tetracyclines/macrolides 68 Flashcards Preview

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Flashcards in tetracyclines/macrolides 68 Deck (40):

tetracyclines (group)
oral absorption

4-ringed structure
oral absorption:
30% chlortetracycline absorbed
60-70%: tetra
95-100% for doxy, mino!

*do not take 1-2 hrs before bed or laying down, take with water, due to risk of esophageal ulceration, don't take w. dairy*



Short acting (T 1⁄2 = 6 - 12 hours approximately)


Doxycycline (generic, Vibramycin, Monodox)

Long-Acting (T 1⁄2 = 16 – 18 hours approximately)
*preferred for serious infections, can be used IV*
-avoids GI upset
*excreted NON-renally, good for renal failure pts*
NOT pumped out by Tet(K) efflux pump in Staph!


Minocycline (generic, Minocin, Arrestin, Dynacin, Myrac)

Long-Acting (T 1⁄2 = 16 – 18 hours approximately)
NOT pumped out by Tet(K) efflux pump in Staph!
-more lipid soluble, used as alt. (to Rifampin) to eliminate meningococcal carrier state


tetracyclines bind to ??

Ca2+ and multivalent cations in antacids, dec. oral abs. of the drugs
*don't admin tetras w. dairy or antacids*
abx tx failure bc these abx often cause GI upset


tissue dist./excretion

widely, cross placenta
exc. via kidney, also bile and elimated in feces
-some drug my be reabsorbed via enterohepatic circulation


tetra pharmko

-enter bac by passive diffusion and active transport
-inhibit protein synthesis by binding *30S ribosomal unit*
-block binding of aa containing aminoacyl-tRNA to acceptor site of ribosome, prevents adding new aa


mechs of tetra resistance

efflux pumps that "spit" drug out of bacteria
-Tet(AE) pump in G- bac
-doxy and mino NOT pumped out by Tet(K) efflux pump in Staph!
-Tet(M) ribosomal protection protein in G+ (prevents drug from binding)

tetra resistant usually marker of MDR
other resistance mechs: enzymatic inactivation, use in animal feed


tetra spectrum

broad spec but lots of resistance:
-G+: resistance to Staph, strep, some pneumococci, *not the drug of choice for many G+ aerobic infections
-G-: pseudomonals, gonorrheae, enterobacter are resistant, active against Brucella, Vibrio spp., CA-E.coli
-anaerobes are resistant (B. fragilis-use metronidazole)
*used for Spirochetes, Rickettsiae, Mycoplasma, Chlamydia


tetra use

Mycoplasma-doxy (erythromycin for preggos, kiddos)
Chlamydia-doxy (can also use macrolides)
Spirochetes-doxy (drug of choice for Lyme)
Periodontitis-doxy tablests, or mino microspheres (inhibit enzyme collagenase)
Acne-(tetra, doxy, mino)
others: UTIs, non-TB mycobac inf.
-alternative for: H. pylori (tetra)
used to be used for bac gastroent, pneumonias, bac UTIs, but *resistance now a big problem*


tetra SEs

-GI upset: reduce by giving food (NOT dairy/Ca2+)
-Superinfections: C. diff, candida
-CONTRAINDICATED during pregnancy and kiddos younger than 8:
*can bind Ca2+, can be deposited in teeth and bone: teeth discoloration, fluorescence, enamel deformities, inhibit bone growth, and cause bone deformities (when used in pregnancy)


tetra tox

-renal damage: outdated tetras can become nephrotoxic and cause renal tubular acidosis and renal damage (throw old pills away!)

-demeclocycline can inhibit actions of ADH in kidney and cause diabetes insipid us like state (peeing too much)

-photosensitivity, sun-burn prone
-impaired liver function in preggos, liver damage pts


Tigecycline (Tygacil)

IV admin, newer, eliminated by non-renal mechs
same MOA as tetras BUT
-not effectively pumped out of bacteria by the Tet(AE) or Tet(K) efflux pumps, which makes it useful in some tetra-resistant bac
-G+ Tet(M) ribosomal protection protein does not effectively block Tigecycline from binding to the 30S ribosomal subunit


Macrolide absorption/metab/excr

-erythromycin base: poor oral absorption, broken down by acid
-clarithromycin and azithromycin have ESTERS in their base: demonstrate improved oral absorption
-erythromycin can be used IV
-IM avoided (painful)
-distr. to most tissues, but *DO NOT ENTER CNS*: not used for meningitis
-crosses placenta

