Antibiotics - Drug & Class Details Flashcards
Penicillin G
MOA: Cell wall synthesis inhibition stage 3, bactericidal
PK: IM, IV (poor oral); renally excreted
Use limited to hospitalized patients with severe infections:
Gram positive cocci (Strep, entero)
C. perfringens
Penicillin V
MOA: Cell wall synthesis inhibition, stage 3; bactericidal
PK: Oral (acid stable); renally excreted
Gram positive cocci (Strep, Entero)
Anaerobes: C. perfringens
Dicloxacillin
Penicillinase-resistant Penicillin
MOA: Cell wall synthesis inhibition; bactericidal
PK: Oral administration; renal excretion
Spectrum/Uses:
Gram positive cocci (Strep, entero) + MSSA
Amoxicillin +/- Clavulanate
Ampicillin
Extended spectrum Penicillin
MOA: Cell wall synthesis inhibition; bactericidal; Increased hydrophilicity allows penetration through porins of gram negative OM; coupling to B-lactamase inhibitor allows activity against penicillinase-producing organisms
PK: Good Oral, Renally excreted
Spectrum:
Gram positive cocci (strep, entero) + MSSA
Gram negative rods (E. coli)
Anaerobes (C. perfringens, Bacteroides)
Adverse Reactions: Superinfection more likely, diarrhea (ampicillin > amoxicillin due to poorer oral absorption)
Piperacillin +/- Tazobactam
Antipseudomonal Penicillin
MOA: Cell wall synthesis inhibition; bactericidal; coupled to Beta lactamase inhibitor Tazobactam
PK: IV only
Spectrum:
Gram positive cocci (strep, entero) + MSSA
Gram negative rods (E. coli, K. pneumoniae, pseudomonas)
Anaerobes (C. perfringens, Bacteroides)
Cefazolin
1st Generation Cephalosporin
MOA: Cell wall synthesis inhibition, stage 3; bactericidal
PK: Oral absorption, renal elimination
Spectrum:
Gram positive cocci (Strep) + MSSA
Gram negative rods (E. coli, K. pneumoniae)
Adverse Reactions: Cross reactivity (1.5%) with penicillin hypersensitivity
Ceftriaxone
3rd generation Cephalosporin
MOA: Cell wall synthesis inhibition, stage 3; bactericidal
PK: IV, IM absorption with good CNS penetration
Spectrum:
Gram positive cocci (Strep) + MSSA
Gram negative cocci (N. gonorrhea)
Gram negative rods (E. coli, K. pneumoniae)
Vancomycin
MOA: Cell wall synthesis inhibition, stage 2; bactericidal
PK: Poor oral absorption - administered IV (except for GI C. diff); renal elimination
Gram positive cocci (Strep, entero) + MSSA + MRSA
Anaerobes (C. diff)
Adverse reactions: Infusion-related reactions (histamine flushing), nephrotoxicity, ototoxicity; Cp levels must be monitored. Pre-treat with diphenhydramine and acetaminophen.
