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
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
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