ESSENTIALS OF ANTIBIOTICS

Jeanne M. Farnan, MD MHPE

Assistant Professor

Section of Hospital Medicine

University of Chicago

Adult Hospitalist Physician Assistant and Nurse Practitioner Boot Camp

Learning Objectives

Identify factors to consider when choosing

antibiotics

Determine appropriate antibiotics for organism

Describe basic antimicrobial spectra of

common antibiotics

Identify patients at risk for pseudomonas and

MRSA

Recognize important side effects of antibiotics

Selection Considerations:

#1. Spectrum

Time-dependent kinetics

(beta-lactams, vancomycin)

Time spent at the binding sit

inhibition of bacterial growth

Concentration-dependent

kinetics (aminoglycosides,

FQ’s)

Concentration must meet certain

level for effectiveness

http://www.antimicrobe.org/history/PK-PD%20Quint.asp

Selection Considerations:

#2. Tissue Penetration

Antibiotic-specific properties (e.g. lipid

solubility)

Tissue-specific properties (e.g. adequacy of

blood flow, presence of inflammation)

Acute vs. chronic infection

Organism-specific properties

Intra-cellular pathogens

Cunhe, Burke 2007. Antibiotic Essentials

Selection Considerations:

#3. Antibiotic Resistance

Natural vs. acquired

Pathogens not covered by the usual spectrum of an

antibiotic (25% of S. pneumonia are naturally

resistant to macrolides)

Acquired resistance-previously sensitive pathogen

NO LONGER sensitive (ampicillin-resistant H.

influenzae)

Intermediate vs. High-level resistance

Cunhe, Burke 2007. Antibiotic Essentials

Selection Considerations:

#3. Antibiotic Resistance

ESBL (Extended-spectrum beta-lactamases)

Klebsiella species

Risk factors: ICU and length of stay, severity of

illness, lines

MRSA

HA-MRSA vs. CA-MRSA

Selection Considerations:

#4. Cost

Early IV to PO conversion SINGLE biggest cost

saving

Choosing mono-therapy when appropriate

Consider patient factors:

Insurance coverage

Non-adherence with increased frequency of dosing

Dosing considerations…

Renal insufficiency:

R.O.T:

If CrCl 40-60cc/min, decrease daily dose by 50%

If CrCl 10-40cc/min, decrease daily dose by 50% AND double dosing interval

Hepatic insufficiency:

R.O.T decrease daily dose by 50% OR use renally cleared drug

Cunhe, Burke 2007. Antibiotic Essentials

Other considerations:

Bacteriocidal vs. Bacteriostatic

MUST use BACTERIOCIDAL agent for:

Endocarditis

Bacterial meningitis

Neutropenic fever

Bacteriocidal agents:

Beta-lactams, FQ, vancomycin, aminoglycosides,

rifampin, flagyl

Bacteriostatic agents:

Erthryomycin, tetracycline, clindamycin

Class: Beta-lactams

Mechanism attack cell wall synthesis bacteriocidal

Includes:

PCN AKA narrow-spectrum, semi-synthetic PCN [methacillin/oxacillin], carbapenems and cephalosporins

Penicillin:

Meningococcus, most Strep, anaerobes

Still drug of choice for many infections including:

Periodontal infxns, PCN-sensitive S. pneumoniae, viridans Streptococci, group A/B strep, syphyllis

Class: Beta-lactams

Ampicillin/Amoxicillin AKA extended spectrum PCN’s:

PCN + some GNR coverage [E. coli, H. flu, Salmonella, Shigella]

D.O.C for Listeria, susceptible UTI [Proteus] and Enterococcus

Semi-synthetics (methicillin/oxacillin):

PCN-ase resistant

Limited spectrum with rising MRSA

Still some utility with susceptible cellulitides

Class: Beta-lactams

Anti-pseudomonal PCN

[ureidopenicillins]

More GNR [Pseudomonas], anaerobes and

Acinetobacter

Beta-lactamase inhibitors

NO antibacterial activity independently

Sulbactam [with Ampicillin= Unasyn®]

Tazobactam [with Pipericillin= Zosyn®]

