Ciprofloxacin

Introduction: A quinolone (Ciprofloxacin) anti-microbial is broad-spectrum bactericides. It shares a bicyclic core structure identified with the compound 4-quinolone. They are utilized to treat bacterial diseases, and in animal husbandry.

Figure: Ciprofloxacin

Mechanism of action of ciprofloxacin:
DNA synthesis is interfered by inhibing DNA gyrase ( topoisomerase II ) and topoisomerase IV.
Two sets of subunits, 2GyrA and 2GyrB that are encrypted by genes gyrA and gyrB severally consists DNA gyrase enzyme. DNA rupturing and association are processed by genes gyrA. Unique negative supercoiling continuation of DNA gyrase is processed by C-terminus of GyrA subunit and any mutation that cause absence of C-terminus of GyrA subunit unable to form negative supercoils. Targeting DNA gyrase is so effective as it is absent in eukaryotic cells and is fundamental for bacterial proliferation. In addition to, two sets of subunits, 2ParC and 2parE that are enciphered by genes parC and parE respectively comprise topoisomerase IV. It denotes two vital roles. Firstly it acts as decatenating enzyme and terminates interconnected daughter chromosomes to separate chromosomes into daughter cells after DNA replication. Thus cell division can be done. Secondly, topoisomerase IV loosens up positive supercoil with the help of DNA gyrase. The important physiologic fuction of both DNA gyrase ( topoisomerase II ) and topoisomerase IV, is the replication and transcription of DNA and decantation of daughter cells by topoisomerase IV following DNA replication. It is evident that topoisomerase II acts before the replication fork while topoisomerase IV functions after the replication fork on freshly made DNA.
Ciprofoxacin interferes functions of both of the enzymes in bacteria.(Aldred, Kerns and Osheroff, 2014)(Fàbrega et al., 2008)

Figure: Mechanism of action of ciprofloxacin

Mechanisms of resistance:
1) Target enzyme resistance mechanism:
Amino acid substitutions occur in a region of the GyrA or ParC subunit. These mutations in gyrase and topoisomerase-DNA IV are called “quinolone-resistance-determining region“ (QRDR). This region exists on the DNA-binding surface of the enzyme. These substitutions reduce vulnerability by declining drug affinity and also weaken or damage target enzyme function.

2) Plasmid-mediated resistance:
a) Qnr gene generates a 219 amino acid protein that reduce
topoisomerase-DNA binding and defend enzyme-DNA complexes from ciprofloxacin.
b) Another resistance mechanism is that aac (6`)-lb cr aminoglycoside
acetyltransferase acetylates free nitrogen on C7 ring of ciprofloxacin. Thus, potency of
drug is decreased.
c) The concentrations of ciprofloxacin in the cell are reduced by
plasmid encoded efflux pumps. Thus resistance to ciprofloxacin has been obtained.

3) Chromosome mediated resistance:
a) If porins in gram-negative species are abnormally underexpressed,
drug uptake is decreased.
b) If chromosome encoded efflux pumps are overexpressed, drug retention in the bacterial cells are decreased. Thus, resistance to ciprofloxacin can grow.(Aldred, Kerns and Osheroff, 2014)(Fàbrega et al., 2008)

Figure: Mechanisms of resistance

Adverse reactions:
1.Gastrointestinal: Nausea, diarrhea and vomiting occur usually in 3-6% of patients. Most common adverse effects of fluoroquinolones includes these three.
2.Central nervous system problems: The most remarkable CNS effects of fluoroquinolones includes headache and light-headache or dizziness. Cautions should be taken during the treatment of CNS disorders.
3.Phototoxicity: Excessive sunlight should be avoided by the patients who are taking fluoroquinolones. When first sign of phototoxicity arises, drug should be discontinued.
4.In some of the cases fluoroquinolones should be avoided. Cases are: Nursing mother, pregnancy, below 18 years children because they are very much prone to occur articular cartilage erosion.
Pharmacokinetics:
Absorption : After oral administration, rapid and well absorption occurs in the gastrointestinal tract. Loss of drug through 1st pass metabolism does not occurs and bioavailability of the drug is approximately 70%.
Volume of distribution :Not Available
Protein binding :20-40%
Metabolism : Hepatic. In human urine, four metabolites have been identified. 15% of an oral dose is accounted by these four metabolites. Unchanged ciprofloxacin shows greater activity than these metabolites still having antimicrobial activities.
Route of elimination : In the urine, approximately 40-50% of orally administered dose is excreted as unchanged drug.
Half life :4 hours
Clearance :Renal cl=300 mL/min
Toxicity: Gastrointestinal irritation is the major adverse effect, though it is common for many antibiotics.
Affected organisms : Enteric bacteria and other eubacteria(Karkare et al., 2013)(Long et al., 2008)(Ohta et al., 2009)(Preissner et al., 2010)(Tanihara et al., 2007)(Surivet et al., 2013)(Ohta et al., 2009)

Pharmacodynamics:

Ciprofloxacin is an expansive range against infective agent of the fluoroquinolone class. Ciprofloxacin has in vitro activity against an extensive variety of gram-negative and gram-positive microorganisms. Organisms resistant to beta-lactams, macrolides, tetracyclines or aminoglycosides might be susceptible to ciprofloxacin. Ciprofloxacin convey both concentration dependent (peak: MIC), and a combination of concentration and time-dependaet killing (AUC:MIC). (Karkare et al., 2013)(Long et al., 2008)(Ohta et al., 2009)(Preissner et al., 2010)(Tanihara et al., 2007)(Surivet et al., 2013)(Ohta et al., 2009)(Class et al., no date)

Drug interactions :
-Anticoagulants: Warfarin (prolonged warfarin half-life)
-Divalent cations: aluminum, magnesium zinc, iron, calcium, antacids, sucralfate – lessened
bioavailability of ciprofloxacin (potential to cause failure of therapeutic)
-Theophylline, caffeine, xanthines: clearance of these are hindered with ciprofloxacin.(Class et al., no date)
Cautions and Contra-indications:
It must be prevented the excessive alkalinity of urine, it is required to take enough fluid to prevent crystalluria, Impaired performance of skilled tasks like driving may be occurred (effects increased by alcohol).(‘Bangladesh National Formulary (BDNF)’, 2015)

Common side effects:
1. Common side effects of ciprofloxacin are diarrhea, nausea and vomiting.
2. Headache, drowsiness and dizziness can also occur.
3. