PHAR 747 Exam 2 Flashcards
Antibiotics than inhibit 30S subunit
Spectinomycin Tetracycline 1 Pactamycin Hygromycin B Streptomycin Paramomycin Geneticin Tetracycline 2
Antibiotics that inhibit the 50S subunit
Thiostrepton Avilamycin Streptogramin A Chloramphenicol Puromycin Pleuromutilins Streptogramin B Lincosamides Macrolides
‘mycin’ vs ‘micin’
Mycin = Streptomyces origin
Micin = Micromonospora origin
Disadvantages of Streptomycin
Resistances emerged quickly
Ototoxic and nephrotoxic
Narrow spectrum (aerobic gram -)
Streptomycin was first antibiotic against ______________
TB
Aminoglycoside general properties
Central aminocyclitol ring with various sugars attached
2-deoxystreptamine (a modified 1,3-diaminocyclohexane) in all BUT streptamycin (has streptidine)
Basic and charged at neutral pH, highly water soluble, usually given IM or IV, some are mixtures.
Use limited to serious aerobic Gram (-)
Aminoglycoside Mechanism of Action
Penetrate outer membrane of Gram (-) actively via O2-dependent transport; can pass through porin; low pH or anaerobic conditions inhibit transport while cell wall synthesis inhibitors can enhance transport
Bind irreversibly to 16S rRNA of 30S subunit (often bactericidal); fuck up protein synthesis by causing misreading of mRNA; inhibit protein synthesis initiation and cause polsomes to dissociate into non-functional monosomes
Gentamicin Family
Mixture of 3 compounds, administered IV for serious gram (-)
Used topically for Ps. aeruginosa in burn patients or inhaled for Ps. aeruginosa in CF patients.
Cross resistance with many other AGs. Administered with carbenicillin for synergistic effect.
Physical incompatability with beta-lactams (administer with separate IVs or sequentially)
Members of Gentamicin family
Gentamicin, sisomicin, netilmicin, isepamicin
Kanamycin Family
All have kanosmine sugar at 6 position of 2-deoxystreptamine
Members: Kanamycin, Amikacin, Tobramycin
Kanamycin
Mixture of 3 compounds (mostly Kanamycin A)
Ototoxicity major problem.
Primarily used for dysentery and sometimes MDR-TB
Amikacin
Semisynthetic derivative of kanamycin A ( (S)-4-amino-2-hydroxybutyramide derivative )
Only 50% as potent as parent drug but less prone to inactivation by AG modifying enzymes.
Active against some gentamicin and tobramycin resistant strains (Mycobacterium spp.)
Tobramycin
3’-deoxykanamycin B
Used for Ps. aeruginosa but NOT active towards Mycobacteria (DO NOT USE FOR TB)
Often used as same time as antipseudomonal b-lactams (Ticarcillin, aztreonam, ceftazidine)
Active against some gentamicin resistant strains
Neomycin family
3 sugars - 2 aminohexoses and a D-ribose attached to the aminocyclitol
Members: Neomycin, Paramomycin
Neomycin
Mixture of B and C and neamine (mostly B)
One of the MOST nephrotoxic AGs
Paromomycin
Also a mixture (like Neomycin)
Used almost exclusively for amoebic dysentery; also used to treat leishmaniasis
Tetracyclines
Broad spectrum, effective against organisms resistant to agents acting on cell wall; use decreased with introduction of broad spectrum cephalosporins
In aqueous solution C-1 ketone to C-3 enol; C-10 phenol to C-12 enol; C-4 dimethylamine
Compounds with a C-6 hydroxyl undergo aicd or base promoted degredation
C-4 can epimerize in weak acid due to the b-dimethylamine
Members: Chlortetracycline, Tetracycline, Doxycycline, Minocycline, Tigecycline
Tetracyclines and metal ions
Tetracyclines can chelate many di- and trivalent metal ions.
