PHL424 ANTIBACTERIALS Dr. Sarah I bukhari Pharmaceutics microbiology Department College of Pharmacy...

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

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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


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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.



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



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

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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


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


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


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


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.


MECHANISM OF ACTION


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


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


SIDE EFFECTSNausea, Vomiting, epigastric distress,

abdominal cramps

oral thrush

Metallic taste


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.


RIFAMYCINSNatural and semi-derived from filamentous soil

bacteriaComplex macrocyclic antibioticsMembers of the class

Rifabutin RifapentineRifampin = rifampicin (The most common used)


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.



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


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.


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


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)


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

PHL424 ANTIBACTERIALS Dr. Sarah I bukhari Pharmaceutics microbiology Department College of Pharmacy...

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