Transcript Lecture 21 Part II- Antibiotic Use:Abusex2016-11

ANTIBIOTIC REVIEW
DR. MAZIN BARRY, MD, FRCPC, FACP, DTM&H
Assistant Professor & Consultant of Medicine
Division of Infectious Diseases
Faculty of Medicine
King Saud University, Riyadh
Head of Infection Control
King Khalid University Hospital
THINGS TO KNOW
 General stuff (Disease States, Bugs, Drugs)
 Practice - Specific
- Local epidemiology (organisms &
resistance trends)
- Formularies, cost
 Patient – specific
- Exposure history, risk factors for specific drugs
- Allergies, organ dysfunction, interacting
medications, weight, height
RESOURCES
 BOOKS
- Mandell, Douglas, and Bennett’s Priciples and Practice of
Infectious Disease
- The Sanford Guide to Antimicrobial Therapy. HIV book also
available.
 ARTICLES
- Treatment Guidelines from the Medical Letter “The Choice
of Antibacterial Drugs”
- Mayo Clinics Proceedings series
 PEOPLE
- Resident, attending: ID Consultation, Infection Control
Personnel; Pharmacy; Micro Lab.
THREE WAYS ANTIBIOTIC USED
Prophylaxis, Empiric, Definitive
 PROPHYLAXIS
- Medical:
~ Exposure to virulent pathogen
- HIV, N. meningitis
~ Immunocompromised
- HIV with CD4<200, Asplenic, Neutropenic
- Procedural (Surgery)
Short course recommended / preferred
~ Endocarditis
THREE WAYS ANTIBIOTICS USED
Prophylaxis, Empiric, Definitive (2)
 Empiric (usually up to 72 hours)
- Diagnosis of infection made based on S/S, lab, etc.
Likely pathogens suspected but specific pathogen not
yet known.
- Pick antibiotics based on:
= Likely pathogens, local susceptibility trends, and
patient-specific factors (allergies, organ dysfunction)
- Pearls:
= Get cultures on the front end (including special tests)
= Start appropriate antibiotics ASAP.
THREE WAYS ANTIBIOTICS USED
Prophylaxis, Empiric, Definitive (3)
 Definitive
- Microbiologic or serologic diagnosis with susceptibilities
known or presumed*
* syphilis is susceptible to penicillin
- Caveats on susceptibility testing:
 Interpretation of MIC or KB zone as S, I, or R is bugdrug specific (relative to concentrations of drug in body)
 Can’t just pick the one with the lowest MIC
- Some results to broad-spectrum agents maybe
suppressed (cascaded reporting)
 Call the microbiology lab
- Additional testing may be needed (KB or E-test)
THREE WAYS ANTIBIOTICS USED
Prophylaxis, Empiric, Definitive (4)
 Definitive
- Use the most effective, least toxic, narrowest spectrum,
and most cost effective agent – the “Drug of Choice” (DOC)
~ May actually be a combination of drugs
- Ampicillin and Gentamicin for enterococcus
endocarditis
- Know the alternatives especially for patients with
allergy to drug of choice.
- Drug, dose, route, interval, and duration is disease state
and patient specific.
How Long to Treat?
 Not well defined!
- Usually less than 14 days!
~ Longer for endocarditis, Osteomyelitis, Prostatitis
(& varies by bug & drugs)
- Track number of days of therapy in progress note &
set endpoint!
~ Coag Neg Staph Bacteremia: 5 – 7 days
~ Staph aureus Bacteremia:
> 28 days (all IV)
Prolonged unnecessary therapy increases risk of resistance,
adverse effects, and cost!
Know Your Bugs!
Gram - Positive
 S. aureus:
- 25 – 50% Methicillin Resistant (MRSA)
Originally in hospitals; Community Acquired strain now
spreading
- MSSA DOC: cloxacillin; Cefazolin
- CA-MRSA: Vancomycin, Linezolid, Daptomycin
~ If uncomplicated: Trimeth/Sulfa (99%), Clindamycin (70%)
 Enterococcus:
- DOC: (Ampicillin or Vancomycin)
PLUS (Gentamicin or Streptomycin)
Nitrofurantoin, Amp or Vanc alone for UTI
- VRE, ARE, HLARE varies by hospital
Know Your Bugs!
Gram – Positive (2)
 S. pneumoniae:
-- 20 – 45% have decreased susceptibility to penicillin.