Erythromycin
Macrolide class
MOA: Protein synthesis inhibition (50S); bacteriostatic
PK: Oral absorption; metabolized in liver and excreted in bile
Spectrum:
Gram positive cocci (Strep, Staph)
Gonorrhea
Atypicals (Mycoplasma, Chlamydia)
ARs: GI upset, DDI due to inhibition of P450 metabolism
Azithromycin
Macrolide class
MOA: Protein synthesis inhibition (50S); bacteriostatic
PK: Oral (empty stomach); biliary excretion
Spectrum:
Gram positive cocci (Strep, Staph)
Gonorrhea
Atypicals (Chlamydia, Mycoplasma)
ARs: GI disturbance (nausea, vomiting, diarrhea)
Clarithromycin
Macrolide class
MOA: Protein synthesis inhibition (50S); bacteriostatic
PK: Absorbed orally, metabolized to active compound that is renally eliminated
Spectrum:
Gram positive cocci (Strep, Staph)
Atypicals (Chlamydia, Mycoplasma)
ARs: GI disturbance, DDI due to inhibition of CYP450
Tetracycline
Tetracycline class
MOA: Protein synthesis inhibition; bacteriostatic
PK: oral administration, renal excretion
Spectrum - Broad (but high resistance)
Gram positive cocci (Strep, Staph + MSSA + MRSA)
Gram negative rods (E. coli, K. pneumoniae,)
Other Gram negatives (V. cholera, H. pylori)
Spirochetes (Borrelia burgdorferi)
Atypical (Mycoplasma, Chlamydia)
Doxycycline
Tetracycline class
MOA: Protein synthesis inhibition; bacteriostatic
PK: Oral administration, biliary excretion; choice for patients with renal disease
Spectrum - Broad (but high resistance)
Gram positive cocci (Strep, Staph + MSSA + MRSA)
Gram negative rods (E. coli, K. pneumoniae)
Atypicals (Mycoplasma, Chlamydia)
Clindamycin
Lincomycin class
MOA: Binds to ribosome preventing translocation of peptidyl tRNA; bacteriostatic
PK: Oral absorption, penetrates most tissues well (especially bone) but not CSF; metabolized by the liver and excreted through the bile
Spectrum:
Gram positive cocci (Strep, Staph + MSSA + MRSA)
Anaerobes (C. perfringens, Bacteroides)
Choice in CA-MRSA
ARs: Selection of C. diff overgrowth leading to pseudomembranous colitis; nausea, diarrhea
Ciprofloxacin
Fluoroquinolone Class, 2nd generation
MOA: Preferential inhibition of DNA gyrase; bactericidal
PK: Oral absorption, primarily renal excretion
Spectrum:
Gram negative rods (E. coli, K. pneumoniae, Pseudomonas)
Atypical (Chlamydia, Mycoplasma)
Levofloxacin
Fluoroquinolone Class, 3rd generation; “respiratory quinolone”
MOA: Inhibition of both DNA gyrase and Topoisomerase IV; bactericidal
PK: Oral absorption, primarily renal excretion
Spectrum
Gram positive cocci (Strep)
Gram negative rods (E. coli, K. pneumoniae, pseudomonas)
Atypical (Chlamydia, Mycoplasma)
Moxifloxacin
Fluoroquinolone Class, 4th generation, “respiratory quinolone)
MOA: Preferential inhibition of Topoisomerase IV; bactericidal
PK: Primarily hepatic excretion (20% renal)
Spectrum
Gram positive cocci (Strep)
Gram negative rods (E. coli, K. pneumoniae)
Atypicals (Chlamydia, Gonorrhea)
Nitrofurantoin
MOA: Reduced in cell to intermediates that damage bacterial DNA; bactericidal
PK: Rapid, complete GI absorption followed by rapid excretion via kidneys (contraindicated in renal impairment); not used for systemic infections because effective Cp cannot be obtained with safe doses
Spectrum:
Gram negative rods (E. coli, K. pneumoniae)
ARs: GI upset, occasional hypersensitivity, neuropathies
Metronidazole
MOA: Reduced intracellularly to active form, a highly reactive radical anion that interferes with DNA function; bactericidal
PK: Oral absorption, distribution includes CSF and bone; hepatic metabolism
Spectrum:
Anaerobes (C. diff, Bacteroides, H. pylori)
Protozoa (trichomoniasis, amebiasis, giardiasis)
ARs: Antabuse-like reaction (via inhibition of aldehyde dehydrogenase), GI upset, candidal superinfections
Penicillins - Adverse Reactions & Toxicity
Type I: Immediate hypersensitivity mediated by IgE & Mast cells (0.05%)
Maculopapular rash most common (1-4%), Diarrhea,
Penicillins - Mechanisms of Resistance
Production of penicillinase enzyme via plasmid transfer
Alterations of penicillin-binding proteins (responsible for MRSA)
Inability to penetrate into bacterial cell
Escape or Persisters - metabolically inactive organisms (“L forms”) that can survive in a hypertonic environment
Penicillins - Pharmacokinetics
Absorption: varies depending on acid stability
