock patients
(grade 2B)
• Practically, this usually means vancomycin + anti-Pseudomonal beta-lactam +
either aminoglycoside or anti-Pseudomonal FQ
Surviving Sepsis Campaign International Guidelines: 2012 Crit Care Med Feb 2013; 41(2): 580-637.
Clinical Scenario Suggested Potential Regimen
GI source Vanc + Pip/Tazo + AG or FQ
GU/Pulmonary source Vanc + Pip/Tazo or Cefepime + AG or FQ
CNS source Vanc + Cefepime or Carbapenem +/- FQ
Prior or high-risk for ESBL Vanc + Carbapenem + Aminoglycoside

20. Question #2
• 72 yo diabetic male with PMHx of BPH presents for
routine clinic visit. He notes that his urine has been
darker than usual but denies dysuria, frequency, or pain
with urination. No fevers and PE is normal. UA shows
15-20 WBC, + LE and Urine Cx shows ≥ 105 cfu/mL ESBL
E. coli in the urine.
• What is the recommended Rx?
1) Meropenem
2) Ertapenem
3) Fosfomycin
4) Bactrim
5) No treatment indicated

21. CAUTI and Asymptomatic Bacteriuria
• CAUTI
• Signs or symptoms of UTI + ≥ 103 cfu/mL of ≥ 1urinary pathogen
• CA-ASB: asymptomatic + ≥ 105 cfu/mL of ≥ 1urinary pathogen
• Presence or absence of pyuria or cloudy, malodorous urine does
NOT distinguish CA-ASB from CAUTI
• Should NOT screen for or treat CA-ASB except in select situations
(see below)
• Asymptomatic Bacteriuria (ASB)
• Screening and treatment only in pregnancy or prior to urologic
procedure (TURP or bleeding anticipated)
• Pyuria or certain colony threshold (≥ 105 cfu/mL) are NOT an
indication for treatment

22. Pathogen-Directed Rx
• MRSA
• VRE
• ESBL
• C. difficile
• Mycobacteria

23. MRSA
• PO options acceptable for SSTI or
completion of osteo Rx; IV
preferred for invasive disease
• Vanc empiric drug of choice in most
serious infections
• If vanc intolerance or failure:
• PNA Linezolid, Ceftaroline
• Bacteremia/Endocarditis
Daptomycin, Ceftaroline (?)
• CNS  Linezolid
• Osteo  Dapto, Ceftaroline
MRSA
Oral TMP-SMX
Clindamycin
Doxycycline, Minocycline
Rifampin (only in combination)
Quinolones (variable susc.)
Linezolid,Tedizolid
IV Vancomycin
Linezolid (PO/IV)
Daptomycin
Ceftaroline
Tigecycline
Quinupristin-Dalfopristin
Dalbavancin
Oritavancin
Tedizolid (PO/IV)
Vanc MIC ≥ 2 associated with
higher rates of Rx failure so
may consider alternative
agentsIDSA MRSA Guidelines. Clinical Infectious Diseases 2011;1–38.

24. MRSA Bacteremia: Basics
• Uncomplicated bacteremia
• Must meet all of following: No IE (by TEE); No prostheses; Negative f/u
blood cultures at 2-4 days; Defervescence within 72 h of effective
therapy; No metastatic infection
• Vancomycin or Daptomycin for minimum 2 weeks
• Complicated bacteremia or endocarditis
• 4-6 weeks at minimum
• No benefit to adding gentamicin or rifampin for native valve IE
• Treatment failure
• Generally defined as persistent bacteremia around day 7 of therapy
(median time to clearance of MRSA bacteremia is 7-9 days)
• May also define failure as patient getting worse on current tx
• Remember SOURCE CONTROL!!!
IDSA MRSA Guidelines. Clinical Infectious Diseases 2011;1–38.

25. VRE
• Vancomycin-resistant Enterococcus (VRE)
• GI or GU infections in patients with prior abx
• Bacteremia, endocarditis in those with extensive HC exposure
• E. faecalis: Often remains sensitive to ampicillin, beta-lactams
• E. faecium: Often multi-drug resistant
• Cystitis Rx
• Consider Nitrofurantoin or Fosfomycin
• Invasive infections Rx
• Amp-sens VRE faecalis: Amp, Amp/Sulb, Pip/Tazo, Imi/Meropenem active
• Linezolid, High dose Daptomycin (8-12 mg/kg daily), Tigecycline 
Consult ID for assistance