Clavulanate/Clavulonic acid

Class: Beta-lactams

Cephalosporins

PCN-ase resistant

NO activity against Enterococci,

MRSA

1st generation AKA cefazolin

Great gram+ activity

Most staph, strep, common

anaerobes

Skin/soft tissue, surgical prophylaxis

Class: Beta-lactams

Cephalosporins

2nd generation:

Less active against GPC, more against GNR

H. flu activity

Cefuroxime

Bacteroides activity

Cefoxitin, Cefotetan

PID, prophylaxis for GI/GYN surgery

Class: Beta-lactams

Cephalosporins

3rd generation:

Stability to common beta-lactamases

More reliable CNS penetration

N. gonorrhea, H. influenza

Activity against Psuedomonas

Ceftazidime

Poor activity against Psuedomonas

Ceftriaxone, Ceftizoxime, Cefotaxime

Class: Beta-lactams

Cephalosporins

4th generation:

Cefepime = GN activity of 3rd generation and GP

of 1st generation

Seizure threshold

5th(!) generation:

Ceftobiprole = Cefipime + Enterococcus

Activity against Enterobacter and Enterococcus

Investigational activity against MRSA

Ceftaroline

CABP, ABSSSI (MRSA!)

Class: Beta-lactams

Cephalosporins

Carbapenems:

B. fragilis, Enterobacter, Pseudomonas

Irtapenem: no activity against Pseudomonas or Acinetobacter

SIDE EFFECTS!

Monobactams AKA Aztreonam:

ONLY GN activity

Enterobacter and Pseudomonas but NOT GPC

Cyclic Peptides

Glycopeptides AKA Vancomycin:

In general is BACTERIOCIDAL

Most GP, including MRSA PCN-resistant pneumococcus

Infusion-related reactions

“Red Man” syndrome

Nephrotoxicity

Macrolides

Erythromycin: atypical pneumonia, Strep.

pneumo

S. pneumo demonstrating increasing macrolide

resistance

Newer agents broader atypical coverage

Enhanced GN coverage

Azithomycin= better H. flu coverage, MAI

Clarithromycin= MAI

Telithromycin

Severe visual disturbance, hepatotoxicity

Sulfas/Lincomycins

Trimethoprim/sulfamethoxizole

Second most common ALLERGY

Bacterio-STATIC

Enterobacter, Chlamydia

PCP!

Clindamycin

GP aerobes, GN anaerobes

CA-MRSA

DOC for pneumonia, septic arthritis, and osteo IF isolate is susceptible and the D-test is negative

Neutropenia/thrombocytopenia

Aminoglycosides

GN!!

Septicemia, complicated UTI/URI

Require AEROBIC metabolism of cell to be effective

so NO ANAEROBE coverage

Gentamicin, tobramycin, amikacin

Infrequent emergence of resistance BUT:

Narrow therapeutic window

Renal/oto-toxicity

FQ’s

GN coverage, including GNR

NOT good against anaerobes

CIPRO [2nd gen FQ] only intermediate GP activity so NOT good choice for empiric CAP coverage

NOT for pediatric population [FDA <18y/o]

QT prolongation…

Tetracyclines

Aerobic GPB/GNR/GNB [Vibrio, H.flu]

Activity against many atypical pathogens:

Spirochetes

Mycoplasma

Chlamydia

Populations (NO pregnant women or children under 8 y/o)

BIG adverse reactions/side effects:

Photo sensitivity

Dose-related GI upset

Hypoplasia of teeth enamel

…and the rest

Flagyl

Anaerobic and GN coverage

C. diff!

WBC suppression

Pertinent anti-fungals

Imidazoles (skin flora, Trichomonas)

Triazoles

Fluconazole: Candida species

Voriconazole: invasive aspergillus, extended or resistant

Candidal species

MRSA treatment

Linezolid

Nosocomial pneumonia AND CSSSI

Safety concerns:

Notably serotonin syndrome, thrombocytopenia, lactic acidosis and ocular toxicity

Tigecycline

CSSSI and complicated intra-abdominal infections

Difficult to use as outpatient 2nd of instability of preparation

MRSA treatment

Resistant to ALL beta-lactam agents

Vancomycin Remains agent of choice

Most clinical experience

Daptomycin Approved for CSSSI

Clinical success rate similar to vancomyin

What about VRE??