Coordinates with Mg2+ to get through porin (gram -) and then Mg2+ released in periplasmic space. Apo-form of drug crosses cytoplasmic membrane, picks up another Mg2+ before drug binds ribosome.
If taken with dairy products, often you get poor absorption (broad spectrum combined with poor absorption = superinfection)
Tetracyclines/Ca2+ complex can be deposited in teeth and bone during gestation and early childhoold.
Tetracycline Mechanism of Action
Binds 16S rRNA of 30S ribosomal.
Blocks binding of aminoacyl-tRNA to ribosome (prevents peptide elongation, is reversible and bacteriostatic)
Toxicity selective to bacteria due to poor penetration of mammalian cells and poor affinity for mammalian ribosomes. Some bacteria will concentrate the drug in cells.
Chlortetracycline
First isolated
Only used topically now
Tetracycline
Produced by catalytic hydrogenation of chlortetracycline
Improved oral availability, high plasma concentration and long duration
Doxycycline
Lacks C-6 hydroxyl
One of most frequently prescribed tetracyclines (often for gonorrhea, syphilis, Lyme disease and malaria prevention)
Minocycline
Semisynthetic with additional dimethylamine at C-7 but no C-6 hydroxyl.
Best absorbed and longest t1/2
Tigecycline
9-tert-butyl-glycylamido derivative of minocycline
First glycylcycline (injectable only).
Not a substrate for efflux pumps that cause resistance to other tetracyclines; active against tet-resistant bacteria; more active than early tetracyclines and forms additional binding contacts with rRNA.
Resistance can develop fast in some gram (-)
Macrolides General Information (Natural Macrolides)
Large cyclic ester (lactone) composed of 12, 14 or 16 atoms; ring has numerous Me and OH groups, deoxysugar and ketone
Produced by fermentation.
Spectrum similar to penicillins and therefore often used if patient is sensitive to penicillin.
Unstable at pH 4 or less; weak bases can be formulated as salts
Macrolides Mechanism of Action
Inhibit protein synthesis by reversibly binding to 50S ribosomal subunit. Inhibits translocation of growing protein chain.
Agents do not bind to mammalian ribosomes and are usually bacteriostatic.
Erythromycin A
Acid labile, bitter and poorly absorbed when taken orally (solved with salt forms)
Erythromycin stearate - stearate salt liberated in alkaline duodenum
Erythromycin Ethyl Succinate - 2’ OH of desosamine esterified with ethyl succinate; absorbed as ester then hydrolyzed (most common oral form given)
Erythromycin Estolate - 2’OH of desosamine esterified as propionate ester and the compound is lauryl sulfate salt; acid stable
Second Generation Macrolides
Semisynthetic derivatives of Erythromycin A; developed to prevent acid degradation and improve pharmacokinetics
Potential side effects: QT interval prolongation and heart arrhythmias
Members: Azithromycin, Clarithromycin, Telithromycin
Azithromycin
First azalide (15-membered ring with N in between C9 and C10); acid stable and better Gram (-) activity than erythromycin A
High tissue concentrations and given as 1g dose one time for uncomplicated gonorrhea (as effective as 7 days on doxycycline)
Clarithromycin
C6 O-Me erythromycin A
Acid stable (methylation at C6 prevents OH from participating in acid catalyzed degredation) and better absorption
2-3x potentcy of erythromycin A towards Gram (-) including Legionella spp.
2-4x more active vs gram (+) cocci than erythromycin A.
Used to treat disseminated MAC
Rapidly metabolized to 14-OH clarithromycin
Telithromycin
Semisynthetic - 1st Ketolide; Cladinose removed from clarithromycin and OH oxidized to ketone.
Ketolides do not include resistance to macrolides BUT active against many macrolide resistant strains.