~
= Highest in children (especially daycare, socioeconomic)
= Example:
Susceptible Intermediate Resistant
Penicillin
51%
40%
9%
Ceftriaxone
92%
9% (6@MIC 1) 0%
Moxifloxacin
98%
2%
0%
~ CNS Infections:
= High dose (HD) Ceftriaxone (2g IV Q 12h) + HD Vanco
~ Outside CNS:
= Ceftriaxone; Respiratory FQ if at risk for resistance
= High dose amoxicillin
= +/- Doxycycline, TMP / SMX, Erythromycin
Know Your Bugs!
Gram – Negative
 E. coli
~ 50% resistant to Ampicillin, Amp / Sulbactam
~ 25% resistant to Trimeth / Sulfa
~ 33% resistant to Ciprofloxacin
 P. aeruginosa
~ “Best” Drugs (> 90% susceptible)
= Ceftazidime, Cefepime, Piperacillin (with or w/o Tazo)
= PLUS an Amikacin for synergy
~ Less effective (80-90% susceptible)
= Tobramycin, Gentamicin
~ If C & S verifies susceptibility (65 – 80% susceptible)
= Imipenem, Meropenem, Aztreonam, Ciprofloxacin
Know Your Bugs!
Gram – Negative (2)
 Bad nosocomial Gram – Negative
~ Acinetobacter baumanii
= Doc Colistin* with meropenem (bleaching effect)
+/- Amikacin
* Alternative is tigecycline
~ Stenotrophomonas maltophilia (resistant to Imipenem)
= DOC Trimethoprin/Sulfamethoxazole (Bactrim)
= 10 mg/kg/day of TMP components (2Ds tablets Q12h)
 Most ICUs have their own flora & susceptibility patterns. Patients
become colonized within 48-72 hrs with these bugs
Know Your Bugs!
Other Bacteria
 Anaerobes
Peptostreptococcus, Clostridium, & Bacteroides
- Overall:
Amox/Clav, Amp/Sulb, Ticar/Clav, Pip/Tazo, Meropenem,
Imipenem, and Tigecycline
- Mouth & Lungs: Clindamycin
- Abdomen: Metronidazole
 Atypical
Legionella, Mycoplasma, Chlamydia
- Macrolides, Tetracycline, Respiratory
fluoroquinolones
Know Your Bugs!
By Mechanism of Action
 Cell –Wall
~ Penicillin – Binding Proteins (PBP): Beta-Lactams
= Penicillins +/- beta-lactamase inhibitors
= Cephalosporins
= Others (imipenem, aztreonam)
~ Percursor molecules: Vancomycin
 Intracellular
~ Ribosomes: Macrolides (5OS), Tetracycline (30S),
Aminoglycosides (30S & 50S)
~ DNA gyrase: Quinolones
~ Folate metabolism: Trimethoprim, Sulfa’s
Know Your Bugs!
Mechanism of Resistance
 Altered target – PBP’s.
~ Absolute Change = no binding
= MRSA is resistant to all beta-lactams et al
~ Relative Change =  binding,  MIC
= Drug resistant S. pneumoniae
 Enzymes destroy – Beta-lactamases
~ Penicillinase: MSSA, H. influenzae, anaerobes
= Add beta – lactamase inhibitor or change
structure
~ Cephalosporinase: Enterobacter et al
~ Extended Spectrum Beta Lactamase (ESBL):
Kleb Pneumo, E. coli
Penicillins
 Penicillin PO, IV & IM
= GP (Strep)
 Amoxicillin PO, Ampicillin IV
= GP (Strep), some GNR (70% H. influenzae)
 Cloxacillin PO, IV
= GP (MSSA)
 Amoxicillin / clavulanate (AUGMENTIN) PO, IV
= GP (MSSA, GNR, Anaerobes)
 Piperacillin / Tazobactam (Tazocin) IV
= GP (MSSA), GNR (> 90% PA), Anaerobes
GP
GN
Ana
DOC
Penicillin
Strep
None
Some
Syphilis, Strep
Ampicillin
Amoxicillin
Strep
Some
Some
Enterococcus.