Risk factors:

Previous hospitalization/long term care

Patient factors

Length of stay

Hardware

ICU stay

Previous antibiotic use

Colonization pre-dates infection

Patients who are colonized have ~8% rate of developing a VRE infection in-hospital or after discharge

VRE treatment

Vancomycin-resistant E. faecalis

Demonstrated susceptibility to beta-lactams

Sinercid:

ONLY enterococcus faecium

Covers both faecium and faecalis

Linezolid (thrombocytopenia)

Daptomycin (myopathy, serial CK’s)

Tigecycline (N/V, unstable prep for outpatient)

Pseudomonas aeruginosa

Predilection for immunocompromised hosts

Neutropenic fever

Notoriety now associated with VAP

Treatment:

REMOVAL of hardware

TIME

Mono-therapy vs. combination therapy

Pseudomonas therapy

Mono-therapy vs. combination therapy

AG + extended spectrum anti-pseudomonal PCN

OR cephalosporin

Greater spectrum of activity

Inhaled therapy (e.g. colistin) for special

populations

FINALLY….cases

Cellulitis

Diagnosis?

Imaging, gram stain/culture of drainage

Organisms?

Group A strep, MRSA, Staph aureus

Treatment?

r/o MRSA, Nafcillin IV, 1st gen cephalosporin

Cases….

Community-acquired pneumonia

Diagnosis? PA/lateral CXR, sputum/blood cultures, bronchoscopy with

BAL, thoracentesis for parapneumonic effusion

Organisms? CAP: S. pneumo, mycoplasma, chlamydia

Other: resistant s. pneumo, pseudomonas, staph aureus, anaerobes, enteric GN

Treatment? CAP: azithro/ceftriaxone, levaquin

Aspiration: clindamycin

Nosocomial: pseudomonal coverage

Cases…

Urinary Tract Infection

Diagnosis?

U/A with micro/culture

Organisms?

Enteric GNR, Proteus, Enterococci

Treatment?

Consider FQ (cipro), sulfas

Cases…

Bacterial Meningitis

Diagnosis? LP opening pressure >180mm, WBC>10/uL,

glucose<40, protein>45mg/dL

Organisms? S. pneumo, N. meningitidis, H. flu, Listeria

Treatment? Decadron 0.4mg/kg IV

Ceftriaxone 2gm IV q12 and Vancomycin 1gram IV q6

Ampicillin for high suspicion for listeria, >55y/o, immunocompromised

Infection & Choice of Antibiotic

Infection & Choice of Antibiotic

Skin and Soft Tissue Infections

Pneumonia

Intra-abdominal Infections

Urinary Tract Infections

Skin & Soft Tissue Infections

Organisms

MRSA!

Most infections are caused by Staph aureus or

Streptococcus spp.

MRSA is the most common cause of suppurative skin

infections in the U.S.

In individuals with DM2, decubitus ulcers, or

surgical wounds, poly-microbial infections with

Gram negative organisms are common

Skin & Soft Tissue Infections

Antibiotic Coverage

Community-acquired MRSA (not HA-MRSA) can

often be covered with Bactrim, Doxycycline or

Clindamycin

Vancomycin for uncomplicated infections

Zosyn/Cefepime can be added for complicated

infections

If susceptibilities are obtained, tailor accordingly

Pneumonia

Organisms

Community Acquired

S. pneumo (haemophilus, moraxella) and atypicals

(Mycoplasma, Chlamydia, Legionella)

Hospital Acquired/Healthcare-associated

Nursing home patients and patients in the hospital >48-

72 hours – (Exception is legionella)

S. pneumo, Staph, and Gram negatives (Klebsiella,

Pseudomonas)

Anaerobes in patients at risk for aspiration

Pneumonia

Antibiotic Coverage

CAP

Respiratory fluoroquinolone (e.g. Moxifloxacin)

Check QTc if prolonged, can cause Torsades

Benefit: Has anaerobic coverage (Moxi only)

Ceftriaxone and Azithromycin

No anaerobic coverage

HAP

Vancomycin

Pip/Tazo or Cefepime or Carbepenems (Cefepime no

anaerobic coverage)

