Transcript
Common Bacteria by Site of Infection
Mouth Peptococcus Peptostreptococcus Actinomyces
Skin/Soft Tissue S. aureus S. pyogenes S. epidermidis Pasteurella
Bone and Joint S. aureus S. epidermidis Streptococci N. gonorrhoeae Gram-negative rods
Abdomen E. coli, Proteus Klebsiella Enterococcus Bacteroides sp.
Urinary Tract E. coli, Proteus Klebsiella Enterococcus Staph saprophyticus
Upper Respiratory S. pneumoniae H. influenzae M. catarrhalis S. pyogenes
Lower Respiratory Community S. pneumoniae H. influenzae K. pneumoniae Legionella pneumophila Mycoplasma, Chlamydia
Lower Respiratory Hospital K. pneumoniae P. aeruginosa Enterobacter sp. Serratia sp. S. aureus
Meningitis S. pneumoniae N. meningitidis H. influenza Group B Strep E. coli Listeria
Protein Synthesis Inhibitors
Tetracyclines Macrolides
Chloramphenicol Aminoglycosides
Clindamycin Streptogramins
Tetracyclines - Structure
Excretion R1 R2 R3 R4 mg/hr
tetracycline (Achromycin) H OH CH3 H 65chlortetracycline (Aureomycin) H OH CH3 Cl 32oxytetracycline (Terramycin) OH OH CH3 H 90demethylchlortetracycline (Declomycin) H OH H Cl 35 doxycycline (Vibramycin) OH CH3 H H 16minocycline (Minocin) H H H N(CH3) 9
Tetracyclines - Uses
Gram- Bacteria Helicobacter pylori (duodenal ulcer) Borrelia recurrentis (Lyme disease, relapsing fever)
Other Organisms Mycoplasma pneumoniae acne
Tetracycline - Mechanism
Inhibits protein synthesis
Static
Chelates divalent cations -- Ca++, Mg++
Tetracycline - Adverse Effects
headache, nausea, vomiting
discoloration of bones and teeth
photosensitivity
liver damage
superinfection
SuperinfectionA new infection appearing during treatment for a primary infection
The organism will be resistant to the antibiotic used for the primary infection
Organisms causing superinfection Staphylococcus aureus - enterocolitis Candida albicans - vagina, mouth Clostridium difficile - pseudomembranous colitis
Risk factorsin hospital > 6 days6 > age > 60broad spectrum antibiotic
Tetracylines Administration Oral administration but interference by food, Ca++, Mg++
Excretion renal, fecal enterohepatic
Chloramphenicol - structure/features
Features Broad Spectrum Inexpensive Oral administration Virtually non-toxic
Chloramphenicol - uses/toxicity
Uses Haemophilus influenzae (meningitis) Typhus Rocky Mountain Spotted Fever Eye infections
Adverse Effects superinfection aplastic anemia
Chloramphenicol - mechanism
Inhibits protein synthesis
Static
Macrolides
• Erythromycin is a naturally-occurring macrolide derived from Streptomyces erythreus – problems with acid lability, narrow spectrum, poor GI intolerance, short elimination half-life
• Structural derivatives include clarithromycin and azithromycin: Broader spectrum of activity Improved Pharmacokinetic properties – better
bioavailability, better tissue penetration, prolonged half-lives
Improved tolerability
Macrolides
Mechanism of Action Inhibits protein synthesis by reversibly binding
to the 50S ribosomal subunit Suppression of RNA-dependent protein synthesis
Macrolides typically display bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms
Time-dependent activity
QUICK REVIEW - Protein Synthesis
Macrolide Spectrum of Activity
Gram-Positive Aerobes – erythromycin and clarithromycin display the best activity
(Clarithro>Erythro>Azithro)• Methicillin-susceptible Staphylococcus aureus
• Streptococcus pneumoniae (only PSSP) – resistance is developing
• Group A/B/C/G and viridans streptococci
• Bacillus sp., Corynebacterium sp.
Macrolide Spectrum of Activity
Gram-Negative Aerobes – newer macrolides with enhanced activity
(Azithro>Clarithro>Erythro)
• H. influenzae (not erythro), M. catarrhalis, Neisseria sp., Campylobacter jejuni, Bordetella pertussis
• Do NOT have activity against any Enterobacteriaceae or Pseudomonas
Macrolide Spectrum of Activity
Anaerobes – activity against upper airway anaerobes
Atypical Bacteria – all macrolides have excellent activity against atypical bacteria including:
• Legionella pneumophila - DOC
• Chlamydia sp.
• Mycoplasma sp.
• Ureaplasma urealyticum
Other Bacteria – Mycobacterium avium complex (MAC – only A and C), Treponema pallidum, Campylobacter, Borrelia, Bordetella, Brucella. Pasteurella
MacrolidesPharmacology
Absorption Erythromycin – variable absorption (15-45%);
food may decrease the absorption • Base: destroyed by gastric acid; enteric coated• Esters and ester salts: more acid stable
Clarithromycin – acid stable and well-absorbed, 55% bioavailable regardless of presence of food
Azithromycin –acid stable; 38% bioavailable; food decreases absorption of capsules
MacrolidesPharmacology
Distribution Extensive tissue and cellular distribution – clarithromycin
and azithromycin with extensive penetration Minimal CSF penetration
Elimination Clarithromycin is the only macrolide partially eliminated by
the kidney (18% of parent and all metabolites); requires dose adjustment when CrCl < 30 ml/min
Hepatically eliminated: ALL NONE of the macrolides are removed during hemodialysis! Variable elimination half-lives (1.4 hours for erythro; 3 to 7
hours for clarithro; 68 hours for azithro)
MacrolidesAdverse Effects
• Gastrointestinal – up to 33 % Nausea, vomiting, diarrhea, dyspepsia Most common with erythro; less with new agents
• Cholestatic hepatitis - rare > 1 to 2 weeks of erythromycin estolate
• Thrombophlebitis – IV Erythro and Azithro Dilution of dose; slow administration
• Other: ototoxicity (high dose erythro in patients with RI); QTc prolongation; allergy
MacrolidesDrug Interactions
Erythromycin and Clarithromycin ONLY– are inhibitors of cytochrome p450 system in the liver; may increase concentrations of:
Theophylline Digoxin, DisopyramideCarbamazepine Valproic acidCyclosporine Terfenadine, AstemizolePhenytoin CisaprideWarfarin Ergot alkaloids
VancomycinMechanism of Action
• Inhibits bacterial cell wall synthesis at a site different than beta-lactams
• Inhibits synthesis and assembly of the second stage of peptidoglycan polymers
• Binds firmly to D-alanyl-D-alanine portion of cell wall precursors
• Bactericidal (except for Enterococcus)
VancomycinSpectrum of Activity
Gram-positive bacteria– Methicillin-Susceptible AND Methicillin-Resistant S.
aureus and coagulase-negative staphylococci– Streptococcus pneumoniae (including PRSP), viridans
streptococcus, Group A/B/C/G streptococcus– Enterococcus sp.– Corynebacterium, Bacillus. Listeria, Actinomyces– Clostridium sp. (including C. difficile), Peptococcus,
Peptostreptococcus
No activity against gram-negative aerobes or anaerobes
VancomycinPharmacology
• Absorption– absorption from GI tract is negligible after oral administration
except in patients with intense colitis– Use IV therapy for treatment of systemic infection
• Distribution– widely distributed into body tissues and fluids, including
adipose tissue; use TBW for dosing– inconsistent penetration into CSF, even with inflamed meninges
• Elimination– primarily eliminated unchanged by the kidney via glomerular
filtration– elimination half-life depends on renal function
VancomycinClinical Uses
• Infections due to methicillin-resistant staph including bacteremia, empyema, endocarditis, peritonitis, pneumonia, skin and soft tissue infections, osteomyelitis
• Serious gram-positive infections in -lactam allergic patients
• Infections caused by multidrug resistant bacteria• Endocarditis or surgical prophylaxis in select cases• Oral vancomycin for refractory C. difficile colitis
VancomycinAdverse Effects
Red-Man Syndrome – flushing, pruritus, erythematous rash on face and
upper torso– related to RATE of intravenous infusion; should be