Pen G: IV or IM (poor oral)
Pen V, Amoxicillin, and Dicloxacillin: Good oral
Piperacillin: IV only
Distribution: strong acid, largely ionized at physiological pH; penetrates tissues poorly but enters inflamed tissues more easily
Metabolism/Excretion: Excreted as active drug via the kidney; also excreted into breast milk
Cephalosporins - Pharmacokinetics
Absorption: Oral, IV / IM
Distribution: Penetrate well into most tissues and fluids, including placenta; only 3rd gen penetrates into CSF
Metabolism-Excretion: Kidneys, requires renal dosing
Cephalosporins - Adverse Reactions
Hypersensitivity
Cross-hypersensitivity with Penicillins <1% - increased risk with 1st gen
Superinfection - increased risk with 2nd and 3rd gen
Alterations of normal gut flora may decrease synthesis of Vitamin K and intensify the anticoagulant effect of Warfarin
Vancomycin - Pharmacokinetics
Administered IV (poor oral absorption)
Excreted by kidneys; half life is extended in renal failure
Vancomyosin - Adverse Reactions
Ototoxicity, chills, fever, rash, renal toxicity
Routine monitoring of Cp levels required with infusion
B-lactamase Inhibitors
i.e. Clavulanic acid and Tazobactam
Resemble B-lactam molecules; they are potent, irreversible inhibitors of B-lactamase; they are coupled to a penicillins to extend the antibacterial spectrum against resistant organisms that exhibit B-lactamase activity
Clavulanic acid + Amoxicillin
Tazobactam + Piperacillin
Cefazolin
1st Generation Cephalosporin
MOA: Cell wall synthesis inhibition; bactericidal
PK: IV / IM
Spectrum:
Cocci: gram + (Strep, Staph, non MRSA)
Bacilli: gram - (Proteus, diarrhea E. coli, Klebsiella)
Aminoglycosides
MOA: Actively transported into cells (O2-dependent), binds irreversibly to bacterial ribosome, blocking initiation of translation; bacteriocidal
PK: IV/IM (poor oral) absorption; distribution is limited to extracellular fluid (excluded from CNS) but accumulates in renal cortex and inner ear; renal elimination - 1x/daily dosing possible due to concentration-dependent killing and post-antibiotic effect
Spectrum:
Gram negative rods (E. coli, K. pneumoniae, Pseudomonas)
ARs: Very toxic! 8th nerve damage, renal toxicity
Macrolides - Adverse Reactions & Toxicity
GI upset (worse with erythromycin due to direct sitmulation of gut motility)
Hepatotoxicity
Prolonged QT interval
DDIs due to inhibition of CYP450 (erythromycin and clarithromycin only)
Macrolides - Mechanism of Action
Macrolides bind to the 23S ribosomal RNA of the 50S subunit, preventing chain elongation and inhibiting protein synthesis
Tetracyclines - MOA and Resistance
MOA: Binds to ribosomal A site, preventing access of aminoacyl-tRNAs to the ribosomal active site; bacteriostatic
Resistance: Decreased influx, increased efflux, alterations to the ribosome that prevent tetracycline binding
Tetracyclines - Adverse Reactions & Toxicity
Inhibition of bone growth & discoloration of teeth (avoid use < 8 years old)
GI disturbance
DDIs with metal ions (antacids, iron) in stomach
Photosensitivity
Fluoroquinolones - MOA in Gram negative vs. Gram positive
Fluoroquinolones target DNA Gyrase and DNA Topoisomerase IV causing release of lethal, double-stranded DNA breaks
DNA gyrase is more susceptible to inhibition in Gram negative bacteria; Ciprofloxacin preferentially targets DNA gyrase and is more active against gram negative bacteria
DNA topoisomerase is more susceptible to inhibition in Gram positive bacteria; Levofloxacin and Moxifloxacin target Topoisomerase and so are effective against gram positive bacteria
Tetracyclines - Pharmacokinetics
Oral absorption BUT impaired by milk products, metal cations, and iron salts
Distribution - good penetration into tissues, including placenta
Elimination - concentrated in liver, secreted into bile; tetracycline is excreted into urine (doxy and mino are not)
Fluoroquinolones - Pharmacokinetics
Oral absorption
Good penetration into most tissues including high urinary levels
Primarily renal excretion
Fluoroquinolones - Adverse Reactions
Overall very well tolerated but rarely GI upset, dizziness, headache
Black Box Warning: increased risk of tendon rupture and potential for arthropathies
DDIs with Theophylline and caffeine due to FQ inhibition of metabolism
DDIs with antacids containing metal cations; reduced oral absorption of FQ
Community- vs. Hospital-acquired pneumonia
CAP: Strep pneumo is a normal flora in the oropharynx that can become micro-aspirated into the lungs, causing infection; treated with B-lactam + macrolide or respiratory fluoroquinolone (i.e. Ceftriaxone + Azithromycin)
HAP: Occurs as a result of colonization with gram negative rods that occurs in over 40% of patients by day 5 of a hospital stay; treated with Vancomycin + Pip-Tazo
B - Lactams Mechanism of Action (Penicillins) & Cephalosporins
B-lactams irreversibly bind to and inactivate Penicillin Binding Proteins (PBPs) in the susceptible organism which carry out the transpeptidase (cross-linking) reaction necessary for peptidoglycan synthesis in the cell wall
B-lactamase
B-lactamases are enzymes that inhibit B-lactam antibiotics by hydrolyzing the B-lactam ring; they can be encoded by chromosomal or plasmid genes and are found in both gram positive and gram negative bacteria; generally associated with gram negative enterics (E. coli, Enterobacter, Klebsiella)
Methicillin Resistant Staph Aureus
MRSA contains an exogenous piece of DNA called staphylococcal chromosome cassette (SCCmec) containing the gene MecA which codes for PBP2a; PBP2a has low affinity for methicillin-type antibiotics
(Remember, MRSA also contains the plasma-encoded narrow spectrum B-lactamase that confers resistance to Penicillin & Ampicillin)
Vancomycin - Mechanism of Action
Vancomycin binds to the terminal D-ala-D-ala portion of the five member peptide chain of the peptidoglycan precursor molecule which hangs off of MurNAc; it physically blocks the ability of the PBPs to put the precursor molecule into the growing peptidoglycan, thereby blocking both transglycosylase AND transpeptidase activity (stage 2 synthesis inhibitor)
Mechanism of Vancomycin-Resistant Enterococci (VRE)
VRE expresses a plasmid-encoded VanA gene, which codes for an enzyme that results in synthesis of precursor peptidoglycan molecules with peptide chains terminating as D-ala-D-lactate; this modified peptidoglycan precursor binds Vancomycin with reduced affinity
Most VRE isolates are E. faecium; VRE is rarer in E. faecalis
*Also VERY RARELY seen in staph (VRSA)
Mechanism of Vancomycin-intermediate S. aureus (VISA)
VISA expresses an unusually thick peptidoglycan cell wall that is less completely cross-linked and therefore contains free D-ala-D-ala tails which can bind Vancomycin, “absorbing” it into the wall and preventing its binding to peptidoglycan precursor molecules and inhibition of peptidoglycan synthesis
Respiratory Fluoroquinolones
Levofloxacin and Moxifloxacin are respiratory fluoroquinolones because they preferentially target Topoisomerase IV in Gram positive organisms common in respiratory infections
Ciprofloxacin is NOT a respiratory fluoroquinolone because it preferentially targets DNA gyrase in gram negative organisms that are less frequently found in respiratory infections
Mechanism of Fluoroquinolone resistance
Fluoroquinolone resistance occurs as a result of the accumulation of point mutations in the region GyrA of DNA gyrase or ParC of topoisomerase IV; these regions are called the quinolone-resistance-determining region (QRDR); these mutations reduce the affinity of the enzyme-DNA complex for the quinolone
Macrolides - Resistance
- The erm gene, usually found on plasmids, encodes an enzyme that dimethylates the 23S ribosomal RNA, preventing macrolide (and clindamycin) binding
erm can be inducible or constitutive; microbes are resistant to Macrolides under inducible or constitutive conditions but resistant to clindamycin only under inducible conditions
- Macrolide-specific efflux pump
D test
When an isolate is found to be macrolide resistant, the D test distinguishes between efflux- and erm-mediated resistance
Disks of erythromycin and clindamycin are placed on a plate spread with the test pathogen; if the pathogen expresses inducible erm then erythromycin will induce resistance to clindamycin and the zone of inhibition for clindamycin will be blunted, forming a “D” shape of colony growth; if the efflux system is present no blunting will occur
Which antimicrobials are effective vs. MRSA?
