Objectives:

Describe process of protein synthesis (review)

Describe/explain the mechanism of action for the agents discussed
Compare/contrast antibiotic characteristics:
structural
pharmacokinetic
Recognize several of the primary therapeutics indications/uses for the
agents discussed
For the agents discussed, identify and recognize:
Spectrum of antibacterial activity
Route(s) of administration & dosing considerations
ADRs
Mechanisms of resistance
Sulfonamide Agents
Sulfonamide Agents:
Sulfonamides - generic name for para-aminobenzene-sulfonamide (sulfanilamide) derivatives
PABA - precursor to DNA
Purines - Guanine and Adenine (GAPUR)
MOA:
Inhibit folic acid synthesis - inhibits enzyme that synthesizes Guanine and Adenine
Activity with Trimethoprim
aka Anti-folate agents
Sulfonamides Alone:
Spectrum of Activity:
G+ bacteria
S. pyogenes
S. pneumoniae
S. aureus (w/ trimethoprim)
G- bacteria
Enterobacteriaceae (E. coli)
H. influenzae
H. ducreyi
Other
Nocardia
Actinomyces
Chlamydiae (C. trachomatis)
Some protozoa
**typically shouldnt see refills on antimicrobials unless a chronic condition
Resistance:
Enzyme Affinity - bacteria modifies 1 or more enzymes
Permeability and/or active efflux
Metabolic pathways
Selected Agents:
Sulfisoxazole (GANTRISIN)
Combo with EES (erythromycin ethylsuccinate) (PEDIAZOLE)
Sodium sulfacetamide (SULAMYD)
topical - ointment and solution
Silver sulfadiazine (SILVADENE)
Sulfonamide Agents
dec microbial colonization
Sulfamethoxazole-Trimethoprim (SMX-TMP)
BACTRIM / SEPTRA / Co-Trimoxazole
Trimethoprim (TRIMPEX / PROLOPRIM) Spectrum of Activity:
similar coverage to SMX (20-100x more potent)
G+ and G- coverage
Resistance
TMP vs. SMX-TMP
TMP has a faster rate of resistance compared to SMX-TMP
SMX-TMP Spectrum of Activity:
G+ bacteria
Staphylococci (S. aureus / MRSA; S. epidermidis)
Streptococci (S. pyogenes / S. Pneumoniae
Enterobacteriaceae (E. coli; Proteus spp.; Klebsiella; Shigella)
G- bacteria
N. Meningitidis; Pneumocystis carinii
Other
Enterobacter; Yersinia spp.; Nocardia
Resistance:
Usually
Ps. aeruginosa;
B. fragilis
entercocci
Increasing concern
Emergence: single agent vs. combo
Plasmid-mediated - encodes for altered enzyme (dihydropteroate synthetase)
SMX-TMP MOA:
Sequential inhibition of folate metabolism
SMX - dihydropteroate synthetase
TMP - dihydrofolate reductase
Synergistic together
Route(s) of Administration:
Injection
Sulfonamide Agents
Suspension
Tablet (ss)
Tablet (ds)
**ALL have a 5:1 ratio for pharmacokinetic matching
Term -->
Rationale - to achieve the optimal in vivo concentration ratio of 20:1 :: SMX-TMP (best
synergy)
Indications and Uses:
UTIs
Enterobacteriaceae
Chronic and recurrent
RTIs
Otitis media (inner ear infection)
Sinusitis
Acute exacerbations of chronic bronchitis (do not clear mucus very well)
GI
Shigellosis (alternate to FQ)
Typhoid fever (2nd line agent to cefriaxone/FQ)
PCP (Pneumocystis carinii pneumonia)--immunocompromised
AIDS patients
Prophylaxis and treatment
ADRs
Dermatological
PHOTOSENSITIVITY
Rash / exfoliative dermatitis / Stevens-Johnson Syndrome
Hematological (~folate deficiency)
Megaloblastosis (cells get larger) / Leukopenia / Thrombocytopenia
GI - NVD
CNS - HA / dizziness / hallucinations (sulfa-related)
Other hematological (sulfa-related)
Hemolytic anemia (G6PD - glucose 6 phosphate dehydrogenase)
Aplastic anemia
Agranulocytosis
Sulfonamide Agents
Quinolones and Fluoroquinolones
Review - DNA replication
Replication requires strand separation
Consequences of strand separation
over-winding --> + supercoil
if unrelieved --> replication ceases
Topoisomerases
Maintain DNA in appropriate state of supercoiling (degree)
Replicating and non-replicating regions of bacterial chromosome
TOPO I
TOPO II (DNA GYRASE - relieves tension in + supercoil)
TOPO III
TOPO IV
**TOPO II & TOPO IV are the targets for quinolones
Topoisomerase II (DNA GYRASE)
relieves supercoiling
location of action
without DNA gyrase-mediated relaxation, what occurs?
