Antibiotic Basics
Steven Bradley, MD
Harborview Chief Medical Resident
Inpatient Services
Antimicrobial Considerations
1.
2.
Likely organism and susceptibilities
Site of infection
- SSTI, bacteremia, pneumonia, meningitis, UTI
3.
Host factors
- Immune deficiencies, age, allergies, renal and
hepatic function
4.
Antimicrobial factors
- Dosage, route, drug interactions, tissue
penetration, toxicity, cost
5.
Public health considerations
- Selection of resistance
Antimicrobial Case 1
20 yo woman presents with 3 days of fever, sore
throat, and cervical adenopathy. Rapid strep test
is positive. What is the preferred therapy?
A. Azithromycin for 5 days
B. Penicillin V for 10 days
C. Levofloxacin 500 mg for 10 days
D. Vancomycin 1 gm BID for 7 days
Antimicrobials: Site of Action
Cell Wall
- Beta-Lactams
- Glycopeptides
Cell Membrane
- Daptomycin
- Polymixin
DNA Inhibitor
- Fluoroquinolone
- TMP-SMX
- Metronidazole
Protein Synthesis
50S Ribosome
- Macrolides/Ketolides
- Clindamycin
- Chloramphenicol
- Quinupristin-Dalfopristin
30S Ribosome
- Aminoglycosides
- Tetracyclines
- Glycylcyclines
70S Initiation Complex
- Linezolid
Adapted from David Spach, MD
Bacteria: Cell Wall Synthesis
Cell Wall Synthesis
Penicillin Binding Proteins
Penicillin Binding Protein
DNA
Cell
Membrane
Cell Wall
Adapted from David Spach,MD
Beta-lactam Antimicrobials
 Penicillins
 Cephalosporins
 Carbapenems
 Monobactams
Site of β-lactamase Activity
O
R1
C
S
NH HC
H 2C
C
N
O
β-lactamase
CH3
C
CH3
C COOH
Beta-Lactam: Mechanism of Action
Cell Wall Synthesis
Beta-Lactam
DNA
Cell Membrane
Penicillin Binding Proteins
Cell Wall
Adapted from David Spach, MD
Penicillins

Penicillin G and penicillin V



Aminopenicillins




Streptococcus pyogenes
Pharyngitis, syphilis
Ampicillin and amoxicillin
H. influenzae, Enterococcus, Listeria
Acute otitis media, acute bacterial sinusitis
Penicillinase-resistant penicillins




Methicillin, nafcillin, oxacillin, dicloxacillin
Staphylococcus aureus (MSSA), Streptococcus
No gram-negative activity
SSTI, osteomyelitis, septic arthritis
Extended-spectrum Penicillins

Carboxypenicillins (Ticarcillin)


Ureidopenicillins (Piperacillin)


Gram-negative coverage including
Pseudomonas
Gram-negative coverage including
Pseudomonas
Penicillin β-lactamase inhibitor
combinations


Amox-clav, amp-sulb, ticar-clav, pip-tazo
Increase Staphylococcus and anaerobic
coverage
Increasing Gram-negative Coverage

First Generation


Second Generation



Cefuroxime
Cefamycins: cefoxitin, cefotetan
Third Generation


Cefazolin, cephalexin
Ceftriaxone, ceftazidime
Fourth Generation

Cefepime
Increasing Gram-positive Coverage
Cephalosporins
Carbapenems

Imipenem/cilastin, meropenem



Ertapenem


Broad spectrum of activity including
Pseudomonas
Meropenem less likely to provoke seizures
Not active against Pseudomonas,
Acinetobacter, and Enterococcus faecalis
Most reliable activity against ESBL and
ampC containing organisms
Monobactams



Aztreonam
Activity restricted to aerobic gramnegative bacteria including most
Pseudomonas
Does not display cross-reactive
hypersensitivity reactions in
patients with penicillin allergies
Beta-Lactam Allergy

10-20% of those reporting PCN allergy are
truly allergic when assessed by skin testing



Potential cross-reactivity with
cephalosporins (8%) and carbapenems, but
not monobactams
Skin test for major (benzylpenicilloyl
polylysine) and minor determinants



Positive predictive value of 14%
Positive skin test: 41-67% risk of significant
allergy
Negative skin test: 1-4% risk, none life
threatening
Desensitization when no other options
Antimicrobial Case 1
20 yo woman presents with 3 days of fever, sore
throat, and cervical adenopathy. Rapid strep test
is positive. What is the preferred therapy?
A. Azithromycin for 5 days
B. Penicillin V for 10 days
C. Levofloxacin 500 mg for 10 days
D. Vancomycin 1 gm BID for 7 days
Antimicrobial Case 2
45 y o woman
presents with 3 day
history of acute onset
of fever 39 C, chills,
cough productive of
green phlegm, SOB,
and right-sided chest
pain. CXR
demonstrates RLL
infiltrate.
Community-Acquired Pneumonia


