INTRO TO ANTIBIOTICS:PART II – CLINICAL PEARLSJuly 28, 2015

Dr. James Cutrell

Infectious Diseases

Outline• Empiric Rx for Clinical Syndromes

• Pathogen-Directed Rx

• Pharmacologic Strategies

Thanks for all the great questions submitted!

Prize Winner: R3 Julie Lin

Questions to Ask When Starting an Abx

• Is an antibiotic indicated based on clinical findings?• Have appropriate cultures been sent before starting

antibiotics?• What is appropriate empiric Rx based on the most likely

pathogens?• Are there important host factors to consider?• What is the best drug dose and route of administration?• What is the anticipated duration of therapy?

Reese RE et al. Principles of Antibiotic Use. In: A Practical Approach to Infectious Diseases 5th ed. 2003

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

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

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.

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 CxIDSA CAP Guidelines. Clinical Infectious Diseases 2007; 44:S27–72.

Nosocomial Pneumonia• General term which includes:

• Hospital-acquired PNA (HAP)• PNA beginning 48 hours after admission

• Ventilator-associated PNA (VAP)• PNA beginning 48-72 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

ATS/IDSA Guidelines for Management of HAP, VAP, HCAP. AJRCCM 2005.

Nosocomial PNA Empiric Rx Algorithm

• MDR Risk Factors:• Hospitalization ≥ 5 days• Abx in prior 90 days• Immunosuppressive

disease or therapy• High frequency of

community or hospital abx resistance

• Presence of HCAP risk factors

ATS/IDSA Guidelines for Management of HAP, VAP, HCAP. AJRCCM 2005.

Defining Risk Factors for MDR Pathogens

Original HCAP Criteria Proposed PNA-specific criteria*

•Hospitalization for ≥ 2 days in last 90 d•Residence in NH or LTAC•Home infusion or IV Abx•Hemodialysis•Home wound care•Family with MDR pathogen•Immunosuppressive disease or Rx

•Hospitalization for ≥ 2 days in last 90 d•Abx use in last 90 days•Non-ambulatory status•Tube feedings•Immunocompromised status•Use of gastric acid suppresants

Adapted from Wunderink RG, Waterer GW. N Engl J Med 2014;370:543-551.

* Risk for MDR pathogens increases with ≥ 2 risk factors and risk factors for MRSA likely unique

Empiric Abx Rx for Early-onset HAP/VAP without MDR Risk Factors

Potential Pathogens Recommended Abx

Streptococcus pneumoniaeHaemophilus influenzaeMSSAAbx-sensitive enteric GNR Escherichia coli Klebsiella pneumoniae Enterobacter spp. Proteus spp. Serratia marcescens

Ceftriaxone 2 gm IV q day ORLevofloxacin 750 mg IV q day or Moxifloxacin 400 mg IV q day ORAmpicillin/sulbactam 3 gm IV q 6h ORErtapenem 1gm IV q day

ATS/IDSA Guidelines for Management of HAP, VAP, HCAP. AJRCCM 2005.

Same abx recommended regardless of disease severity

Empiric Abx Rx for Late-onset HAP/VAP or with MDR Risk Factors

Potential Pathogens

Early-onset pathogens +Pseudomonas aeruginosaESBL Klebsiella pneumoniaeMRSAAcinetobacter spp.Stenotrophomonas maltophilaLegionella pneumophila

ATS/IDSA Guidelines for Management of HAP, VAP, HCAP. AJRCCM 2005.

Same abx recommended regardless of disease severity

Combination Abx Therapy

Bacterial Meningitis• Empiric Rx determined by age and other host risk factors

Pt Factors Suspected Organisms

Empiric Abx

Age 2-50 yo Strep pneumoN. Meningitidis

Ceftriaxone 2 q12h + Vancomycin (high dose)

Age > 50 or risk factors (Immunosuppressed, alcoholism, steroids)

Strep pneumoN. MeningitidisListeriaAerobic GNR

Ceftriaxone 2g q12h + Vancomycin (high dose) + Ampicillin 2g q4h

Nosocomial (Post-NSG, CSF shunt)

Staph aureusCONSGNR (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.

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!

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.

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.

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

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

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

Pathogen-Directed Rx• MRSA• VRE • ESBL• Mycobacteria

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-SMXClindamycin

Doxycycline, MinocyclineRifampin (only in combination)

Quinolones (variable susc.)Linezolid,Tedizolid

IV VancomycinLinezolid (PO/IV)

DaptomycinCeftarolineTigecycline

Quinupristin-DalfopristinDalbavancinOritavancin

Tedizolid (PO/IV)

Vanc MIC ≥ 2 associated with higher rates of Rx failure so consider alternative agents

IDSA MRSA Guidelines. Clinical Infectious Diseases 2011;1–38.

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.

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

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) Amikacin2) Ertapenem3) Piperacillin-

tazobactam4) Meropenem5) Fosfomycin

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.

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.

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

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

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.

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.

Combination GNR Rx: Don’t forget Aminoglycosides!• Empiric AG likely superior to FQ as 2nd agent due to 1)

trend toward better outcomes in critically ill and 2) higher likelihood to add additional GNR coverage

Beardsley, et al. Chest 2006; Nair G, et al. Crit Care Clin, 2013

PseA E. coli K. pneumo

If resistant to Pip/Tazo: N=44 N=52

LevofloxacinGentamicinTobramycin

25%34%61%

33%83%75%

If resistant to Cefepime: N=62 N=144 N=32

LevofloxacinGentamicinTobramycin

24%19%40%

17%54%40%

47%38%25%

If resistant to Meropenem: N=46

LevofloxacinGentamicinTobramycin

17%28%50%

Data courtesy of Dr. Francesca Lee, UHSP

% Susceptibility to 2nd Gram Negative Agent, UHSP Data

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

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

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

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)

AmbisomeMicafungin

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

“The Art of De-escalation”: Example of PNA

ATS/IDSA Guidelines for Management of HAP, VAP, HCAP. AJRCCM 2005.

Must consider patient’s clinical status AND culture results

Tools for Abx De-escalation• Critical to de-escalation is obtaining lower respiratory tract

cultures prior to starting or changing abx within last 72 hours

• Tools for Abx De-escalation• Gram stain and Culture• Physiologic parameters (e.g., CPIS score)• Biomarkers

• No single marker or tool is sufficiently accurate by itself but must be interpreted in context of overall pt. status

ATS/IDSA Guidelines for Management of HAP, VAP, HCAP. AJRCCM 2005.

Nosocomial PNA: Microbiologic Cultures

• Gram stain and Culture• Negative tracheal aspirate (no WBCs or bacteria) has very high NPV

(94%) for VAP• Quantitative cut-offs for infection vs. colonization:

• ET aspirate: >106 cfu/mL• Bronchoscopic BAL: > 104-105 cfu/mL• PSB: > 103 cfu/mL

• MRSA and MDR gram-negatives readily cultured so their absence in high quality LRT specimen reliable

Translation: If MRSA does not grow, it probably isn’t there and Vancomycin can be stopped!

ATS/IDSA Guidelines for Management of HAP, VAP, HCAP. AJRCCM 2005.

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• Can 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 to be presented 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

Proposed PCT Algorithm for High-Acuity Infections in ICU Setting

Schuetz P, et al. Arch Intern Med. 2011;171(15):1322-1331.

De-escalation: What can you do?

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• 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.

New FDA-Approved Antibiotics (2014-15)Drug Name Indication Spectrum of

ActivityComments

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

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

Questions?