-conc. in liver and exc. in bile
*metab by hep p450 enzymes (p4503A, DYP3A)
5% excredted in urine
*worry about hepatic dysfunction*


macros pharmko

*bacteriostatic, any high conc. may be tidal
*bind to *50S subunit*, prevent movement of pp chain from acceptor site to donor site-->prevents protein synthesis
*close to binding site for chloramphenicol-competition!*


macrolide resistance mechs

*most important mech*:
-modifications of 50S subunit by
mutation or by a macrolide-inducible/constitutive enzyme (Methylase, erm genes) which alters the binding site and *prevents the drug from binding*.
-dec. influx or active efflux
-breakdown by esterases (i.e. Enterobacteriaceae)


erythromycin spectrum

G+: GAS, PCN sus strp, MRSA, Corynebacterium, B. antracis
G-: M. cat, N. gon, Legionella, Campy, B. pertussis, Haemophilus ducreyi
-mycoplasmas, chlamydiae, spirochetes

-many H. flu strains are resistant
-Enterobacteriaceae are resistant (E. coli, Klebsiella, Enterobacter)
-Anaerobes: active against some but B. fragalis is resistant, generally not a good anaerobic agent


macro uses

-*Mycoplasma pneumonia(use macrolide in pregnancy over tetra!)* (test question)
-Legionella-Legionaires' pneumonia
-nonstrep pharyngigtis
-Chlamydial inf (resp, neonatal, ocular, genital) *erythromycin 1st line in pregnancy for UG inf*
-tx/ppx for whooping cough (B. pertussis)
-alternative for pts w. allergies to B-lactam abx (PCN): staph, strep (PCN-resistant S. pneumo are usually also resistant to erythromycin)
-preventing bac endocarditis with dental procedures, and prophylaxis for RF
-Campy gastroenteritis


macro SEs

*GI upset* due to direct stim of GI motility, use therapeutically to inc. gastric emptying


more macro adverse

-*liver toxicity* (esp. estolate form of erythromycin: cholestatic hepatitis)
-allergic rxn: fever, rash, rarely anaphylaxis
-cytP450 inhibitors increase levels of erythromycin-->ventricular arrhythmias, QT prolongation
-erythromycin can inhibit cyt P450 enzymes, increase serum levels of other drugs (theophylline, oral anticoagulants, antihistamines: terfenadine, astemizole pulled)


new macros: clarithromycin and azithromycin

more acid stable, better abs, less GI intolerance, clarith more $$ than erythromycin
-longer 1/2 life: vs. eryth (1.5 hrs) clarithromycin (6 hrs), azith (3 days!)
-azith: slow release from tissue stores, dose for 5 days
-clarithromycin inhibits cyt P450 enzymes, *azithromycin does NOT!*


new macro uses

clarith and azith active against Mycobacterium avium complex infections in AIDS pts
-both better activity against H. flu (azith)
-Azith: highly active against Chlamydia (see notes)
clarith: RTIs, skin inf.


Telithromycin (Ketek)

sim to macros
CAP, activity against methyl's prod. G+ cocci
SE: inhib of cup P4503A4, reserved for serious pneumonias


case 2: 24 yo male naval officer, stationed in Philippines, complains of dysuria and profuse yellow urethral discharge, started sev. days ago

N. gonorrhea

how to tx:
1st line:
+ azithromycin OR + doxycycline

2nd line: Cefixime + azithromycine

tx for confection w. Chlamydia: 2 g oral azithromycin, or doxycycline will cover both!

FQs will cover Chlamydia but not Neisseria


Macrolides: Erythromycins

Erythromycin base (generic, ERY, PCE) Film coated
Erythromycin Estolate
Erythromycin Stearate
Erythromycin Ethylsuccinate
Erythromycin Lactobionate – IV use


Clarithromycin (generic, Biaxin)

used for:
-Pharyngitis/tonsillitis: Strep progenies (PCN is the drug of choice)
-Acute maxillary Sinusitis: due to Strep. Pneumo
-Bronchitis: acute exacerbations of chronic bronchitis caused by S.
pneumo, M. catarrhalis, and H. flu
-CAP: Mycoplasma pneumo and Strep pneumo
-Uncomplicated skin infections: Strep pyogenes and Staph aureus
-Prevention and treatment of Mycobacterium avium complex (MAC)