Listeria
cloxacillin
MSSA
None
None
MS – SA
Amox / clav
Strep
Some;
H. Influenzae
Great
Mixed
Community
Pip / Tazo
Strep
MSSA
H. influ.
Pa et al
Great
Mixed
Nosocomial
Cephalosporins & Other Beta-Lactams

Cephalexin PO
Cefazolin IV
- GP (MSSA), GNR
• Cefuroxime
 Ceftriaxone IV, IM
- GP (S. pneumo),
-GNR
 Ceftazidime IV
- GNR (> 85% PA)
 Cefepime IV
- GP (S. pneumo)
- GNR (>90% PA)
• Ceftaroline IV
– GP (MRSA)
– GNR (NOT PA, ESBL)
 Aztreonam
- Beta-Lactam allergy
- GNR (80% PA)
 Imipenem/cilastatin
Meropenem
- GP (including MSSA)
- 95% GNR
- Anaerobes
GP
GN
Ana
DOC
Cefazolin
Strep
MSSA
E.Coli
None
SPPLX
SSTI
Ceftriaxone
Strep
S. Pneiumo
E.coli, Kleb
None
CAP
Meningitis
Ceftazidime
Poor
E coli, Kleb, PA
None
HAP et al
Cefepime
Strep
MSSA
Ecoli, Kleb, PA
None
HAP et al
Nosocomial
Imipenem
Meropenem
Strep
MSSA
Most including ESBL
Great
Mixed
Nosocomial
Colsitin
None
Most GNB
(No activity against:
serratia, proteus,
burkholderia, moraxella,
providencia, morganella)
None
KPC, PDR PA,
acinetobacter
Beta-Lactam Adverse Effects
• Allergic / Hypersensitivity in 3 – 10% of pts.
= Rash (4-8%) to anaphylaxis (0.01-0.05%, 10-20
minutes)
~ Carbapenems: 5% cross reactive, Cephs 10%
~ Vasculitis, Cytopenias, Fever, Interstitial
Nephritis
• N/V with PO
• Seizures w/ high dose in renal insufficiency
• Ceftriaxone: Biliary sludging and bilirubin
displacement (don’t use in neonates)
VANCOMYCIN
• Exclusively Gram-Positive Spectrum, IV only*
• “Last Line of Defense”
- Methicillin Resistant Staph
- Ampicillin Resistant Enterococcus
- Multi-drug Resistant S. pneumonia
- 2nd line for C. difficile Colitis (*only indication for PO Vanco)
• IV only, Check levels & adjust frequency for renal impairment
• Troughs = 10 – 20 (15-20 for pneumonia et al)
• Peaks = 20-40 (higher in pneumonia et al) ?Clinical Utility?
• 15 – 20 mg/kg/dose (1g) IV Q8 – 12h (Q24h+ for CICr < 60)
- Call pharmacy for help with dosing.
QUINOLONES
• Ciprofloxacin
- GNR (75% PA)
• Levofloxacin, Moxifloxacin
- GP (S. pneumo), GNR (respiratory; PA
70% w/ Levo)
• Cl in pregnancy & children
- Rash/photosensitivity, Chelates (PO),
CNS side effects, Tendon Rupture
QTc prologation, Hypo/Hyperglycemia
AMINOGLYCOSIDES (all IV or IM)
• Gentamicin, Tobramycin
– GNR (Tobra > Gent vs. P. aeruginosa)
• Amikacin, Streptomycin
- TB, Multi-drug Resistant GNR
• Renal elimination, variable penetration in to tissue
CNS < 5%, Lungs 50%, Urine 10 – 100 X
• Dosing:
- Pick dose based on site/bug and interval per renal function
(GFR < 60).
- “Once Daily” for select patients only GNR; good renal
function).
• Nephrotoxicity (non-oliguric) & Ototoxic
–
Prolonged exposure to elevated levels (troughs >2).
Macrolides & Lincosamides
• Erythromycin
– GP (Strep) & Atypicals
– GI side effects and inhibits CYP450 = drug interactions
• Azithromycin IV, PO
Clarithromycin PO
- GP (Strep), Atypicals & Respiratory GNR;
Mycobacterium
•
Clindamycin (all PO, IV)
- GP (GP 75% MRSA), Anaerobes
- C. difficile colitis
Other Antibacterials
•
Tetracycline PO, Doycyclne PO & IV
- GP, GN, Atypicals; Brucella
- Binds orally with calcium deposits on teeth, photosensitivity
• Trimethoprim / Sulfamethoxazole
- GP (98% MSSA & MRSA), 80% GNR
- Rash and other ADE’s, Drug interactions with warfarin
• Metronidazole
- Anaerobes & Protozoa
- Reactions with EthOH, Metallic taste, drug interactions with
warfarin
• Nitrofurantoin
- UTI (including VRE)
- Contraindicated at GFR < 60
Know your Drugs!