introduces negative supercoiling into DNA
Topoisomerase IV
decatenation of daughter DNA - separates interlinked daughter DNA produced by
replication
MOA:
inhibit TOPO II (DNA gyrase)
inhibit strand cutting function of gyrase -OR-
DNA-DNA gyrase complex is stabilized
replication fork hits complex
replication ceases
correlation --> G- activity
inhibit TOPO IV
inhibits separation of interlinked daughter DNA molecules
replication ceases
correlation --> G+ activity
Nalidixic acid was the first quinolone (1963)
Newer agents are FLUORONATED
hence FQ
structural differences based on changes in position R1, R6, R7, and X
Sulfonamide Agents
BROAD SPECTRUM - G+, G-, and anaerobes
well absorbed - moderate-to-excellent bioavailability
SAR:
R1 - interaction with theophylline
X - influence phototoxicity (major)
CF>CCl>N>CH>COCH3
influence NSAID interactions (major)
R7 -
GABA binding (major)
NSAID interactions (major)
Theophylline interaction (major)
R6 - -F substituent except nalidixic acid
R5 - influence phototoxicity
CH3>>H>NH2
=O and COOH -
metal binding / chelation
Ca2+, Fe2+, Zn++, dec absorption
Fluoroquinolones MOA:
inhibit TOPO II - inhibits replication
inhibit TOPO IV - inhibits decatenation
bactericidal
Resistance:
mutations to genes encoding DNA gyrase (gyrA and gyrB)
A subunits perform strand cutting
mutations to genes encoding TOPO IV (parC and parE)
permeability
efflux mechanisms
inc resisistance noted for Psuedomonas and Staphylcocci
inc resistance noted Salmonella, N. gonnorrhoeae, S. pneumoniae
Agents:
Generic Formulations
noroxacin po
ooxacin po
Sulfonamide Agents
Generic Formulations
ciprooxacin po
parenteral
opthalmic
otic
levooxacin po
parenteral
ophthalmic
moxioxacin po
parenteral
gemioxacin po
besioxacin opthalmic
gatioxacin opthalmic
Spectrum of Activity:
G- bacilli
Enterbacteriaceae - E. coli, Salmonella, Shigella, Enterobacter
Campylbacter; Pseudomonas (Ps. aeruginosa)
G- cocci - Neisseria spp.
G+ cocci
Staphylococci (MSSA) / MRSA - marginal to poor activity (depends on strain)
Streptococci (S. pneumoniae) - respiratory fluoroquinolones - Levofloxacin, Gemifloxacin,
Moxifloxacin (depends on agent and bug)
Intracellular / Atypical
Chlamydia; Mycoplasma; Legionella; Brucella; Mycobacterium
Anerobes
Gemifloxacin / Moxifloxacin
Patterns of Activity:
Group 1
Norfloxacin - poor G- and poor G-
Group 2
Cipro / Oflox / Levoflox (isomers)
excellent G- moderate G+
poor anaerobe coverage
Group 3
Gemiflox / Moxiflox
Good G-
Sulfonamide Agents
Good G+
Excellent anaerobe coverage
good for atypicals
Pharmacokinetics:
Agent Primary Route of
Excretion
Cipro renal
Gemiox renal + nonrenal
Oox renal
Levoox renal
Moxi nonrenal
Nor renal
well absorbed - good-to-excellent bioavailabilty
2x/day - cipro / oflox / nor
1x/day - gemi / levo / moxi (respiratory FQ)
administration with food delays Tpeak / does not dec absorption (most agents)
elimination - varied / dosage adjustment in - interval (time)
renal impairment - moxifloxacin
hepatic impairment - any besides moxi and gemi
ADRs:
fairly well tolerated
GI - NVD
dermatological - rash / photosensitivity / pruritis
CNS
HA / dizziness / drowsiness / confusion / insomnia
delirium / depression / hallucinations / seizures
other
arthropathy / joint swelling / tendon rupture (avoid in children under 18)
rare - leukopenia / eosinophilia / elevated transaminases
pregnancy --> contraindicated
Indications and Uses:
UTIs / Prostatis
GI / abdominal
Sulfonamide Agents
bone / joint / soft tissue
STDs
RTIs - bronchitis, pneumonia, sinusitis
other - multidrug-resistant TB
Mycobacterial infections - and Mycobacterium avium complex (MAC) in AIDS
Drug Interactions:
inhibit theophylline metabolism
inc digoxin concentrations
inc anticoagulant effect of warfarin
dec absorption of FQ due to multi-valent cations - Ca2+ Mg2+ Al3+ Fe2+ Zn2+
antacides
bismuth subsalicylate
nutritional supplements (multi-vitamin/minerals)
also - sulcrafate - binds neg charges of exposed proteins
counseling point - do NOT take with antacids - if you have to take 2 hours before or 4 hours
after - that also goes for cheese and diary
Sulfonamide Agents