Intra-abdominal Infections

Organisms

Enteric Gram negatives

E. coli, Pseudomonas, Klebsiella, Proteus

Enterococci

Anaerobes

B. fragilis

Fungal (usually related to perforation)

CDAD (C. difficile-associated disease)

Intra-abdominal Infections

Antibiotic Coverage

Empiric therapy should cover probably

Pseudomonas and anaerobes

No immediate need for anti-fungals unless

perforation is suspected or pt does not respond to

initial management

Anti-pseudomonal penicillin (Pip/Tazo)

Fluoroquinolone (Cipro – only FQ that covers

Pseudomonas)

Anaerobic coverage (Flagyl)

C. difficile

C. difficile produces two toxins, A and B

PCR new gold standard – High sens/spec!

Stool assay is not very sensitive

If your clinical suspicion is high enough and stool is

negative empiric treatment is fine

Treatment

Flagyl (PO and IV)

Vancomycin (PO)

Antibiotics should ideally be given PO

Urinary Tract Infections

Organisms

E. coli, Proteus spp, and other Gram negative rods

S. saprophyticus (young adult females)

Occasional Enterococcus

Urinary Tract Infections

UTI Definition

>105 CFU in symptomatic or catheterize patients

Treat asymptomatic bacteria in pregnant women

Uncomplicated UTI

A UTI in a healthy nonpregnant woman

Complicated UTI

A UTI in anyone else (male, catheter, pregnant female,

pyelo, immunosuppression, structural disease)

Urinary Tract Infections

Antibiotic Coverage

Uncomplicated UTI

Fluoroquinolone (NOT Moxifloxacin)

TMP/SMX

Penicillin (e.g. Amoxicillin)

Complicated UTI

Fluoroquinolone

3rd generation cephalosporin (e.g. Ceftriaxone)

Anti-pseudomonal penicillin (e.g. Pip/Tazo)

MDR organisms – what's the big deal?

What are they – ESKAPE organisms

Enterococcus (VRE)

Staph Aureus (MRSA and VISA)

MDR Klebsiella

Acinetobacter

Pseudomonas

Enterobacter sp.

Pseudomonas – Coverage options

Antipseudomonal penicillins – eg. Pip/Tazo

4th generation and one 3rd generation

Cephalosporins – (eg Cefepime, Ceftazidime)

Carbapenems – NOT ertapenam

Ciprofloxacin – Not respiratory

flouroquinolones

Monobactams – eg Aztreonam

Polymyxins – eg. Colistin

Acinetobacter

Follow up sensititivies!

Colistin and Ampicillin/Sulbactam (around 50%

susceptible)

MDR gram negatives

Extended spectrum beta-lactamases – (ESBL) Usually E. coli and Klebsiella – Tx of chioce carbapenems

Inducible Amp C beta-lactamases SPACE (Serratia, Pseudomonas, Proteus, Acinetobacter, Citrobacter,

Enterobacter) organisms – may be reported as suseptible to pip/tazo

Tx of choice 4th generation Ceph or Carbapenem

Klebsiella producing carbapenemases (KPC) Colistin is treatment of choice

BEWARE! New Delhi metallo-beta lactamases (NDM-1) Colistin is treatement of chioce

Enterococcus – Coverage

Enterococcus faecalis and E. faecium

E. faecalis generally more susceptible and is

frequently covered by aminopenicillins, anti-

pseudomonal PCN, and carbapenems (not

ertapenem)

E. faecium frequently resistant to ampicillin and

more likely to be VRE – Daptomycin or Linezolid

treatment of choice

MRSA

HA-MRSA vs. CA-MRSA (distinction blurring) CA – MRSA – usually susceptible to TMX/Sulfa,

Clindamycin, Doxy in addition to Vancomycin

HA – MRSA – Not usualy susceptible to TMP/Sulfa, Clinda, or Doxy

Vancomycin, Daptomcyin or Linezolid are treatment options

VISA (Vanco MIC 4-16 microgram/ml)

VRSA (Vanco MIC > 16) Although MIC > 2 (and even > 1 in MRSA pneumonia)

may be more likely to lead to treatment failure