• Get an ID consult for:
- Linezolid
MRSA, VRE lungs; bacterostatic
- Daptomycin
MRSA, VRE; endocarditis, not lungs
- Tigecycline, Colistin
PDR Acinetobacter baumanii
Antiviral
• Antivirals
- HSV: Acyclovir, Valacyclovir; Famiclovir
- CMV: Ganciclovir, Valgancyclovir; Foscarnet
- Influenza: Oseltamivir (Tamiflu), Zanamivir; Amantadine
Infection
Drugs
Adult Dosage
Cost
Hepatitis B Virus (HBV)
Chronic Hepatitis
Lamivudine- Epivir HBV
Interferon alta 2b-Intron A
Peginterferon alta 2a-Pegasys
Acelovir - Heparia
10 mg PO 1X
$2,452.80
7,292.40
18,712.80
8,486.05
Hepatitis C Virus (HCV)
Chonic Hepatitis
Peginterferon alfa-20 PEG
lotion plus tavirin –generic
Coaguia
Bocepravir
Telapravir
1.5 mcgkg once/wk SC
x 48 weeks
800-1200mg PO/d x
48 wks
180 mcg once/wk SC x
48 wks
800-1200 mg PO/d x
48 wks
Interferon alfa 2b
5 million___x 3 wks
Then 3d/wk x 20 wks
Acute Hepatitis
19,043.04
9,852.16
13,749.12
18,712.80
9,932.16
9,354.24
1,875.32
4,888.30
Antifungals
• Binds Ergosterol (makes cell walls leak)
Amphotericin B
- Life – Threatening systemic mycosis
• Inhibit cell wall synthesis (Beta 1, 3 D glucan)
- Echinocandins (Anidulafungin,
Caspofungin, Micafungin)
- Candida (including azole R sps.)
Azoles Inhibit Ergosterol Biosynthesis
•
•
Fluconazole
Candida albicans, Crypto
Itraconazole PO;
Histo, Blasto, Aspergillus
Voriconazole
Aspergillus et al
Posiconazole PO
Zygomycosis
Ketoconazole, Miconazole,
& Clotrimazole
topical/dermatophytes
Table I Azoles
Drug
Usual Dosage
Cost
Parenteral
Fluconazole-
100-800 mg 1x/d
$357.62
Voriconazole
4 mg/kg bid
364.89
Oral
Fluconazole-
100-800 mg 1 x/d
57.20
71.15
Itraconazole
200 mg 1 x /d bid
43.75
Posaconazole
100 mg 1 x/d-200 mg qid
145.80
Isavuconazole :
invasive aspergillosis and mucormycosis Voriconazole
200-300 mg bid
116.97
Know your Drugs!
Pharmacodynamics
• Pharmacodynamics (PD)
- Bacteriostatic: Inhibit
~ Generally avoid for endocarditis, meningitis,
osteomyelitis, and febrile neutropenia
~ Tetracyclines, Macrolides, TMP / SMX, Linezolid
- Bacteriocidal: Kill
~ Dose dependent (Peak:MIC > 10)
- Aminoglycosides, Quinolones
~ Exposure dependent (T >MIC)
- Beta – lactams, vancomycin
~ May require a combination of drugs (e.g.,
enterococci)
Know your Drugs!
• Absorption: IV vs PO
- Great PO absorption with fluconazole,
fluoroquinolones (watch drug interactions),
Metronidazole, TMP/SMX, doxycycline.
- IV only:
~ Vancomycin (except for C. difficile)
~ All antipseudomonal agents except ciprofloxacin
~ 3rd and 4th generation cephalosporins (may give
IM)
~ Meropenem, Imipenem, ertapenem (IM available) and
Aztreonam
~ Aminoglycosides (gentamicin et al)
- may give small dose IM
Know Your Drugs!
