phl424 antibacterials dr. sarah i bukhari pharmaceutics microbiology department college of pharmacy...
Post on 17-Jan-2016
216 Views
Preview:
TRANSCRIPT
PHL424ANTIBACTERIALSDr. Sarah I bukhari
Pharmaceutics microbiology DepartmentCollege of PharmacyKing Saud University
PHL424 DNA inhibitors1 04/21/23
ANTIBIOTIC CLASSES
Inhibit cell wall synthesis β-lactams Glycopeptides Bacitracin Fosfomycin cycloseine Inhibit protein biosynthesis Aminoglycosides Macrolides & Lincosamides Oxazolidinones &
Streptogramins Tetracyclines &
Chloramphenicol
Act on cell membrane
Polymyxins Lipopeptides
(Daptomycin)
Inhibit DNA synthesis Sulfonamides Trimethoprim Quinolones Metronidazole and
Nitrofurantoin Rifamycins
04/21/23PHL424 DNA inhibitors2
04/21/23PHL4243
A-QuinolonesMECHANISM OF
ACTION• Quinolone Target: 2 essential bacterial enzymes
1. DNA gyrase (The main target in Gram negative bacteria)2. Topoisomerases IV (The main target in Gram +ve bacteria)• DNA gyrase is responsible for supercoiling of DNA• Composed of 2 GyrA & GyrB subunits, encoded by gyrA &
gyrB.• Quinolones interfere with DNA gyrase and prevent
conversion of relaxed DNA to super-coiled DNA.• Topoisomerase IV decatenates or removes the
interlinking of daughter chromosomes.• Composed of 2 subunits, ParC & ParE encoded by parC &
parE• Quinolones interfere with topoisomerse II & prevent
decatenation of DNA
04/21/23PHL424 DNA inhibitors4
04/21/23PHL4245
MECHANISM OF RESISTANCE
1. Chromosomal mediatedA. Alterations in the targets of quinolones• Single step mutation in DNA gyrase & topoisomerase IV• High level of resistance was resulted due to Mutation
in QRDR of DNA gyrase and topoisomerase II
B. Decreased accumulations of drug inside bacteria
i. Impermeability of the membrane and/orii.Decrease in level of expression of OmpF in E. coliiii.An over-expression of efflux systems.
04/21/23PHL424 DNA inhibitors6
MECHANISM OF RESISTANCE
2. Plasmid mediated quinolone resistance (PMQR)
responsible for low level of resistance.PMQR detected only in EnterobacteriacaeThree known PMQR mechanisms to date:
A. Qnr determinants (qnrA, qnrB, qnrS, qnrD, qnrC)Protect DNA gyrase & topoisomerase IV from
quinolone inhibition.(inhibit DNA binding)B. Aminoglycoside acetyltransferase (AAC(6)-Ib-cr).
AAC(6)-Ib-cr is a variant of AAC(6)-Ib and is responsible for reduced susceptibility to ciprofloxacin or norfloxacin by N-acetylation of a piperazinylamine
C. QepA (quinolone efflux pump)04/21/23PHL424 DNA inhibitors7
Correlation between MIC and QRDR mutations
Single mutation in gyrA results in high-level resistance to nalidixic acid & reduce susceptibility to Fluoroquinolones
To obtain high levels of resistance to fluoroquinolones, the presence of additional mutation(s) in gyrA and/or in another target such as parC is required
MIC of nalidixic acid could be used as a generic marker of resistance for the quinolone in Gram-negative bacteria
The most frequent mutation observed in quinolone-resistant E. coli is at codon 83 followed by 87 of gyrA
In the parC gene of E. coli the most common substitutions occur at codons 80 and 84
04/21/23PHL424 DNA inhibitors8
04/21/23PHL424 DNA inhibitors9
Pipemidic acid
Classification of quinolones1st generations (Narrow spectrum)
Nalidixic acid, oxolinic acid and pipemidic acidNalidixic acid was introduced in 1962.Active against aerobic G -ve
(Enterobacteriaceae).Pipemidic acid has extra activity against Ps.