infused over at least 60 minutes– resolves spontaneously after discontinuation– may lengthen infusion (over 2 to 3 hours) or
pretreat with antihistamines in some cases
VancomycinAdverse Effects
• Nephrotoxicity and Ototoxicity– rare with monotherapy, more common when
administered with other nephro- or ototoxins– risk factors include renal impairment, prolonged
therapy, high doses, ? high serum concentrations, other toxic meds
• Dermatologic - rash• Hematologic - neutropenia and
thrombocytopenia with prolonged therapy• Thrombophlebitis
Linezolid
Mechanism of Action
• Binds to the 50S ribosomal subunit near to surface interface of 30S subunit – causes inhibition of 70S initiation complex which inhibits protein synthesis
• Bacteriostatic (cidal against some bacteria)
Linezolid Spectrum of Activity
Gram-Positive Bacteria– Methicillin-Susceptible, Methicillin-Resistant AND
Vancomycin-Resistant Staph aureus and coagulase-negative staphylococci
– Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group streptococcus
– Enterococcus faecium AND faecalis (including VRE)– Bacillus. Listeria, Clostridium sp. (except C. difficile),
Peptostreptococcus, P. acnes
Gram-Negative Aerobes – relatively inactive
Atypical Bacteria– Mycoplasma, Chlamydia, Legionella
Linezolid Pharmacology
• Concentration-independent bactericidal activity
• Absorption – 100% bioavailable
• Distribution – readily distributes into well-perfused tissue; CSF penetration 70%
• Elimination – both renally and nonrenally, but primarily metabolized; t½ is 4.4 to 5.4 hours; no adjustment for RI; not removed by HD
Linezolid Adverse Effects
• Gastrointestinal – nausea, vomiting, diarrhea (6 to 8 %)
• Headache – 6.5%
• Thrombocytopenia – 2 to 4%– Most often with treatment durations of > 2
weeks– Therapy should be discontinued – platelet
counts will return to normal
Linezolid (Zyvox®)Drug–Drug/Food interactions
Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Tyramine rich foods, adrenergic drugs and serotonergic drugs should be avoided due to the potential drug-food and drug-drug interactions. A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content.
Linezolid and Tyraminecont
Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses (0 to 15 mg tyramine per ounce); fermented or air-dried meats such as pepperoni (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 ounces); soy sauce (5 mg tyramine per 1 teaspoon); tap beers (4 mg tyramine per 12 ounces); red wines (0 to 6
mg tyramine per 8 ounces). The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.
Clindamycin
Mechanism of Action Inhibits protein synthesis by binding
exclusively to the 50S ribosomal subunit Binds in close proximity to macrolides –
competitive inhibition
Clindamycin typically displays bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms
Clindamycin Spectrum of Activity
Gram-Positive Aerobes • Methicillin-susceptible Staphylococcus
aureus (MSSA)
• Methicillin-resistant Staphylococcus aureus (MRSA) – some isolates
• Streptococcus pneumoniae (only PSSP) – resistance is developing
• Group and viridans streptococci
Clindamycin Spectrum of Activity
Anaerobes – activity against Above the Diaphragm Anaerobes (ADA)
Peptostreptococcus some Bacteroides spActinomyces Prevotella sp.Propionibacterium FusobacteriumClostridium sp. (not C. difficile)
Other Bacteria – Toxoplasmosis gondii, Malaria
ClindamycinPharmacology
Absorption – available IV and PO Rapidly and completely absorbed (90%); food with
minimal effect on absorption
Distribution Good serum concentrations with PO or IV Good tissue penetration including bone; minimal CSF
penetration
Elimination Clindamycin primarily metabolized by the liver; half-
life is 2.5 to 3 hours Clindamycin is NOT removed during hemodialysis
ClindamycinAdverse Effects
• Gastrointestinal – 3 to 4 % Nausea, vomiting, diarrhea, dyspepsia
• C. difficile colitis – one of worst offenders Mild to severe diarrhea Requires treatment with metronidazole
• Hepatotoxicity - rare Elevated transaminases
• Allergy - rare
New Guys on the Block
• Tigecycline (Tygacil®)
• Daptomycin (Cubicin®)
Tigecycline
Mechanism of Action
Binds to the 30S ribosomal subunit of susceptible bacteria, inhibiting protein synthesis.