• DISTRIBUTION
– CNS Penetration:
- Excellent: Metronidazole, chloramphenicol,
fluconazole, TB drugs
- Adequate with high doses: Ceftriaxone,
ceftazidime, ampicillin
- Problematic: Vanconmycin, aminoglycosides
- Lungs:
- Good: quinolones, Macrolides, beta-lactams
- Modest: aminoglycosides
Know Your Drugs!
• Metabolism / Elimination
- Kidneys
- Adjust for renal dysfunction (Cl Cr)
- May use lower doses for UTI
- Liver
- Adjust for liver dysfunction (???)
- Potential for drug interactions
Dosing in Renal Dysfunction
• (140 – Age) X ibw / 72 X S. Cr.
- Multiply result by 0.85 if patient female
- Round S. Cr. Up (0.8?) if <1 and elderly
• Cl Cr <60 adjust interval +/- dose of:
-
Penicillins (not Nafcillin, Oxacillin)
Cephalosporins (not Ceftriaxone)
Imipenem else 10 X  risk seizures
Aztreonam
Vancomycin
Aminoglycosides
Dosing in Renal Dysfunction
• Misc agents
- TMP / SMX (and generally avoid)
- Fluconazole
- Acyclovir
- Ganciclovir
- Most nucleoside RTI’s
• Avoid (nephrotoxic)
- Amphotericin B (lipid forms less toxic)
Dosing in Hepatic Dysfunction
• Note – also generally don’t need to be
adjusted for renal dysfunction.
- Ceftriaxone, Nafcillin
- Clindamycin, Metronidazole
- Macrolides, Tetracyclines
- Rifampin, Isoniazid
Drug Interactions!
• Drugs cleared by CYP 450
Statins, Cyclosporine, Benzodiazepines, Theophylline,
Anticonvulsants, oral hypoglycemic
- Levels increase by (Metabolism inhibited by)
 Macrolides (Erythromycin)
 Azoles (Fluconazole, Itraconazole)
 Protease inhibitors
 Ciprofloxacin
- Levels decreased by (Metabolism induced by)
 Rifampicin, rifabutin
• Oral Contraceptives
- Decreased with rifampin & nafcillin +/- others
Drug Interactions!
• Warfarin:
- Effect & INR profoundly increased by
 trimethoprim/sulfamethoxazole
 metronidazole
- Significant increase with
 fluconazole, +/- Ciprofloxacin
- Decreased by
 Rifampicin/rifabutin
• Multivalent Cations (Ca, Mag, Iron) +/- TF
- Decreases absorption of:
 Fluroquinolones
 Tetracyclines
Adverse Effects
Allergies (NEJM 2006; 354-601-9)
• Penicillin Allergy:
- Fully cross- reactive with other penicillins
- May cross-react with cephalosporins
 10% to 1st generation, 1 – 2% to3rd
- Not cross reactive with aztreonam.
• Sulfa Allergy:
- other sulfonamides (including diuretics)
- not sulfites, sulfates; +/- sulfones
Adverse Effects
Other
•Antibiotics generally safe but….
- Rash: almost any of them
- Diarrhea, C. difficile colitis: most of them
- Nephrotoxicity: Aminoglycosides, amphotericin
- Photosensitivity: fluoroquinolones, tetracyclines
- Relatively contraindicates in pregnancy:
Aminoglycosides, fluoroquinlones, tetracycline,
fluconazole, ribavirin et al..
Preventing the Use of Antibiotics
• Verify diagnosis & need for antibiotics
- Consider other (non-infections) causes of
symptoms
- Remember: antibiotics don’t work against
viruses
• Vaccinate at risk patients
- Children, elderly, immunocompromised,
healthcare professionals.
• WASH YOUR HANDS!