Dosing: qd for 7 days to treat CAP
Can exacerbate symptoms of myasthenia gravis
Lincosamides
Clindamycin (semisynthetic) and Lincomycin (natural product)
Active towards gram (+) and some anaerobes; effective for staph in bones and joints
Can lead to fatal colitis: Superinfection by clindamycin-resistant toxin producing Clostridium sp. requires vancomycin or metronidazole
Not used for infections that are susceptible to other antibiotics
Lincosamide MOA same as macrolides
Oxazolidinones (SAR and MOA)
Eperezolid, Linezolid, Tedizolid
SAR:
3’-fluorine for activity, oxazolidinone ring must be intact
Mechanism of Action:
Bacteriostatic interruption of protein synthesis; binds 23S of rRNA of 50S near interface with 30S, blocking formation of functional 70S complex; do NOT affect peptidyl transferase activity or translation termination
No cross resistance between oxazolidinones and other antibiotics
Linezolid
Gram (+) methicillin or vancomycin resistant organisms (e.g. MRSA, VRE)
Some gram (-) activity including H. influenza and Legionella spp. but no Enterobacteriaceae or Pseudomonas spp. Also active against Mycobacterium tuberculosis and M. avium.
IV or oral (usually being IV in hospital and continue oral on discharge)
Side effects: myelosuppression (monitor blood regularly) and inhibition of monoamine oxidase (reversible and non-selective)
Linezolid resistance
Mutation in 23S rRNA gene where guanine changed to thymine
Chloramphenicol
Natural product for Streptomyces venezuelae (produced by synthesis now) - R,R form naturally occurring
Good access to the CNS - used still for bacterial meningitis.
Does not require energy-dependent transport
Chloramphenicol MOA
Acts at 50S subunit
Blocks correct binding of aminoacyl-tRNA and inhibit peptide bond formation; effect is reversible
Binding occurs near macrolide site (will compete with macrolides/clindamycin/linezolide)
Cheap, effective, broad spectrum, but has adverse effects
DON’T COMBINE CHLORAMPHENICOL WITH?
Macrolides
Clindamycin
Linezolide
Chloramphenicol adverse effects
High mitochondrial 70S affinity but no 80S form found in cytosol
Fatal effect on one marrow causes pancytopenia (reduction in RBCs, WBCs and platelets)
Toxicity thought to arise from metabolite involving nitrophenyl (florfenicol lacks this group)
Toxicity worse in neonates due to low glycuronosyl activity, inadequate renal excretion, resulting in high plasma concentrations. Chloramphenicol also inactivates hepatic CYP450s.
Gray baby syndrome 3-4 days after dose; hypothermic and hypotension
Retapamulin
Derivative of pleuromutilin from fungus, used in vet med; semisynthetic modifications allow for better formulation and decreased metabolism
Similar type of modification that is added to quinupristin.
Approved for impetigo caused by S. aureus or S. pyogenes
Retapamulin MOA
Acts at 50S subunit at unique site that involves ribosomal protein L3 in the ribosomal P site and peptidyl transferase center (inhibits peptidyl transfer, blocks P-site and prevents formation of 50S subunits)
Bacteriostatic against S. aureus and S. pyogenes but bactericidal at higher concentrations.
No specific cross-resistance
Retapamulin Resistance
Efflux in some bacteria
Mutation in ribosomal L3 protein
Fidaxomicin
Used against CDI with almostm no activity against normal fecal flora; minimal intestinal absorption
Equivalent efficacy and comparable safety to vancomycin for CDI (less recurrences of CDI and faster symptom resolution)
Structurally very similar to macrolide
Fidaxomicin MOA
Inhibits sigma-dependent transcription of bacterial RNA polymerase
Bactericidal with prolonged post-antibiotic effect
Quinolones/fluoroquinolons general information
Initially developed from impurity found during chloroquine synthesis
Used initially for UTIs; early agents most active towards gram (-)
Quinolones/Fluoroquinolones MOA
Disrupt DNA replication and function - targets 2 topoisomerases ( 2 = gyrase and 4)
DNA gyrase
Relaxes supercoiled DNA
Only enzyme that can also supercoil DNA
DNA topoisomerase 4
Decatenating enzyme - resolves interlinked daughter chromosomes following DNA replication
Relaxes supercoil but can not induce supercoil
Describe quinolone inhibition of Bacterial DNA gyrase
Gyrase and Topo4 bind dsDNA and break both strands - FQs bind this topoisomerase + broken DNA intermediate
Release of fragmented chromosome correlates with cell death; can also cause generation of hydroxyl radicals
Quinolones can only recognize and bind the topoisomerase-DNA complex
Mammaliain cells don’t have DNA gyrase and quinolones have low affinity for mammalian topoisomerase 2
Quinolone/fluoroquinolone SAR
Most common heterocyclic nucleus is 3-carboxy-4-quinone
Position 2 should be unsubsituted; N-1 must have small alkyl; N can replace C at position 8 with no activity loss
Groups C5 and position 8 can affect photosensitivity
Fluorine at C6 increases activity
Substituents at C7 increase activity - piperazine extends spectrum into Ps. aeruginosa
Absorption decreased with divalent ions
Nalidixic Acid
First generation (no C6 fluorine, spectrum limited to uncomplicated UTI)
First quinolone, strong acid pKa ~ 1, extensively metabolized to 7-hydroxymethyl nalidixate
Norfloxacin
Second generation (increased potency and spectrum due to C6 fluorine)
First fluoroquinolone
100x more potent than nalidixic acid and broader gram (-) including Ps. aeruginosa
Some gram (+)
Ciprofloxacin
2nd gen fluoroquinolone
More potent than norfloxacin and better absorbed; good distribution in bone and soft tissue; more potent vs Ps.
Good safety record = widespread use
Good serum levels allowing for use beyond genitourinary tract infections
Cyclopropane contributes to photosensitivity
Ofloxacin and Levofloxacin
2nd gen fluoroquinolone
3S levo (-) isomer is most potent; 8-125x difference in potency based on species; 1,4-oxazine ring between N1 and C8
High CSF concentrations
Active vs Mycobacteria (e.g. MDR-TB)
Levofloxacin may cause QT prolongation leading to cardiovascular incidents
Sparfloxacin
3rd gen fluoroquinolone
More potent against Pneumococcus and anaerobe
Difluoroquinolone; only example with C5 amine
Improved gram (+) activity
T1/2 = 8 hours
Perks of 4th generation fluoroquinolones
Longer t1/2 and more potent vs Pneumococcus and anaerobes
Moxifloxacin
4th gen fluoroquinolone
8-methyl-fluoroquinolone with enhanced bactericidal action, decreased rate of resistance and no P450 metabolism
Inhibit topoisomerase 4 and gyrase
Very effective against TB; NO urinary excretion so can’t be used for UTI
Gemifloxacin
4th gen fluoroquinolone
Orally active and broad spectrum (gram - activity equal to ciprofloxacin but better gram +)
Indicated for CAP and acute bacterial exacerbation of chronic bronchitis.
8-30x better than ciprofloxacin against S. aureus and S. pneumoniae
Inhibitor of topo4 and gyrase in vitro
Rashes common in women under 40 and those over 40 receiving hormone replacement therapy
General mechanisms of fluoroquinolone resistance
Mutations in gyrase and topo4 genes
Decreased intracellular accumulation of drug (efflux pumps, modification in membrane proteins)
In S. aureus, recG can repair damage from fluoroquinolones
Fluoroquinolone toxicity/side effects
Overall safe
Can affect cartilage development (tendon rupture and tendonitis)
Qt prolongation may be related to halogen at C8
Phototoxicity with ciprofloxacin, lomefloxacin and norfloxacin (due to photodegradation products and reactive oxygen species) –> caused by cyclopropane OR halogen (skin lesion, blister, 2nd degree burn, visual disturbances)
Peripheral neuropathy
Sulfonamide antibacterial agents general information
Protonsil active in vivo but no in vitro activity
Protsonil converted to aminobenzenesulfonamide (sulfanilamide) in vivo
Largely replaced by penicillins
Sulfonamidea MOA
Inhibition of folic acid biosynthesis
Folate derivatives co-enzymes in important biological processes: thymidine and purine synthesis for DNA/RNA, Amino acid synthesis (Gly, Ser, Met)
Sulfonamides competitively inhibit dihydropteroate synthase (DHPS) by closely resembling natural substrate PABA –> resulting dihydropteroate derivative can’t be further transformed to tetrahydrofolate
Inhibition of DHPS causes ______________
bacteriostasis
How are sulfonamides selectively toxic?