Vancomycin
Clindamycin
Macrolides
Which antimicrobials are effective vs. Pseudomonas?
Pip/Tazo Aminoglycosides Aztreonam Ciprofloxacin Levofloxacin
Which antimicrobials are effective vs. Atypical organisms (Mycoplasma, Chlamydia)?
Macrolides
Tetracyclines
Fluoroquinolones (all)
SMX / TMP
Which antimicrobials are effective vs. C. diff?
Vancomycin
Metronidazole
1st generation Cephalosporins (2)
Cephalexin
Cephazolin
Second generation Cephalosporins (2)
Ceflacor
Cefuroxime
Third generation Cephalosporins (4)
Ceftriaxone
Ceftazidime
Cefdinir
Cefepime
Carbapenem Agents (2)
Imipenem / Cilastatin
Ertapenem
Carbapenem - Mechanism & Pharmacokinetics
Structurally related to B-lactams but are B-lactamase resistant; cell wall synthesis inhibitor (Stage 3)
IV/IM administration only
Penetrates CSF
Renal excretion
Carbapenems - Spectrum
Gram positive cocci (except MRSA)
Gram negative rods (including Pseudomonas)
Anaerobic (including Bacteroides; not C.diff)
Carbapenems - Adverse Reactions
Nausea, vomiting, diarrhea
Skin rash
Rarely seizures - usually in patients with a history of CNS and renal disease
Cilastatin
Inhibits dihydroreductase in the kidney, which prevents Imipenem from being prematurely inactivated
Aztreonam - Mechanism & Pharmacokinetics
Monobactam class; synthetic B-lactam ring that is resistant to B-lactamases
Administered IV/IM only
Penetrates CSF
Renal elimination
Aztreonam - Spectrum
Gram negative, aerobic bacteria ONLY
Synergistic use with aminoglycosides vs. Pseudomonas
Chloramphenicol - Mechanism, Pharmacokinetics
Protein synthesis inhibitor; binds 50S bacterial ribosome; bacteriostatic
Oral absorption with good distribution to the CNS
Hepatic elimination
Gray baby syndrome
Toxic complication of chloramphenicol
Occurs in infants 2-9 days after therapy initiated with vomiting, abnormal respiration, cyanosis, and vasomotor collapse
40% mortality rate
Chloramphenicol - Spectrum and Toxicity
Wide spectrum BUT not used in the US due to toxicity
Gram positive cocci (except MRSA) Gram negative cocci (Gonorrhea) Gram negative rods (except Pseudomonas) Anaerobes (except C. diff) Atypicals
Poor selectivity for bacterial ribosome; also inhibits ribosomes in mammalian bone marrow. Causes aplastic anemia / myelosuppression, requiring CBC monitoring every 2-3 days; also causes Gray Baby syndrome
Streptogramins - Combo agent mechanisms & pharmacokinetics
Quinupristin / Dalfopristin (30:70)
Quinupristin binds to 50S ribosome (same sate as Macrolides) to inhibit peptide elongation
Dalfopristin binds at a nearby site on the 50S ribosome, inducing a conformational change that enhances Quinupristin binding
IV Administration only
Streptogramins - Spectrum
Gram positive cocci (including MRSA and VRE)
Use held in reserve for life-threatening infections only
Streptogramins - Adverse Effects
Irritation at infusion site
Arthralgias / myalgias
Nausea, diarrhea
Rash
Linezolid - Mechanism & Pharmacokinetics