- Also stethoscopes
ANTIBACTERIAL AND ANTIFUNGAL PHARMACODYNAMIC
CHARACTERISTICS
Class
Mechanism of
Action
Concentration
vs Time
Dependent
Activity
Bactericidal vs
Bacteriostatic
Activity
Mechanisms of Resistance
Antibacterial Agents
B-Lactams
Penicillins
Cephalosporins
(e.g., cefazolin)
Inhibition of PBP activity
resulting in
peptidoglycan layer
synthesis in cell wall
Carbapenems
(e.g., imipenem)
• Altered PBP (MRSA, PRSP)
• B-Lactamase production (PPNG; TEM
and SHV-producing organisms; ESBLproducing K. pneumonia and E. coli;
AmpC gene induction in Enterobacter,
Citrobacter, Morganella, Providentia,
Serratia, and Pseudomonas species)
Time
Cidal
Time
Cidal
Time
Cidal
• Loss of outer membrane porin
channels for entry (Pseudomonas
aeruginosa)
Aminoglycosides
(e.g., gentamcin)
• Ionic interaction with
cell wall
• Disruption of protein
synthesis of 30S
ribosomal subunit via
codon misreading
Conc
Cidal
• Production of aminoglycosides
modifying enzymes (acetylases,
adenylases, phosphorylases) resulting
in drug inactivation
• 30S ribosomal mutation
• Decreased membrane permeability
Fluoroquinolones
(e.g., ciprofloxacin)
Inhibition of DNA gyrase
and topoisomerase IV
activity
Conc
Cidal
• Altered binding site due to mutation
in DNA gyrase and/or topoisomerase
IV
• Active efflux pump
ANTIBACTERIAL AND ANTIFUNGAL PHARMACODYNAMIC
CHARACTERISTICS (CONT’D)
Class
Mechanism of Action
Concentration vs.
Time Dependent
Activity
Bactericidal
vs
Bacteriostati
c Activity*
Mechanisms of Resistance
Glycopeptides
(e.g., vancomycin)
Binding to D-ALA-D-ALA terminus
complex in peptidoglycan layer of
cell wall to inhibit PBP binding &
activity
Time
Cidal
• Ligase conversion of D-ALA-D-ALA
to D-ALA-D lactate which prevents
vancomycin binding
Macrolides
(e.g., erythromycin)
Binding to 50S ribosomal subunit
and interruption of protein
synthesis via transpeptidation or
translocation inhibition
Time
Static
• 23S Ribosomal subunit
methylation by erm gene products
• Active efflux (e.g., efflux pump
from msr gene inducton in S.
aureus or from mef induction in S.
pneumonia or S. pyogenes)
• Macrolide modification or
inactivation
Nitroimidazoles
e.g., metronidazole
Toic free radical formation
Conc
Cidal
•
Unclear / uncommon
Oxazolidinones
(e.g., linezolid)
Disruption of protein synthesis at
30S/50S ribosomal subunits
Time
Static (cidal to
streptococci)
•
Ribosomal binding site alteration
Streptogramins
(e.g., quinupristin/
Dalfopristin)
Binding to 50S subunit of ribosome
resulting in inhibition of peptide
chain elongation and peptidyl
transferase activity; quinupristin
and dalfopristin are synergistic
Time
Cidal
(staphylococci,
streptococci,
Enterococcus
faecium)
•
23S Ribosomal subunit
methylation by erm gene
products (MLSB resistance)
Active efflux
Enzyme inactivation
(Azithromycin –
Conc)
Static
(Enterococcus
•
•
ANTIBACTERIAL AND ANTIFUNGAL PHARMACODYNAMIC
CHARACTERISTICS (CONT’D)
Class
Mechanism of Action
Concentration
vs. Time
Dependent
Activity
Bactericidal vs
Bacteriostatic
Activity*
Mechanisms of Resistance
Lincomycins
(e.g., clindamycin
Disruption of protein synthesis at 50S
ribosomal subunit via inhibition of
amino acid linking
Time
Static
•
23S ribosomal
mutation/methylation
(MLSB resistance)
Rifamycins
(e.g., rifampin
Binding interference at 30S ribosomal
subunit / mRNA complex binding
interference
Time
Static
•
Single step mutation in ßsubunit of DNA-dependent
RNA polymerase (e.g., S.
aureus)
Tetracyclines
Binding to 30S ribosomal subunit and
disruption of protein synthesis at 50S
subunit via inhibition of amino acid
linking
Conc
Static
•
•
Decreased uptake
Active efflux pump
Sulfa
(e.g.,
sulfamethoxazole/trim
ethoprim
Disruption of folate synthesis;  DNA
synthesis
Conc
Static
•
Production of new
dihydrofolate reductase
and dihydropteroate
synthetase
 PABA
Decreased membrane
permeability
•
•
Antifungal Agents
Polyenes
(e.g., amphotericin B)
Disruption of cell membrane via
intercalation with sterols, disrupting
cell integrity
* Nature of activity at recommended doses against usual pathogens
Cidal
• Uncommon
• Decreased ergosterol cell
membrane content (e.g., via
previous azole use)
ANTIBACTERIAL AND ANTIFUNGAL PHARMACODYNAMIC
CHARACTERISTICS (CONT’D)
Class
Mechanism of Action
Concentration vs.
