Transcript AB_ClinConsid_07ho

Antimicrobials:
Clinical Considerations
Timothy H. Dellit, MD
Director, Infection Control and
Antimicrobial Management
Harborview Medical Center
Case 1
60 y o 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 is the clinical concern?
What empiric antibiotics should be started?
Antimicrobial Considerations
1. Likely organism and susceptibilities
2. 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
Bacterial Meningitis
Condition
Pathogen
Antimicrobials
< 1 month
S. agalactiae, E. coli
L. moncytogenes
Ampicillin + cefotaxime
Ampicillin + aminoglycoside
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
Vanco + (cefepime,
ceftazidime, or meropenem)
Clin Infect Dis 2004;29:1267-84
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.
Streptococcus pneumoniae
Community-Acquired Pneumonia
• Most common pathogens S. pneumoniae, H.
influenzae, Moraxella with concern for C. pneumonia,
M. pneumoniae, and Legionella
– Outpatient
• Macrolide or doxycycline
• Respiratory fluoroquinolone, if recent antimicrobial tx
– Inpatient medical ward
• -lactam + macrolide vs fluoroquinolone
• 2002-2003 US Survey revealed 34% non-penicillin
susceptible (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
S. pneumoniae Resistance
Antimicrobial
Percent Resistant
Macrolide
29%
TMP/SMX
32%
Tetracyclines
16%
Fluoroquinolones*
2.3%
*21.9% of S. pneumoniae isolates in 2002-2003 had fluoroquinolone
mutations in parC and/or gyrA compared to 4.7% in 1997-1998.
Clin Infect Dis 2005;41:139-48
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)
• Fluoroquinolone targets
– DNA gyrase (GyrA and GyrB subunits) separates DNA strands
during replication
– Topoisomerase IV (ParC and ParE subunits) partitions replicated
chromosomal DNA
• Newer fluoroquinolones (gatifloxacin, gemifloxacin, moxifloxacin)
bind equivalently to both enzymes compared to earlier
generations such as ciprofloxacin and levofloxacin
• 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
Ciprofloxacin (750 bid)
Levofloxacin (500 qd)
Levofloxacin (750 qd)
Gatifloxacin (400 qd)
Gemifloxacin (320 qd)
Moxifloxacin (400 qd)
MIC90 AUCFree AUC:MICFree
1.0
1.0
1.0
0.25
0.03
0.12
28
34
70
26
24
28
34
70
106
140-280
200
Cutoff criterion of AUC:MIC >33.7 for gram-positives?
Clin Infect Dis 2005;41:S127-35
Pseudomonas and Fluoroquinolones
Drug
Dose
Ciprofloxacin
400 q12 4.1
400 q8
4.1
750 q24 12.1
400 q12 4.6
400 q24 4.2
Levofloxacin
Gatifloxacin
Moxifloxacin
Cmax
MIC
0.125
0.125
0.5
1.0
2.0
AUCfree:MIC
144
184
152
28
10
IDSA and ATS Guidelines recommend
Ciprofloxacin 400mg IV q8hr or Levofloxacin 750 mg qd
Am J Respir Crit Care Med 2005;171:388-416
Case 3
49 y o man with a 1 week h/o viral syndrome
with progressive dyspnea, hypoxia, and
hypotension. Sputum, pleural fluid, and blood
cultures with Gram-positive cocci in clusters.
Case Continued
CA-MRSA Pneumonia
Clin Infect Dis 2005;40:100-7
Chest 2005;128:2732-8
MRSA Resistance to Beta-Lactams
Alternative Penicillin
Binding Protein PBP2a
Beta-Lactam
DNA
Cell
Membrane
Cell Wall
Modified from David Spach, MD
Local MRSA Susceptibilities
Clindamycin*
Levofloxacin
Tetracycline
TMP/SMX
Vancomycin
Harborview
65%
24%
93%
95%
100%
UW
15%
6%
97%
98%
100%
*D-zone test should be done to look for inducible resistance to clindamycin
8% at HMC and 13% at UWMC
Treatment Options for MRSA Infections
Intravenous*
Oral*
•
•
•
•
•
•
•
•
•
•
Vancomycin
Linezolid
Daptomycin
Quinupristin/dalfopristin
Tigecycline
TMP-SMX
Minocycline/Doxy
Clindamycin
Fluoroquinolone
Linezolid
*with or without rifampin, however NEVER use rifampin
monotherapy due to rapid emergence of resistance
Concerns with Vancomycin
• Association between increasing MIC and clinical
failure, particularly prolonged bacteremia
– Breakpoint lowered to < 2 mcg/ml
• Monitoring of serum levels
– No clear relationship between level and efficacy or
toxicity
– Routine monitoring not necessary
• Changing renal function or renal insufficiency
– Peak levels should not be measured as vancomycin
is not “concentration-dependent” and peak level
predictably 15-20 mcg/ml above trough
– Trough of 15-20 mcg/ml 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
Vancomycin-Resistant
Staphylococcus aureus
• Intermediate resistance (VISA or GISA) first
documented in Japan 1996, US in 1997
– Increased cell wall thickness limiting
glycopeptide access to site of cell wall synthesis
• Vancomycin-resistant S. aureus (VRSA or
GRSA) isolated in June 2002
– Contained vanA resistance gene identical to
vanA gene in patient’s vancomycin-resistant
Enterococcus faecalis
Daptomycin: Mechanism of Action
1. Ca2+-Dependent Binding to Cell
Membrane
2. Depolarizes Membrane & K+
Efflux
 Aztreonam (Azactam)
Adapted from David Spach, MD
Daptomycin
• Novel lipopeptide class causing depolarization of the
bacterial membrane
• Active against MSSA, MRSA, VRSA, coag-neg Staph, S.