Oxazolidinone class; binds to 50S ribosome at a different site than other agents, so no cross-resistance with other protein synthesis inhibitors
Inhibits early formation of 70S ribosome complex; bacteriostatic
Administered oral or IV
Renally excreted but no dosage adjustment necessary in mild renal impairment
Linezolid - Spectrum & Uses
Gram positive cocci (including MRSA and VRE)
Linezolid - Adverse Effects / Toxicity
Well tolerated with minor side effects - diarrhea, headache, nausea
Rarely, thrombocytopenia
Inhibits MAO - risk of hypertensive response with co-administration of sympathomimetics or foods high in tyramine; serotonin syndrome if given with SSRIs
Sulfamethoxazole / Trimethoprim - Mechanism
Sulfamethoxazole inhibits dihydropteroate synthetase
Trimethoprim inhibits dihydrofolate reductase
In combination, these two agents inhibit two sequential steps in the enzymatic conversion of PABA to tetrahydrofolic acid, necessary for synthesis of DNA and certain AAs
Bacteriostatic with delayed onset of action
SMX / TMP - Pharmacokinetics & Adverse Effects
Good oral absorption with distribution into CSF
Hepatic acetylation to an inactive compound which can be toxic due to low solubility, causing renal crystalluria; Na-HCO3 alkalinizes the urine and decreases crystal formation
SMX / TMP - Spectrum and Uses
Gram positive cocci including MRSA
Gram negative cocci (Gonorrhea)
Gram negative rods (including pseudomonas)
Atypical
SMX / TMP - Adverse Effects
Sensitization - fever, rashes
Rarely - agranulocytosis, aplastic anemia, Stevens-Johnson Syndrome
Renal damage via crystalluria
Hemolytic anemia in patients with G6PD deficiency
Displaces bilirubin from albumin binding sites in infants, causing kernicterus
Polymixins
Cell membrane disrupter; interacts with membrane phospholipids to lyse cells with detergent-like action; bactericidal
Active against gram negative only; used for pseudmonas meningitis after other agents have failed
Highly nephrotoxic
Daptomycin
Binds to bacterial cell membrane causing rapid depolarization which inhibits protein, DNA, and RNA synthesis resulting in cell death (bactericidal)
Spectrum similar to Vancomycin; active against MRSA, including Vancomycin-resistant MRSA
IV administration
Renal elimination
Treatment of uncomplicated Gonorrhea
Ceftriaxone - 250mg IM
Azithromycin (1g oral) OR Doxycycline (100mg 2x/day for 7 days) - empirical coverage of Chlamydia
Treatment of ocular Chlamydia in infants
1% silver nitrate OR 1% tetracycline OR 0.5% Erythromycin topical to eyes at time of birth
Treatment of pregnant women with Gonorrhea
3rd Generation Cephalosporins
Treatment of uncomplicated Chlamydia
Azithromycin - 1g oral
OR
Tetracycline - 100mg BID x 7 days
Prevention of neonatal transmission of Chlamydia
Erythromycin or amoxicillin to treat the mother
Treatment of neonatal inclusion conjunctivitis (chlamydial)
Erythromycin (oral)
Treatment of syphilis
Penicillin is first line
Azithromycin for patients who are penicillin allergic