Time Dependent
Activity
Bactericidal vs
Bacteriostatic
Activity*
Mechanisms of
Resistance
Azoles
(e.g., fluconazole)
Disruption of fungal sterol
synthesis via inhibition of
cytochrome P450dependent 14ademethylase which is
required for conversion of
lanosterol to ergosterol
Static
• Modification of
cytochrome P450dependent 14ademethylase
• Active efflux pumps
5-Flucytosine
Cellular conversion to 5fluorouracil, a false
pyrimidine, and
subsequent interference
with DNA and protein
synthesis
Cidal
• Common, especially if
agent used alone
Echinocandins
(e.g., caspofungin)
Inhibition of ß-1, 3glucan synthetase
resulting in disruption of
cell membrane synthesis
Cidal
(Candida species)
• Unknown
PBP = penicillin-binding proteins
MRSA = methicillin-resistant Staphylococcus aureus
PRSP = penicillin-resistant Streptococcus pneumonia
PPNG = penicillin-producing Neisseria gonorrhoeae
ESBL = extended-spectrum ß-lactamase
D-ALA = D-alanine
PABA = para-aminobenzoic acid
Acute Otitis Media (AOM)
• Dx: bulging TM, or new otorrhea
• Pathogen:
– No pathogen (4%)
– Virus (70%)
– Bacteria + virus (66%)
– Bacteria (92%)
• Strept. Pneumo (49%)
• H. Influenzae (29%)
• Moraxella catarrhalis (28%)
AOM
• Need to know prior antibiotic use and local
susceptibilities for S. pneumonia
• Amoxocillin, Amoxocillin/clavulinate, cefpodoxime,
moxifluxacin (10 days)
• Failure to respond in children: tympanocentesis
Malignant Otitis Externa
• Sever ear pain, swelling, fever unusual, high ESR
• Bony involvement common, can progress to OM of base of
skull and TM joint (do CT and treat 6 weeks with surgical
debridement)
• RF: Elderly, DM, AIDS, chemotherapy
• Usually Pseudomonas aeruginosa (95%)
 Imipenem or Meropenem
 Ceftazidime or Cefepime
 Piperacillin (+/- tazobactam) and
tobramycin
 Ciprofloxacin
- PO if mild / early, check
susceptibilities
Tonsillitis, pharyngitis
•
•
•
•
•
•
•
Streptococcus sp. (Group A, C, G)
Viral: EBV, CMV
C. diphtheria
Arcanobacterium haemolyticum (rare)
Mycoplasma pneumonia (with cough)
Fusobacterium necrophorum
STD: primary HIV, HSV, N. gonorrhea, rarely
secondary syphilis
Tonsillitis, pharyngitis
• Focus on group A strept. (GAS) (10%)
– Decrease symptoms, prevent suppurative complications, decrease contagion,
eradicate GAS to prevent acute rheumatic fever
• Dx: symptom score above 1 (1 point each for):
– History of fever, absence of cough, tender cervical LN,
tonsillar exudate
• NOT GAS: rhinitis, hoarseness, cough then
• Rapid strep Ag test
• Rx: Penicillin V 500mh bid for 10 days, cefuroxime if allergic
– Can use clindamycin, azithromycin but resistance reported
UTI (Acute uncomplicated)
• Causes: Enterobacteriacaeae (E.Coli, Klebsiella sp), Staphylococcus
saprophyticus,Enterococci, streptococcus agalactiae (BpB strep.)
• Rx:
–
–
–
–
–
–
TMP-SMX DS 1 tab BID 3 d +/- pyridium 200mg 2 d
Nitrofurontoin 100mg bid 5 d
Fosfomycin 3gm 1 dose
Amoxocillin (enterococcus) 500mg TID 5-7d
Ciprofluxacin 250 bid 3 d
Cefuroxime 500 bid 5-7 days
• Do urine culture if failure of Rx for 3 d
• Pregnant treat for 7 days (TMP-SMX stopped 2 weeks before EDC)
• Ertapenem
Asymptomatic bacteriuria
• Treat only in the following:
– Pregnant
– Renal transplant
– Urological procedure