pyogenes, S. pneumoniae, E. faecium, and E. faecalis
including VRE
• Initially approved for complicated skin and soft tissue
infections at 4 mg/kg/d IV
• Subsequently FDA approved for S. aureus bacteremia
and right-sided endocarditis at 6 mg/kg/d IV
(N Engl J Med 2006;355:653-65)
– 6/19 with microbiologic failure developed resistance with
increasing MIC
• Not active in lung due to surfactant
• Monitor CK for myositis
Reduced Susceptibility to Vancomycin
Associated with Reduced Susceptibility to
Daptomycin in S. aureus
No. (%) of Isolates
Vancomycin
MIC, mcg/ml
<2
4
8-16
> 32*
Daptomycin
MIC < 1 mcg/ml
Daptomycin
MIC > 2 mcg/ml
812 (97)
11 (20)
1 (7)
5 (100)
30 (3)
43 (80)
15 (93)
0 (0)
* vanA mediated resistance
Clin Infect Dis 2006;42:1652-3
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
• 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%
• Possible survival benefit in MRSA pneumonia?
• Adverse events:
–
–
–
–
–
–
GI (nausea and vomiting)
Marrow suppression (thrombocytopenia, anemia, leukopenia)
Serotonin syndrome (weak monoamine oxidase inhibitor)
Lactic acidosis
Optic neuritis, peripheral neuropathy, Bell’s palsy
Inhibition of mitochondrial protein synthesis
• Linezolid-resistant VRE and MRSA reported due to
mutation in 23S rRNA
Case 4
34 y o man h/o HIV with CD4 100 presents
with 1 month h/o cough, fever, night sweats,
and weight loss. CXR with right upper lobe
cavitary lesion and sputum with 4+ AFB.
Mycobacterium tuberculosis
Case 4 Questions
• Why do we use 4 drug to treat TB?
(isoniazid, rifampin, pyrazinamide, ethambutol, plus B6)
– Rate of spontaneous mutations
• Rifampin: 1 in 108
• INH: 1 in 106
• Cavitary disease with 109 organisms
– INH resistance 10% in King County
• What should we start first, TB meds, HIV meds,
or all at the same time?
• What are the potential drug interactions and how
do they impact our therapy?
Antiretrovirals and P450
• Protease inhibitors may induce or inhibit
– Ritonavir potent inhibitor of P450 CYP3A4
• Low dose ritonavir boosting (standard PI dosing)
• Simplified regimens with decreased toxicity
• Non-nucleoside RT inhibitors
– Efavirenz and nevirapine are inducers
– Substrate of CYP2B6
•
•
•
•
G516T polymorphism
3% Caucasians, 20% African-Americans
Higher drug levels, delayed clearance
Higher CNS adverse events
Clin Infect Dis 2006;42:408-10
Tuberculosis, HIV, and P450
• Rifampin and protease inhibitors
– Rifampin induces PI metabolism
• Reduces (Fos)amprenavir 82%, lopinavir/ritonavir 75%
– PI inhibits rifampin metabolism
• Increased toxicity
– Generally cannot use rifampin in combination
– Dose-reduced rifabutin (150 mg qod with lopinavir/rit)
• Rifampin and efavirenz
– Rifampin decreases efavirenz by 26%
– Increase efavirenz from 600mg to 800 mg qhs
http://depts.washington.edu/madclin/
Case 5
30 y o patient is admitted to the psychiatry service with
suicidal depression. Two days after admission it is noted
that the patient has fever, chills, cough, and myalgias that
began 4 days ago. A nasal wash is positive for influenza B.
Which of the following is true?
A. The patient should be treated with amantadine
B. The exposed staff should receive amantadine
prophylaxis if they were not vaccinated
C. The patient and exposed staff should receive oseltamivir for
treatment and prophylaxis, respectively
D. Although the development of amantadine resistance during therapy
is common, resistance has not been reported for oseltamivir
Antivirals for Influenza
• Adamantanes
– Amantadine and rimantadine
– Target M2 ion channel, interfering with viral uncoating
– Only active against influenza A
• High rate of resistance (91%) among H3N2 during 20052006 influenza season
• Neurominidase inhibitors
– Oseltamivir and zanamivir
– Development of oseltamivir resistance during therapy
(N Engl J Med 2005;353:25:2667-72)
– Unknown dose or duration for avian influenza
– Stockpile and limited supply
Clinical Antimicrobial Principles
• Considerations when selecting antimicrobials
–
–
–
–
–
Likely organism and susceptibility patterns
Site of infection
Host factors
Antimicrobial factors
Emergence of resistance
• Understanding antimicrobial
pharmocokinetics/dynamics and resistance
mechanisms can help guide appropriate usage
• Knowledge of local susceptibility patterns is
essential
• Paucity of new drugs in the pipeline