aeruginosaDisadvantagesNo activity against G +ve or anaerobic bacteria.Limited spectrum and poor tissue penetrationTheir use is restricted to treatment of UTIToxicity especially to CNS and GITRapid emergence of resistance
04/21/23PHL42410
CLASSIFICATION2. 2nd generation (Broad spectrum) Quinolones were a little-used drug class until the
early 1980s when introduced 2nd generationfluorination at 6-position Fluoroquinolones (FQ)ring substituent (piperazine, methylpiperazine) at
C7FQ modification of other side chains led to:
Improved activity against Gram negative (Enterobacteriaceae, Peudomonas, Acinetobacter, Haemophilis, Moraxella & Neisseria)
Enhanced anti-Gram-positive activity Improved potency against pneumococcus Improved PK & longer serum half-lives
Lack activity against anaerobic bacteria04/21/23PHL424 DNA inhibitors11
CLASSIFICATION2. 2nd generation (Broad spectrum) Nor-, Cipro-, Ofloxacin, Pefloxacin, Lomefloxacin NOR is the first 2nd generation
confined for treatment of UTI and STD because of low serum levels and poor tissue penetration
CIPRO is the most common 2nd generation CIPRO is the most potent quinolones against Gram-
ve. CIPRO is alternative to parenterally antibiotics for
the treatment of osteomyelitis caused by susceptible organisms due to its good penetration into bone
Of the 2nd generation, Ofloxacin has the greatest activity against Chlamydia trachomatis
treatment of complicated UTI, pyelonephritis, STD, selected pneumonias and skin infections
04/21/23PHL424 DNA inhibitors12
CLASSIFICATION3. 3rd generation (Expanded spectrum)
Levo-, Gatifloxacin, Sparfloxacin, Grepafloxacin. In 1990s, 3rd generation was introduced.expanded activity against gram-positive organisms,
particularly S. pneumoniaehas activity against mycoplasma, Chlamydia,
legionellahas good activity against anaerobic bacteria. less active than ciprofloxacin against Pseudomonas
4th generation (Extended spectrum)Trovafloxacin, Moxifloxacin, Gemifloxacin. In 2000s, 4th generation was introduced.Has potent activity against anaerobes and
increased activity against pneumococci
04/21/23PHL424 DNA inhibitors13
PHARMACOKINETICS
taken orally: well absorbed from GIT-bioavailability of≥ 50%
Some FQ’s are available parenterally/ophthalmicNewer FQ’s have longer serum half-lives than
ciprofloxacin allowing for once daily dosingCIPRO: 500 – 750 mg q 8-12hLEVO:500-750 mg q24hMOXI: 400mg q24h
achieve high intracellular concentrations (e.g. PMNs)widely distributed in body tissues (except CNS).Elimination: most are eliminated by the kidneys
(unchanged & as metabolites), although some are eliminated by the liver
04/21/23PHL424 DNA inhibitors14
Approved clinical uses for selected fluoroquinolones.
Vincent T. Andriole Clin Infect Dis. 2005;41:S113-S119
CLINICAL USEEmpiric therapy of CAP (community-acquired
pneumonia)Oral therapy of un-/complicated UTI or RTIOral therapy of serious infections such as
osteomyelitis, pneumonia or soft tissue infectionsTreatment of STD: gonorrhea, chancroid,
chlamydial urethritisEmpiric therapy of travelers diarrheaTreatment of typhoidTherapy for multidrug-resistant tuberculosis
04/21/23PHL424 DNA inhibitors16
SIDE EFFECTS• Generally very safe antibiotics which do not cause
serious or life-threatening adverse reactions• The most frequent side-effects are:• GIT(nausea, dyspepsia, vomiting) • CNS reactions such as dizziness, insomnia,
headache• Should not be used in children and in pregnancy
• Drug interactions: • ↓ absorption: Al3+, Mg2+ and Ca2+ antacids• CYP450 inhibition potential drug interactions for
ciprofloxacin• (Ex) can increase warfarin exposure (real
changes in INR are rare, but monitor)04/21/23PHL424 DNA inhibitors17
B. Nitroimidazoles and nitrofurans
METRONidazole (Prodrug): 5-nitroimidazole derivative Specifically active against anaerobic organisms.Effective against protozoa: E. histolytica, Giardia lamblia.Mechanism of ActionAntimicrobial action is due to unstable metabolites produced
by reduction inside anerobic bacteria after uptakeNitro gp converted to nitrite radical by low redox potential.Metabolites covalently bind to DNA, disturb its helical
structure, fragmentation of microbial chromosomeFinally inhibit nucleic acid biosynthesis bacterial deathResistance to metronidazole does not occur.
04/21/23PHL424 DNA inhibitors18
MECHANISM OF ACTION
04/21/23PHL424 DNA inhibitors19
PHARMACOKINETICSWell absorbed orallyT max is 1- 2 h, and C max is 25 mg/mL. Oral bioavailability is not affected by food, but peak
serum levels will be delayed to 2 h. Metronidazole appears in CSF, saliva, and breast milk
in concentrations similar to those found in plasma. Less than 20% is protein bound.
Elimination is via urine (60% to 80%) & feces (6%-5%)
half-life is 8 h and the hydroxy-metabolite half-life is 15 h
Decreased renal function does not alter single-dose pharmacokinetics of metronidazole
Hepatic Function Impairment: PO/IV Use lower doses cautiously and close monitoring of plasma metronidazole levels and toxicity is recommended
04/21/23PHL424 DNA inhibitors20
DOSAGE AND ADMINISTRATION
Anaerobic Bacterial InfectionsGive IV initially when treating most serious anaerobic
infections.IV infusion: 15 mg/kg over 1 h (1 g for 70 kg adult);
then a maintenance dose of 7.5 mg/kg over 1 h every 6 h (500 mg for 70 kg adult). Do not exceed 4 g in 24 h.