Most common pathogens S. pneumoniae, H.
influenzae, Moraxella with concern for C.
pneumonia, M. pneumoniae, and Legionella
2002-2003 US Survey revealed 34% nonsusceptible (16% intermediate, 18% resistant)


WA 2003: 16% intermediate, 7% resistant
S. pneumoniae do not produce beta-lactamase


Alteration in penicillin binding protein with decreased
affinity for beta-lactam
Beta-lactamase inhibitors (clavulanate or sulbactam)
will not improve efficacy
Streptococcus pneumoniae Resistance
Antimicrobial
Percent
Resistant
Macrolide
29%
TMP/SMX
32%
Tetracyclines
*21.9% of 16%
S. pneumoniae isolates in 2002-2003 had fluoroquinolone
mutations in parC and/or gyrA compared to 4.7% in 1997-1998.
Fluoroquinolones*
2.3%
Clin Infect Dis
2005;41:139-48
Community-Acquired Pneumonia

Outpatient



Macrolide or doxycycline
Respiratory fluoroquinolone, if recent antimicrobial tx
Inpatient medical ward


-lactam + macrolide vs. fluoroquinolone
Retrospective analysis of 14,000 Medicare patients
found lower mortality with cephalosporin + macrolide
or fluoroquinolone compared to cephalosporin alone
(Arch Intern Med 1999;159:2562-72)

Lower in-hospital mortality among patients with
bacteremic pneumococcal pneumonia treated with lactam + macrolide compared to -lactam alone
(Clin Infect Dis 2003;36:389-95)
Clin Infect Dis 2003;37:1405-33.
Fluoroquinolone: Mechanism of Action
Fluoroquinolone
DNA Topoisomerase IV
DNA Gyrase
DNA
Cell
Membrane
Cell Wall
Adapted from David Spach, MD
Fluoroquinolones



Concentration-dependent killing (AUC:MIC)
Moxifloxacin is hepatically eliminated, not for
urinary infections
Adverse events






GI
CNS
Photosensitivity
Prolonged QTc
Tendonitis/arthropathies
Hyperglycemia or hypoglycemia, particularly elderly
with DM
S. pneumoniae and Fluoroquinolones
Drug
MIC90
AUCFree
AUC:MICFree
Ciprofloxacin (750 bid)
Levofloxacin (500 qd)
Levofloxacin (750 qd)
Gatifloxacin (400 qd)
Gemifloxacin (320 qd)
280
Moxifloxacin (400 qd)
1.0
1.0
1.0
0.25
0.03
28
34
70
26
28
34
70
106
140-
0.12
24
200
Cutoff criterion of AUC:MIC >33.7 for gram-positives?
Clin Infect Dis 2005;41:S127-35
High-dose, Short-course Levofloxacin for
CAP



Attempt to increase AUC:MIC ratio
while decreasing overall drug exposure
Multi-center, randomized, double-blind
study comparing 750 mg qd x 5 days
vs. 500 mg qd x 10 days in the
treatment of CAP
Found equivalent clinical and
microbiological outcomes
Clin Infect Dis 2003;37:752-60
Case Modified


The patient
decompensated
and required
intubation. He
became afebrile
after 48 hours.
They remained
intubated at 96
hours and
developed a new
fever and infiltrate
on CXR.



What infection are
you concerned for?
What pathogens
need to be
considered in this
setting?
What antibiotic
choices are
appropriate?
Nosocomial Pneumonia/Ventilator
Associated Pneumonia


Common pathogens include
coliforms, Staph and Pseudomonas
aeruginosa
Coverage should now cover broadly
for gram positives, gram negatives,
and Pseudomonas



Anti-pseudomonal penicillin (pip/tazo)
or fluoroquinolone
MRSA coverage (vanco)
Eight day therapy equivalent to 14
day
Pseudomonas and Fluoroquinolones
Drug
Dose
Ciprofloxacin
400
400
750
400
400
Levofloxacin
Gatifloxacin
Moxifloxacin
q12
q8
q24
q12
q24
Cmax
4.1
4.1
12.1
4.6
4.2
MIC
0.125
0.125
0.5
1.0
2.0
AUCfree:MIC
144
184
152
28
10
New IDSA and ATS Guidelines for HAP/VAP recommend
Ciprofloxacin 400mg IV q8hr or Levofloxacin 750 mg qd
Am J Respir Crit Care Med 2005;171:388-416
Antimicrobial Case 6
20 y o woman presents with 2 day h/o
dysuria, urgency, and frequency. UA
with >50 WBC/hpf, +leukocyte esterase
Cystitis treatment options:
Amoxicillin, 40-50% resistance among E. coli
Nitrofurantoin x 7 days
-cystitis only, does not achieve adequate blood levels
TMP-SMX x 3 days, though increasing resistance
-culture selection bias reflecting hospital setting
-85% predicted clinical cure rate with 30% resistance
Fluoroquinolone, ? if >10-20% resistance to TMP-SMX
Clin Infect Dis 1999;29:745-58
Antimicrobial Case #3