Mammals do not synthesize folate and do not have DHPS
Bacteria can’t use folate from mammalian diet to replace depleted levels
Sulfonamide general SAR
Sulfonamide NH is acidic (pKa 6 in most useful agents, 5-10 range) - analogs with high pHa crystalized in kidney
R2 should be small heteroaromatic ring for best activity
Aniline NH2 is essential
If R1 is not H it must be removed in vivo
Trisulfa
Sulfadiazine (pKa 6.5)
Sulfamerazine (pKa 7.1)
Sulfamethazine (pKa 7.4)
Higher sulfadiazine concentrations to avoid kidney stones
Sulfisoxazole
pKa 5 (most acidic sulfonamide)
Bitter but can be acetylated at the sulfonamide N to make more palatable
In sulfisoxazole acetyl, acetyl is hydrolyzed in intestines and absorbed as sulfisoxazole
Sulfisoxazole acetyl + erythromycin = _____________
PEDIAZOLE
Sulfacetamide
Only for topical use
Used in suspension to treat acne; drops to treat eye infection
Combined with prednisolone as BLEPHAMIDE and VASOCIDIN
Sulfamethoxazole
Closely related to sulfisoxazole but not as completely or rapidly absorbed.
Commonly combined with trimethoprim for synergism (combination usually bactericidal w/ optimum ratio being 20:1 SMX:TMP)
Commercial combination product usually 5:1 ration since trimethoprim not absorbed well
Trimethoprim MOA
Disrupts folate biosynthesis by inhibiting dihydrofolate reductase (DHFR)
Potent antibacterial agent alone (20-100x that of sulfamethoxazole) but resistance is rapid
Selective difference between bacteria and mammals for sulfonamides and trimethoprim
IC50 for bacteria DHFR = 5nM
IC50 for mammalian DHFR = 2.6 x 10^5 nM
Mupirocin
Used primarily for skin infections (impetigo) by Staphylococcus spp.
bacteriostatic but can be bactericidal at low pH
MOA: Inhibits protein biosynthesis by binding bacterial isoleucyl-tRNA synthetase (IleRS)
Selective toxicity from low affinity for mammalian IleRS; used topically due to quick inactivation by hydrolysis of fatty acid ester linkage; 95% serum bound resulting in poor bioavailability
Metronidazole and Tinidazole
5-nitroimidazoles
Active against many obligate anaerobic gram (-) and gram (+); treatment for bacterial vaginosis and parasitic infections, including trichomoniasis and intestinal parasitic infections giardiasis and amebiasis
Can access the CNS
Bactericidal
Adverse effects: Can discolor urine reddish-brown; carcinogenic in rodents; selectively toxic against anaerobes and microaerophilic organisms; taking with alcohol may cause disulfiram-like reactions
How does metronidazole reduction take place
Ferredoxin reduces metronidazole in single electron transfer into toxic free radical
Reduced Fd in Trichomonas vaginalis related to resistance
Nitrofurantoin
Comes in capsules or oral suspension; macrocrystalline and monohydrate
Active against aerobic and facultative gram (+) and gram (-); no activity against Proteus, Serratia and Ps. spp.
MOA: Reduced by bacterial flavoprotein (nitrofuran reductase) to multiple reactive intermediates that attack DNA, proteins and other macromolecules in the cell (similar to metronidazole)
Can interfere with urine tests for glucose, can discolor urine dark yellow or brown, and are antagonistic with quinolone antibiotics in vitro
Tuberculosis
Contagious airborne disease caused by Mycobacterium tuberculosis
Typically affects the lungs but may affect any other organ.