26. Question #3:
• 73 yo male presents with fever and flank pain consistent
with pyelonephritis. UCx is shown to right.
• Which agent(s) would not be a reliably effective Rx?
1) Amikacin
2) Ertapenem
3) Piperacillin-
tazobactam
4) Meropenem
5) Fosfomycin

27. ESBL
• Extended spectrum beta-lactamases (ESBL)
• Family of heterogeneous enzymes, 100s of different types
• Mostly seen in E. coli, Klebsiella spp. but other GNR may produce
• Causes resistance to PCN, cephalosporins and aztreonam
• Do not inactivate carbapenems
• Do not affect non-beta lactams abx, but co-resistance common
• Rx options:
• Cystitis: Fosfomycin, Nitrofurantoin, Bactrim, FQ if sensitive
• Serious infections: Carbapenems preferred
• Rx failures seen with Cefepime (? inoculum effect) but may be able to
overcome with higher doses and continuous infusion based on MIC
Lee N-Y, et al. Clinical Infectious Diseases 2013;56(4):488–95.

28. C. difficile infection
• Most common recognized cause of diarrhea in healthcare
setting
• Key Guidelines:
• IDSA/SHEA 2010
• ACG April 2013
• Testing:
• Only unformed stool in patients with 3 or more unformed stools in
24 hrs (except ileus)
• PCR most sensitive (now at all 3 hospitals)
• Repeat testing or test of cure discouraged

29. C. difficile Infection Severity
IDSA 2010 Guidelines ACG 2013 Guidelines
Mild CDI Diarrhea alone Diarrhea alone
Moderate CDI Diarrhea + other sxs not
severe
Diarrhea + other sxs not
severe
Severe CDI Diarrhea + WBC > 15k or
Cr > 1.5x baseline
Diarrhea + Alb < 3.0 + either
WBC > 15k or abdominal
tenderness
Severe,
Complicated CDI
Shock, ileus, toxic
megacolon
ICU admission, shock, Fever
> 38.5, Ileus, End organ
failure, WBC > 35k, Lactate
> 2.2

30. C. difficile Treatment
IDSA 2010 Guidelines ACG 2013 Guidelines
Mild CDI Metro 500 po TID x 10-14d Metro 500 po TID x 10d
Moderate CDI Metro 500 po TID x 10-14d Metro 500 po TID x 10d
Severe CDI Vanco 125 po QID x 10-14d Vanco 125 po QID x 10d
Severe, Complicated
CDI
Vanco 500 po QID + Metro
500 IV TID +/- Vanc enemas
if ileus
Vanco 500 po QID + Metro 500
IV TID +/- Vanc enemas if ileus
1st recurrence Same as initial episode Same as initial episode
2nd recurrence Vanc po pulse and taper Vanc po pulse regimen;
Consider FMT for recurrence
General Principles:
- Stop offending abx or change to less pro-CDI abx if possible
- No evidence to support extending beyond 10-14 days of Rx
- Early surgical consult for pts with toxic megacolon or severe,
complicated CDI. Lactate > 5, WBC > 50k predict high mortality.

31. Mycobacteria: TB and non-TB
• Require multi-drug therapy for prolonged duration
• Suspected M. tuberculosis is only situation where empiric
mycobacterial Rx is routinely initiated
• ID and abx susceptibilities critical to guide NTM Rx and
should only be done with ID or pulmonary consultation
• Diagnosis and Rx of NTM disease (esp. pulm) requires:
• Clinical Symptoms +
• Compatible Radiographic Findings +
• Microbiologic culture (2 positive sputum or 1 BAL/Bx specimen)
ATS/IDSA NTM Guidelines. Am J Respir Crit Care Med Vol 175. pp 367–416, 2007.

32. Pharmacologic Strategies and Tips
• Therapeutic Drug Monitoring
• Combination Therapy
• Fluoroquinolones
• Antifungals
• “The Art of De-escalation”

33. Therapeutic Drug Monitoring (TDM)
• Why do we do “drug levels” for certain drugs?
• Variable, unpredictable pharmacokinetics
• Correlation between drug concentration and efficacy or toxicity
• Vancomycin
• Check trough before 4th or 5th dose on steady dose
• Goal troughs: > 10 mcg/mL; 15-20 mcg/mL for serious infections (bacteremia,
endocarditis, PNA, meningitis, osteo)
• Aminoglycosides
• Once-daily dosing for GNR: Random level 8-12 hrs after dose to adjust with
nomogram, Trough < 1 mcg/mL (only for renal failure)
• Synergy for GPC endocarditis: Peak 2-4 mcg/mL, Trough <1 mcg/mL
• Azoles (treatment of invasive fungal infections)
• Voriconazole: goal troughs 1.0 - 5.5 mcg/mL
• Itraconazole: goal troughs > 1.0 mcg/mL (itra + hydroxy-itra by HPLC)
• Posaconazole: goal troughs > 0.7 mcg/mL