What if this patient was 75 and had
a chronic foley catheter?
Complicated UTI


In the setting of obstruction (BPH),
reflux, catheter
Similar pathogen profile




Enterobacteriaceae (E.coli), enterococci
Nosocomial bugs
Treat for extended period (2 weeks)
and remove obstruction if possible
Beware of asymptomatic bacteruria

Treatment leads to resistance
Antimicrobial Case 5
35 y o man with a history of
methamphetamine use presents to
clinic with a right biceps abscess.
Previous “Standard of Care”



If abscess appreciated, I&D
performed without culturing
Depending on severity of SSTI,
either admitted for IV beta-lactam
(cefazolin or nafcillin), or discharged
empirically on cephelexin without
concern for resistant organisms
This approach is no longer
appropriate
Proportion of S. aureus Nosocomial
Infections Resistant to Oxacillin (MRSA)
Among Intensive Care Unit Patients,
1989-2003*
Percent Resistance
70
60
50
40
30
20
10
0
1989
1991
1993
1995
1997
1999
2001
Year
*Source: NNIS System, data for 2003 are incomplete
2003
Community-Associated MRSA
 Clinical
manifestations

Predominantly skin and soft tissue

Necrotizing fasciitis

Necrotizing pneumonia
(JAMA 2003;290:2976-2984)
53)
2005;40:100-7)
 Different

(N Engl J Med 2005;352:1445(Clin Infect Dis
from HA-MRSA
Panton-Valentine Leukocidin exotoxin
associated with tissue necrosis and leukocyte
destruction
(JAMA 2003;290:2976-2984)
Nasal Carriage of S. aureus
20-40% of people colonized with S. aureus
–20% persistent, 60% intermittent, 20% never
Increased Rates of MRSA

Healthcare contact








Surgery
Dialysis
Indwelling devices
IDDM
HIV
Long-term care facilities
IDU (Clin Infect Dis 2002;34:425-33)
Correction facilities (Clin Infect Dis

2003;37:1384-8)
MSM (Clin Infect Dis 2005;40:1529-34)
Native Americans, Pacific Islanders

Other close contact


Athletic (N Engl J Med 2005;352:468-75)
Antimicrobial Susceptibility Patterns
Clindamycin
Erythromycin
Fluoroquinolone
Rifampin
94
Tetracycline
TMP/SMX
Vancomycin
JAMA 2003;290:2976-2984
CA-MRSA
83
44
79
96
92
95
100
HC-MRSA
21
9
16
92
90
100
Treatment Options for MRSA Infections
Intravenous*





Vancomycin
Linezolid
Daptomycin
Quinupristin/dalfopr
istin
Tigecycline
Oral*





TMP-SMX
Minocycline/Dox
y
Clindamycin
Fluoroquinolone
Linezolid
*with or without rifampin, however NEVER use rifampin
monotherapy due to rapid emergence of resistance
TMP/SMX Mechanism
The Folic Acid Pathway
Sulfonamides
PABA
//
Trimethroprim
Dihydrofolic
Acid
Tetrahydropteroic
acid synthetase
//
Tetrahydrofolic
Acid
Dihydrofolate
reductase
Adverse Events:
-Hypersensitivity reaction
-Marrow suppression
-Hemolysis (G6PD deficiency)
-Displace bilirubin from albumin
Purines
DNA
Oxazolidinone: Mechanism of Action
50S Ribosome
30S Ribosome
fMet-tRNA
Oxazolidinone
50
S
30
S
70 S Initiation
Complex
DNA
Modified from David Spach, MD
Linezolid




Oxazolidinone
Active against MSSA, MRSA, VRSA, coag-neg Staph,
S. pyogenes, S. pneumoniae, E. faecalis, E. faecium
including VRE, as well as some Nocardia and
mycobacteria
Oral bioavailability 100%
Adverse events:






GI (nausea and vomiting)
marrow suppression (thrombocytopenia, anemia,
leukopenia)
serotonin syndrome (weak monoamine oxidase
inhibitor)
lactic acidosis
optic neuritis
Linezolid-resistant VRE and MRSA reported due to
mutation in 23S rRNA
Concerns with Vancomycin


Association between increasing MIC and clinical
failure, particularly prolonged bacteremia
Monitoring of serum levels




No clear relationship between level, efficacy and
toxicity
Routine monitoring not necessary
 Changing renal function or renal insufficiency
Peak levels should not be measured as vancomycin is
not “concentration-dependent”
Trough of 15-20 mg/L in endocarditis, osteomyelitis,
and VAP though clinical data is limited
Clin Infect Dis 2006;42:S51-7
Am J Respir Crit Care Med 2005;171:388-416
MRSA Nosocomial Pneumonia

Retrospective analysis of a prospective,
randomized, double-blind study





Vancomycin +/- aztreonam vs. linezolid +/aztreonam
Survival benefit with linezolid in the subset of patients with MRSA pneumonia
Vancomycin group with higher rates of
bacteremia and co-morbidities (cardiac,
diabetes, renal)
Role of toxin inhibition with linezolid or
clindamycin?
Awaiting prospective confirmation
Chest 2003;124:1789-1797
Chest 2005;128:2732-2738
Antimicrobial Case X
60 yo male admitted to the hospital with
one day history of fever, headache,
photophobia, and neck stiffness. CSF
reveals WBC 542 with neutrophil
predominance, protein 90, and glucose
30. What empiric antibiotics should be
started?
Bacterial Meningitis
Condition
Pathogen
Antimicrobials
2-50 years
S. pneumoniae,
N. meningitidis
Vanco + ceftriaxone
> 50 years
S. pneumoniae,
N. meningitidis,
L. monocytogenes
Vanco + ceftriaxone+ amp
Post-neuroSurgery
Gram-neg (Pseudomonas),
S. aureus, Coag-neg Staph
< 1 month
S. agalactiae, E. coli
L. moncytogenes
Clin Infect Dis 2004;29:1267-84
Ampicillin + cefotaxime
Ampicillin +aminoglycoside
Vanco + (cefepime,
ceftazidime, or
meropenem)
Antimicrobial Case 4
70 y o woman with bronchitis
treated with moxifloxacin who
develops fever, abdominal pain, and
profuse, watery, maloderous
diarrhea. WBC 24K.
Clostridium difficile

Colonization



Unintended consequence of antimicrobial therapy





3% healthy adults
20-40% of hospitalized patients
Perturbation of competing flora
Cephalosporins, clindamycin, and fluoroquinolones
Recent reports of increasing frequency and severity
Epidemic strain with 18-bp tcdC deletion and binary
toxin
Metronidazole or oral vancomycin


90% vs. 88% response rates (Lancet 1983;2:1043-6)
?Increasing recurrence and failure with metronidazole
Clin Infect Dis 2005;40:1586-90
Clin Infect Dis 2005;40:1591-7
N Engl J Med 2005;353:2433-41
N Engl J Med 2005;353:2442-9
Metronidazole





Reduced metabolites damage bacterial
DNA
Active against anaerobic gram-negative
bacilli and most Clostridium
Favored in management of C. difficile
Absorbed well with good CSF penetration
(used in CNS abscess as opposed to
clindamycin which has poor CSF
penetration)
Adverse events:


Nausea, metallic taste
Disulfiram-like reaction
Antimicrobial Case 7
42 y o sexually
active man
presents with 3
day h/o dysuria
and purulent
urethral
discharge.
Increasing fluoroquinolone resistance
IM ceftriaxone or PO cefpodoxime
15% co-infection with Chlamydia
-azithromycin or doxycycline
Neisseria gonorrheae
Bad Bugs, No Drugs

Gram-positive bacteria



MRSA and VRE
Emergence of vancomycin-resistant S. aureus
and linezolid-resistant Enterococcus
Gram-negative bacteria

Pan-resistant Acinetobacter and Pseudomonas

Colistin/Polymixin E



nephrotoxicity 20-30%
neurotoxicity 7%
Extended-spectrum β-lactamase organisms
Clin Infect Dis 2006;42:657-68
Antimicrobial Principles

Judicious use of antimicrobial therapy to optimize
clinical outcomes while minimizing unintended
consequences







Toxicity, drug-drug interactions
Emergence of resistance
C. difficile
Understanding antimicrobial
pharmocokinetics/dynamics and resistance
mechanisms can help guide appropriate usage
Knowledge of local susceptibility patterns is
essential
Development of antimicrobial resistance is directly
related to antimicrobial usage
Paucity of new drugs in the pipeline