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