Management Of Community Acquired Infections

MANAGEMENT OF COMMUNITY ACQUIRED INFECTIONS The Importance of Quinolones

History and Development  Nalidixic

Acid was the first Quinolone antibiotic synthesized in 1962  It has activity against most Gram -ve bacteria (except Pseudomonas spp.)  And no activity against Gram +ve bacteria  Use was limited to urinary tract infections as therapeutic concentrations are high, especially for Proteus spp.

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History and Devlpmt.  In

the 1980’s the structure of Nalidixic acid was modified by addition of fluorine atom and a piperazine ring to form 6-fluoroquinolone structure  This conferred improved activity against Gram +ve organisms and an extended Gram -ve spectrum  These are second generation fluoroquinolones  Further basic quinolone structure modification has produced third generation quinolones.

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Mechanism of Action  Act

by inhibition of bacteria DNA synthesis  During bacteria cell multiplication, the chromosomal DNA must uncoil to allow replication  During uncoiling, there are points of localized strain along individual strands  These torsional stresses are relieved by 2 enzymes- DNA gyrase and Topoisomerase 4  Topoisomerase 4 maintains the structural integrity of the DNA strands  Quinolones inhibit this enzyme and the bacteria DNA degrades. Quinolones- Crystal Foods and Drugs

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Mech of Action  When

bacterial duplication is complete, the long double strand of DNA must be recoiled accurately in order to assume the normal resting state  Positive supercoiling is balanced by negative supercoiling so that there is no strain on the DNA molecule  +ve & -ve supercoiling are controlled by different sets of enzymes  Quinolones inhibit the enzyme DNA gyrase responsible for negative supercoiling  The DNA thereby undergoes only positive supercoiling and irreparable damages occur along the strands  The bacteria are unable to function with damaged DNA and the bacteria cells die. Quinolones- Crystal Foods and Drugs

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Spectrum of Activity First Generation  Nalidixic acid, inhibits gram negative bacteria including proteus spp.  Inactive against G+ve bacteria and Gram-ve Psudomonas spp. Second Generation  Ciprofloxacin  Ofloxacin  Pefloxacin  Norfloxacin Quinolones- Crystal Foods and Drugs

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Spectrum of Activity Third Generation  Sparfloxacin  Levofloxacin These inhibit both Gram +ve and Gram -ve bacteria especially; – Salmonella - Shigella - Helicobacter - Neisseria - Psudomonas Quinolones- Crystal Foods and Drugs

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Spectrum of Activty Third generation quinolones retain the activity of First and Second generations against G-ve and have extended activity against G+ve, anaerobes and atypical pathogens e.g. Chlamydia, Mycoplasma, and Legionella spp.  They are active against S. pneumonia and other respiratory pathogens. 

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Quinolones Use in Clinical Practice

First Generation  Used for uncomplicated UTI’s only Second Generation  Widely used in UTIs, RTIs, SSTIs, etc  Only Norfloxacin is used in UTI only Third Generation  Used in treating different types of infections  Particularly useful in both upper and lower RTIs, UTIs and some Skin and Soft Tissue Infections Quinolones- Crystal Foods and Drugs

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Prescribers’ Perspective on the Quinolones Doctors who use quinolones regularly find them  Reliable  Highly effective (if prescribed for the right indication and patient)  Fast acting  Convenient to dose (once or twice daily)  Safe in elderly except in hepatic and renal impairment  Useful in urinary tract infections  Restricted use especially in young adults. Quinolones- Crystal Foods and Drugs

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Development of Resistance  Development

of resistance to the quinolones is extremely rare and has not been reported

 Plasmid

mediated resistance can be found with βlactam antibiotics and tetracycline

 Fluoroquinolones

are neither chemically nor structurally related to other bactericidal agents, thus cross resistance cannot occur.

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KRISTAB  KRISTAB

is the brand of CIPROFLOXACIN marketed by Crystal Foods and Drugs Ltd.

 Acts

by inhibiting the enzyme DNA gyrase which is responsible for negative supercoiling of the DNA strands

 KRISTAB

exhibits a high selectivity/specificity for the bacteria gyrase, leaving the mammalian enzyme un-inhibited.