34. Combination Therapy
• Standard of care for certain infections (e.g. TB, HIV)
• Recommended for prosthetic device infections
• Vancomycin/Gent/Rifampin for MRSA prosthetic valve IE
• Addition of rifampin for Staph PJI and hardware infections
• Recommended for necrotizing or severe SSTI
• Addition of clindamycin or linezolid to beta-lactam in order to inhibit
toxin production, esp. Group A Strep TSS or necrotizing fasciitis
• Recent prospective, population-based surveillance from Australia
showed substantial reduced mortality (OR 0.28 [95% CI, 0.1-0.8])
with addition of clindamycin in invasive GAS infections
Carapetis J, et al. Clin Infect Dis. (2014) 59 (3): 358-365.

35. Combination Therapy: What about PseA?
• Empiric combo Rx: Yes, increases chances of at least 1
active drug if serious infection (neutropenic bacteremia,
severe sepsis/shock) or high MDR risk
• Definitive Rx: No convincing data of mortality benefit
Vardakas VZ, et al. International Journal of Antimicrobial Agents 41 (2013): 301-310.

36. Fluoroquinolones: Comparisons
Ciprofloxacin Levofloxacin Moxifloxacin
Dose 400 mg IV BID-TID
500-750 mg PO BID
750 mg qd PO
or IV
400 mg qd PO
or IV
Elimination Renal Renal Mixed
Urinary
penetration
Good Good Poor
Staph spp. +/- +/- +/-
Strep spp. No Yes Yes
Pseudomonas Yes-high dose Yes-high dose No
Anaerobes No No Yes
QTc effect +/- + ++
• Ciprofloxacin has best Gram negative activity
• Moxifloxacin has best Gram positive and anaerobe activity
• Levo and moxi = “respiratory FQ” due to S. pneumoniae activity

37. Question #4:
• 52 yo male with ESLD presents with 4 days of fevers,
increasing ascites, SOB and AMS with headache. Started
on broad-spectrum abx without much improvement and
now obtunded, and on day #3 admission blood Cx
growing yeast.
• What is the most appropriate empiric anti-fungal Rx?
1) Fluconazole
2) Ambisome
3) Micafungin
4) Voriconazole
Or call the
Micro lab to ask
what the yeast
looks like

38. Anti-Fungals: Spectrum of Activity
• Azoles (fluc-, itra-, vori-, posaconazole)
• Echinocandins (caspo-, anidula-, micafungin)
• Polyenes (amphotericin B, liposomal AmB)
Mayo Clin Proc. Aug 2011;86(8):805-817

39. Anti-Fungals: Empiric Rx
• Rx depends on host factors and most likely pathogens
Clinical Scenario Likely Fungal
Pathogens
Appropriate Empiric
Antifungal
Sepsis in ICU pt (TPN,
CVC, abd surgery,
long-term abx)
Candida (incl azole-
resistant spp.)
Micafungin
Neutropenic fever* Candida (incl resistant
spp.), Molds
(Aspergillus, Mucor)
Ambisome
Micafungin
Voriconazole
Sepsis in IC host
(AIDS, cirrhosis, TNF-
inhibitors, SOT/BMT)
Endemic fungi (Histo,
Crypto, Cocci);
Candida; Molds
(Aspergillus, Mucor)
Ambisome
Yeast in UA from Foley
or ET aspirate
Candida spp. (likely
colonization)
None; Only azoles
reliably penetrate urine
* Consider site of infection and prior fungal prophylaxis

40. “The Art of De-escalation”
Garnacho-Montero J, et al. Curr Opin Infect Dis 2015; 28:193-98.