Azithromycin (Zithromax)

macrolide: longest half-life (3 days)
-penetrates tissues well (not CNS) 10-100x higher conc. than plasma, not used for bacteremia/sepsis
-may use single dose for uncomplicated genital chlamydial inf. (as effective as a 7-day course with doxy!)
-slightly less active against staph and strep than eryth/clarith, but more active against *H. flu*
*does not interfere with cytP450 enzymes*


Telithromycin (Ketek)

macrolide (like macrolide in structure)
-approved in '04 for bac respiratory infections (CAP)
-admin orally(+/- food, 1x/d) metab./elim by liver
-macrolide-resistant bac may be susceptible to telithro
-activity against some methylase (erm genes) producing G+ cocci since it can bind to a part of the 50 S ribosomal subunit that is not inhibited by methylase
-poor substrate for the efflux pump
-inhibitor of CYP3A4 and will increase serum concentrations of other drugs metabolized by CYP3A4 (e.g. Simvastatin, Lovastatin, Atorvastatin)
-limited by potential to cause severe liver toxicity


Chloramphenicol (not emphasized in class)

-nitrobenzene moiety and is a derivative of dichloroacetic acid
-oral administration (active drug and a prodrug (palmitate)), broken down to active in duodenum
-parenteral: Chloramphenicol succinate
-widely distributed, penetrates CSF: useful for meningitis and brain abscesses
-secreted in breast milk, crosses placenta, 50% plasma protein bound


chloramphenicol metabolism/excretion

metab. in liver to the inactive glucorinide conjugate, excreted in urine
*adjust for liver but not kidney failure*
*lower dose for premies and newborns less than 1 week old (decreased liver metabolic function)


Chloramphenicol prevents ??
can also inhibit ??
bacteriostatic or cidal??

Protein Synthesis by reversibly binding to the 50S subunit of the bacterial 70S ribosome
-mitochondrial protein synthesis in mammalian cells: responsible for many of its toxic effects
-mostly bacteriostatic. but appears to be bactericidal for H. flu, N. meningitidis, and S. pneumo


resistance to chloramphenicol caused by ??

bac production of an enzyme acetyltransferase which acetylates chloramphenicol and prevents the drug from binding to the bacterial ribosome (acq. via conjugation)

other mechs: dec. perm of drug, mutations in ribosome that prevent binding


chloramphenicol is limited due to ??

its toxic side effects (e.g. aplastic anemia)
-only used in infections for which the benefits of the drug outweigh the risks of potential toxicities
*not a first line agent and is used for life threatening bacterial meningitis or rickettsial infections*


chloramphenicol spectrum of activity

G+: most, not MRSA
G-: N. meningitidis, H. flu (including Amp-resistant) (NOT pseudomonas)
anaerobes: including B. fragilis
Rickettsiae: RMSF, Q fever, typhus


clinical uses of chloramphenicol

-alternative for meningitis from N. meningitides, H. flu, S. pneumo in pts. w. allergies to PCNs, cephs
-brain abscesses (+ PCN or + metronidazole)
-Rickettsial diseases (Rocky mountain spotted fever, murine typhus, tick bite fever, Q fever)
*usually tetracyclines are preferred, but chloramphenicol can be used in preggos, kiddos


chloramphenicol SEs

bone marrow toxicity
gray baby syndrome
GI: N/V/D w. oral admin


chloramphenicol drug interactions

-phenobarbitol and rifampin (induce liver enzymes-->dec. levels)
-can inhibit microsomal cytochrome P450 enzymes and prolong the half-life of drugs metabolized by this system (e.g. phenytoin, tolbutamide).


chloramphenicol: bone marrow tox

-reversible BM suppression: anemia, leukopenia, thrombocytopenia (dose/time-dep, inc. risk in neonates, liver dis.)
-aplastic anemia: deficient RBC production (rare but fatal, not dose related) (time/incidence-dependent), genetic


chloramphenicol: gray baby syndrome

premies/neonates can't conjugate/excrete due to deficient glucuronyl transferase, also decreased renal excretion
-occures 2-9 days after tx: vomiting, inc. RR, abd. distention, cyanosis-->ashen gray (death in 40%)


Tigecycline spectrum/uses

-MRSA, B-lactamase producing G- s, Acintobacter sp.
-skin/skin structure and intra-abdominal infections