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Pharmacokinetics of KRISTAB  KRISTAB

is adm orally and parenterally  Has good tissue penetration and excellent Gve cover.  Peak plasma concentration is achieved within 2hrs  Bioavailability is 70-85% and is not altered in patients with renal insufficiency  Elimination half life is 4-5hrs  Protein binding is 20-30%  Absorption is not affected by food  Mainly eliminated unchanged via the kidneys Quinolones- Crystal Foods and Drugs

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Indications KRISTAB is mainly used in;  Upper and Lower Respiratory tract infection (URTI/LRTI)  Kidney & Urinary tract infections  Gonorrhoea  Skin and Soft tissue infections  Bacteria infection of the GIT (including Typhoid fever)  Septicemia  Bones and Joint infections Quinolones- Crystal Foods and Drugs

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Dosage and Administration Most infections:  Adults – 500mg to be taken twice daily for 5days. PRESENTATION  KRISTAB is available in blister packs as 500mg x 10 tablet and 200mg/100ml infusion. Quinolones- Crystal Foods and Drugs

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Contraindications and Restrictions

 Hypersensitivity

to the Quinolones  Children and adolescents in the growth phase.  Pregnant women and breast feeding mothers  Ciprofloxacin interacts with antacids, hence defered administration may be necessary  Concomitant administration with theophyline. Quinolones- Crystal Foods and Drugs

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OFLOMORE  OFLOMORE

is a brand of OFLOXACIN marketed by CF&D.  It is a fluoroquinolone containing a fluorine atom at the 4-quinolone ring and a piperazinyl group at position 7 of the ring  This piperazinyl grp is methylated and contributes to greater bioavailability of OFLOMORE Quinolones- Crystal Foods and Drugs

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Pharmacokinetics of OFLOMORE

 OFLOMORE

is rapidly and almost completely absorbed from the GIT  Widely distributed into the following body tissues/fluids after oral administration - bones & cartilages, skin, sputum, aqueous humor, tears, tonsils - gynecological tissues, prostatic tissue and fluid  Elimination half life is 4-8 hrs  Ofloxacin and its metabolites are excreted in the urine. Quinolones- Crystal Foods and Drugs

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Indications  Complicated

and Uncomplicated Urinary tract infection such as cystitis, pyelonephritis, etc  Prostatitis caused by susceptible E. coli & other G – ve bacteria  Lower respiratory tract infections – bronchitis, lung abscesses, pneumonia & acute cases of bronchitis caused by susceptible organisms  Skin & soft tissue infections  Acute PID (combination with metrnidazole)  Salmonella infections (200-400mg bd x 7-14 days)

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Drug Interactions & Side Effects  Interacts

with Antacids, iron and multivitamin preparations  Anti diabetic drugs (monitor blood glucose level) OFLOMORE is generally well tolerated, but the following side effects have been reported;  Diarrhoea, nausea, vomiting  Insomnia, dizziness  Rashes, pruritis, urticaria, vasculitis, photosensitivity rxns. Quinolones- Crystal Foods and Drugs

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Dosage & Administration Depending on the severity of infection and for most infections:  200-400mg every 12hrs for 5-14 days. PRESENTATION  Blister packs containing 200mg Ofloxacin caplets x 10’s

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CRIFLACIN  Second

generation fluoroquinolone  A brand of PEFLOXACIN marketed by CF&D  Administered orally (and parenterally) acts by inhibition of DNA via interaction with DNA-gyrase subunit  Has an oral bioavailability of almost 100%  Major elimination pathway is non-renal  One of its metabolise is a drug (Norfloxacin)

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Pharmacokinetics of CRIFLACIN  Absorption

is rapid (cin 30mins) and total on a 400mg dose  Peak plasma level is reached in 1-3 hrs  Elimination half life is 11-12hrs  Low plasma protein binding of 20-30%  60% of metabolites are active and include; - N-Demethylpefloxacin (Norfloxacin) - Pefloxacin-N-oxide - Oxo- Pefloxacin - Oxo-desmethylpefloxacin  Low MIC for sensitive strains  High level and prolonged plasma and tissue concns Quinolones- Crystal Foods and Drugs

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Excellent Bioavailability J A Chemotherapy 1992

CRIFLACIN CIPROFLOXACIN CSF

50-60%

15-20%

BONE TISSUE

40%

25-40%

AQUEOUS HUMOUR GYNEACOLOGICA L TISSUES

60%

20-30%

95%

62%

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Indications  Sepsis

and Endocarditis,  Cerebrospinal meningitis (CSM)  Infections of the respiratory, renal or urinary tract, gynecological and obstetrical infections  Hepato-billiary infection  Bone and Joint infections  Skin infections Quinolones- Crystal Foods and Drugs

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Dosage and Administration  Usually

400mg twice daily for 5-10 days  An initial dose of 800mg may be given to achieve an effective blood concentration quickly  Dosage adjustment is needed in patients with severe hepatic dysfunction  To be taken with meals to avoid GIT disturbances.

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Side Effects  GIT

include stomach ache, nausea and vomiting  CNS includes sleep disturbances, headache, seizure  SKIN: Allergic syndrome, photosensitivity rxns  BLOOD: Thrombocytopenia might occur  Others include muscle & joint pain, tendinitis. Quinolones- Crystal Foods and Drugs

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Contraindications  Pregnancy

and breast feeding mothers  Children under 15 years  Glucose -6- phosphate dehydrogenase deficiency patients  Hypersensitivity to quinolones  Epileptic patients  Patients with history of tendonitis, tendon damage related to quinolones.

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