Infects nearly 1/3 of world (1 death every 15 seconds)
Differences between Mtb infection and TB disease
Only 5% of those with Mtb have active TB (they will show symptoms within a few years)
90% will never get TB
Unique problems associated with Mtb infection
Complex out membrane with complex glycolipids.
Slow growing (divides every 15-18h); typical therapy lasts 6-9 months with treatment extended 18-24
Intracellular bacteria that are able to colonize macrophages to avoid destruction; can remain quiescent for decades
Poor patient compliance (solved with DOTS) and widespread resistance
HIV/TB deadly as shit
Tuberculosis resistance
Multidrug Resistance Mtb (resistant to isoniazid and rifampin) –> requires 18-24 months of drug therapy (regiment includes injectable aminoglycoside for 3-4 months and fluoroquinolone + any additional second line agents)
Extensively Drug Resistant Mtb: XDR TB defined as strain resistant to isoniazid and rifampin plus any fluoroquinolone and at least one of the injectable second-line agents –> requires 2 years of drug therapy
Antitubercular Agents
First line drugs
Isoniazid
Isoniazid
Isonicotinic acid hydrazide
Bacteriostatic versus resting cells but bactericidal against dividing organisms
Nearly idea: very selective for mycobacteria, inexpensive, good oral availability and low toxicity
Side effects: hepatotoxicity due to further metabolism of N-acetyl metabolite
Resistance develops quick in monotherapy and cross resistance is rare
Combination formulations of Isoniazid
Isoniazid + Rifampin (Rifamate)
Isoniazid + rifampin + pyrazinamide (Rifater)
Isoniazid MOA
Inhibits mycolic acid biosynthesis; specifically targets the enoyl-acyl carrier protein reductase (InhA) involved in mycolic acid synthesis; NADH is cofactor that INH reacts with
INH must be activated by KatG (a catalase-peroxidase) to inactivate InhA
Rifampin
Derivative of rifamycin; first line treatment for all TB forms; active against rapidly dividing and semi-dormant bacterial populations
Most potent anti-TB agent (MIC as low as 5ng/mL)
Oral or parenteral; given qd or 3/week for 6 months
Activity against most gram (+); can access CNS
Side effects: GI - nausea, anorexia, discoloration of body fluids; strong CYP450 inducer
Rifampin MOA
Inhibits bacterial DNA-dependent RNA polymerase; binds b-subunit
No effect on mammalian enzyme at concentrations under 5 micrograms/mL
Rifabutin
Substitute for rifampin in treatment of all TB forms (reserved for those who are taking medications that react with rifampin)
Primarily used to treat M. avium complex, AKA MAC (or M. intracellulare)
MAC symptoms similar to chronic bronchitis (over 40% of AIDS patients become infected) –> Rifabutin often prescribed as a preventative measure in those with HIV/AIDS
Rifapentine
Cyclopentyl derivative of rifampin
Advantage is less frequent dosing than rifampin (2/week for intensive phase, 1/week after)
Long t1/2
Rifaximin
Indicated for traveler’s diarrhea
Less than 1% of an oral dose absorbed
Use is for noninvasive enteroaggregative E.coli
Ethambutol
Synthetic; bacteriostatic; active only towards actively dividing cells
Good oral availability and well tolerated
Synergism with rifampin (may enhance intracellular access of rifampin)
Helps prevent emergence of rifampin resistance when primary INH resistance may be present
Side effects: decreased visual acuity or red-green color discrimination; effect is dose related; not recommended for children who cannot read eye charts
Ethambutol MOA
Inhibits Mtb cell wall biosynthesis by inhibiting arabinosyltransferase and thus formation of cell wall arabinogalactan; may interfere with transfer of arabinose to cell wall acceptor
Causes accumulation of lipid carrier decaprenyl phosphoarabinose