Tigecycline Spectrum of Activity
Broad spectrum of activity
• Treatment of complicated skin and skin structure infections caused by susceptible organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-sensitive Enterococcus faecalis; treatment of complicated intra-abdominal infections
Tigecycline Pharmacokinetics
• Metabolism: Hepatic, via glucuronidation, N-acetylation, and epimerization to several metabolites, each <10% of the dose
• Half-life elimination: Single dose: 27 hours; following multiple doses: 42 hours
• Excretion: Urine (33%; with 22% as unchanged drug); feces (59%; primarily as unchanged drug) – No dose adjustment required in renal dysfunction
TigecyclineAdverse Effects
• >10%: Gastrointestinal: Nausea (25% to 30%), diarrhea (13%)• 2% to 10%:• Cardiovascular: Hypertension (5%), peripheral edema (3%), hypotension
(2%)• Central nervous system: Fever (7%), headache (6%), dizziness (4%), pain
(4%), insomnia (2%)• Dermatologic: Pruritus (3%), rash (2%)• Endocrine: Hypoproteinemia (5%), hyperglycemia (2%), hypokalemia (2%)• Hematologic: Thrombocythemia (6%), anemia (4%), leukocytosis (4%)• Hepatic: SGPT increased (6%), SGOT increased (4%), alkaline phosphatase
increased (4%), amylase increased (3%), bili increased (2%), LDH increased (4%)
• Neuromuscular & skeletal: Weakness (3%) • Renal: BUN increased (2%)• Respiratory: Cough increased (4%), dyspnea (3%)
Daptomycin
Mechanism of Action Daptomycin binds to components of the cell
membrane of susceptible organisms and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein.
Daptomycin is bactericidal in a concentration-dependent manner
Daptomycin Spectrum of Activity
Gram-Positive Aerobes
Treatment of complicated skin and skin structure infections caused by susceptible aerobic Gram-positive organisms;
• Staphylococcus aureus bacteremia, including right-sided infective endocarditis caused by MSSA or MRSA
DaptomycinPharmacokinetics
• Absorption – available IV only• Half-life elimination: 8-9 hours (up to 28 hours in
renal impairment) • Excretion: Urine (78%; primarily as unchanged
drug); feces (6%)• Dosage adjustment in renal impairment:
– Clcr <30 mL/minute: Administer dose q48hr
DaptomycinAdverse Effects
• Hematologic: Anemia (2% to 13%)
• Gastrointestinal: – Diarrhea (5% to 12%) – vomiting (3% to 12%) – constipation (6% to 11%)
FDA Categorization of Antibiotics in Pregnancy
• Category A– Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no
evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.
• Category B– Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies
in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).
• Category C– Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other)
and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
• Category D– There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be
acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
• Category X– Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal
risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
Antibiotics in Pregnancy
FDA Category Antibiotics in Category
A
B Penicillins, Cephalosporins, Carbapenems (except Imipenem), Daptomycin, Vancomycin (oral), Clindamycin, Erythromycin, Azithromycin, Metronidazole (avoid first trimester), Nitrofurantoin, Acyclovir, Amphoterocin B, Ethambutol
C Quinolones, Chloramphenicol, Clarithromycin, Imipenem, Linezolid, Trimethoprim/Sulfa (D if used near term), Vancomycin (IV), Rifampin, INH, PZA, PAS, Fluconazole, Caspofungin
D Tetracyclines (Doxy, Tige, Mino), Voriconazole, Aminoglycosides (some put gentamicin as a category C)
X Ribavarin
Antibiotics Penetration into Eucaryotic Cells (esp. Macrophages)
Antibiotic Class Intracellular Accumulation Ratio
Predominant Subcellular Localization
Beta Lactams <1 Cytosol
Glycopeptides (Vancomycin)
8 (after 24 hrs) Lysosomes
Oxazolidinones (linezolid)
1 Unknown
Aminoglycosides 2-4 (after several days) Lysosomes
Macrolides 4-300 Lysosomes/cytosol
Fluoroquinolones 4-10 Cytosol
Clindamycin 5-20 Unknown
Tetracyclines 1-4 Unknown
Antibiotics in bold print are generally considered most effective for intracellular organisms
top related