41. General Approach to De-escalation
Serious Infection clinically suspected
(shock/severe sepsis, HAP/VAP, meningitis)
Obtain appropriate cultures, then start empiric
antibiotics (local antibiogram or order sets)
“48-72 hr Abx Time-out”
Reassess clinical status and Cx results
Pursue
Aggressive
source control!
Consider
PCT
Clinical improvement at 48-72 hours ?
Consider
repeat PCT Yes No
Cultures –,
alternate Dx
made:
Stop Abx
Cultures – ,
infxn suspected:
De-escalate abx,
treat for shortest
duration
appropriate
Cultures +:
De-escalate abx,
treat for shortest
duration
appropriate for
site
Cultures +:
Optimize abx
Consider complications,
other Dx/pathogens
Cultures -:
As above, consider non-
infectious causes

42. De-escalation: Practical Tips
• If cultures positive:
• Choose narrower spectrum agents (e.g., anti-Staphylococcal beta-lactam for MSSA)
• Stop double GNR coverage if single active agent available and clinically improving
• If cultures negative:
• Stop anti-MRSA coverage if no MRSA isolated (or no hx colonization)
• Stop double GNR coverage if no MDR pathogen isolated
• Switch to highly bioavailable oral antibiotic
• Reassess need for atypical or anaerobic coverage
• Consider collateral damage to microbiota (C. diff risk)
• Use shortest duration appropriate (possibly guided by PCT)
• Don’t forget about non-infectious ID mimickers (e.g., “bilateral cellulitis from
venous stasis)

43. Biomarkers
• Various biomarkers have been studied (procalcitonin [PCT], CRP, etc.)
but have failed to reliably aid initial VAP diagnosis
• However, RCT and meta-analysis suggest serial PCT measurements
can be used to safely de-escalate abx/reduce Rx duration (average
decrease of 3-4 abx days compared to control)
• Key Points for Procalcitonin Use in ICU:
• Need in-house testing to be clinically useful
• Should NOT use to withhold or delay initial empiric abx in suspected
severe infections or high-risk ICU patients
• May be useful to de-escalate or shorten duration of abx Rx
• PCT should be used for validated indications (sepsis and respiratory
infections) with the guide of an interpretive algorithm or its real-world utility
is diminished (Unpublished VANTHCS data presented at ICAAC 2014)
Bouadma L, et al. Lancet, 2010; Tang H, et al. Infection, 2009; Schuetz P, et al. Cochrane Database Syst
Rev, 2012; Schuetz P, et al. Arch Intern Med. 2011;171(15):1322-1331

44. Proposed PCTAlgorithm for High-Acuity
Infections in ICU Setting
Schuetz P, et al. Arch Intern Med. 2011;171(15):1322-1331.

45. De-escalation: Duration of Rx
De-escalate/stop antibiotics or shorten
duration of therapy when appropriate
• Importance of “antibiotic timeout” to reassess clinical status
and culture results at 48-72 hours
• Multiple RCT and meta-analyses demonstrate non-inferior
outcomes with shorter Rx courses
• VAP (Non-PseA)= 8 days; 7 days per new guidelines
• Cellulitis = 5 days ≈ 10 days
• UTI or pyelonephritis = 7 days
• CAP = 5 days (with high dose FQ)
Bartlett J, et al. Clin Infect Dis. 2013; 56(10):1445-50.

46. New FDA-Approved Antibiotics (2014-16)
Drug Name Indication Spectrum of
Activity
Comments
Tedizolid
(Sivextro)
Acute bacterial skin
and skin structure
infection (ABSSSI)
Gm + including MRSA
and VRE
Similar to linezolid,
except qday dosing
Dalbavancin
(Dalvance)
ABSSSI Gm+ including MRSA Prolonged ½ life
Oritavancin
(Orbactiv)
ABSSSI Gm + including MRSA Prolonged ½ life
Ceftolozane-
tazobactam
(Zerbaxa)
Treatment of cIAI and
cUTI
MDR-GNRs including
MDR-PseA
Inadequate anaerobic
coverage alone
Ceftazidime-
avibactam
(Avycaz)
Treatment of cIAI and
cUTI
MDR-GNRs including
PseA, ESBL and some
CRE
Inadequate anaerobic
coverage alone
Isavuconazonium
(Cresemba)
Invasive aspergillosis
and mucormycosis
Mold infections
including aspergillus,
Mucor
Non-inferior to vori for
aspergillus; limited
data in single arm trial
for Mucor

47. Conclusions
• Consider the most likely pathogens and utilize guidelines
to help determine empiric abx Rx
• In critically ill patients, early broad spectrum abx are
appropriate, but don’t forget to get cultures and reassess
clinical status and chance to de-escalate Rx
• Respect MRSA bacteremia and ensure all criteria met for
uncomplicated before giving short course Rx
• Use the minimum necessary duration of abx based on
type of infection and clinical response

48. Questions?