For prophylaxis, loading dose is to be completed 1 h before surgery, followed by maintenance dose 6 & 12 h later.
Flagyl 750 ER, 500, 375 , 250 mg tablets; Injection, solution 5 mg/mL
7.5 mg/kg (500 mg for 70 kg adult) every 6 h (max, 4 g/24 h) for 7-10 days.
Children dose: PO 5 mg/kg/dose 3 times daily for 7 days
04/21/23PHL424 DNA inhibitors21
SIDE EFFECTSNausea, Vomiting, epigastric distress,
abdominal cramps
oral thrush
Metallic taste
04/21/23PHL424 DNA inhibitors22
B. Nitroimidazoles and nitrofurans
NITROFURANTOIN is used in the treatment of
UTI.
Antibacterial levels are not reached in the blood
and the drug is concentrated in the urine.
NITROFURAZONE is used mainly as a topical
agent in the treatment of burns and wounds
and also in certain types of ear infections.
04/21/23PHL424 DNA inhibitors23
RIFAMYCINSNatural and semi-derived from filamentous soil
bacteriaComplex macrocyclic antibioticsMembers of the class
Rifabutin RifapentineRifampin = rifampicin (The most common used)
04/21/23PHL424 DNA inhibitors24
C. RIFAMPIN (RIFAMYCIN)
Bactericidal broad spectrum antibiotic.Bactericidal (aerobic & anaerobic Gram+ve cocci)Bacteriostatic (enterococci)
Very effective in treatment of tuberculosis.Penetrates well into CSF Treatment of tuberculous meningitis
Active against N. gonnorhea, N. meningitis, H. Influenzae.It is frequently used in prophylaxis of meningitis
Active against Enterobacteriaceae.Inhibits Brucella sp. and Coxeilla burnetti
intracellularly. 04/21/23PHL424 DNA inhibitors25
MECHANISM OF ACTION
Inhibits DNA-dependant RNA polymerase. Forms a stable complex with DNA dependant
RNA polymerase. Binds to -subunit of the core enzyme of RNA
polymerase & blocks the action of the enzyme at initiation stage of transcription.
Prevents the initiation stage of transcription. Doesn’t inhibit transcription once it has been
initiated. Does not affect mammalian RNA synthesis.
04/21/23PHL424 DNA inhibitors26
MECHANISM OF RESISTANCE
Resistance to rifampicin develops quickly.
Rifampin-Resistant isolates posses an altered
DNA-dependant RNA polymerase, which
arises easily by single step mutations during
therapy.
missense mutations in the rpoB gene
04/21/23PHL424 DNA inhibitors27
PHARMACOKINETIC
Rapid & complete absorption after oral administration. Absorption is improved when taken on an empty stomach Wide distributed into most body tissues & fluids including CSFIt concentrates intracellularly up to five times that of
extracellular concentrations, primarily in PMN. The protein binding of rifampin is approximately 80 %.Rifampin undergoes extensive hepatic metabolism to less
active metabolites, with a half-life of 3 hours. Renal elimination of unchanged drug is minimal (<30 %);
thus, no dose adjustments are required in renal insufficiency.
Caution should be used when rifampin is administered to patients with significant hepatic disease, especially when used in combination with other hepatotoxins, such as isoniazid.
04/21/23PHL424 DNA inhibitors28
DOSING AND ADMINISTRATION
For treatment of TB is 10 mg/kg (maximum 600 mg daily) given daily or either twice or three times weekly by DOT.
IV doses are similar to those administered orally. Oral doses should be administered 1 h before or
2h after meals.The therapeutic range for rifampin against M.
tuberculosis is a two-hour post-dose concentration of 8 to 24 microgram/mL
No dose adjustments are needed for renal dysfunction or dialysis
04/21/23PHL424 DNA inhibitors29
ADVERSE EFFECTS
Gastrointestinal effects (nausea, vomiting, diarrhea),CNS effects (headache, fever)Dermatologic effects (rash, itching, flushing)Hematologic effects (thrombocytopenia,
neutropenia, and acute hemolytic anemia)Hepatitis is infrequently associated with rifampinPatients should be advised that rifampin typically
causes an orange or red-orange discoloration of body fluids (including urine, sweat, saliva, and tears)
04/21/23PHL424 DNA inhibitors30
DRUG INTERACTIONS
Decreases half life of many drugs by inducing
CYPs cytochrome P450 isoenzyme CYP3A4
Potentially decreasing serum concentrations of co-
administered drugs.
oralcontraceptives,corticosteroids, cyclosporine, w
arfarin, phenytoin, theophylline, azole antifungals,
oral hypoglycemics, verapamil, beta-blockers &
HIV protease inhibitors as well as the
nonnucleoside reverse-transcriptase inhibitors is
not recommended. 04/21/23PHL424 DNA inhibitors31
top related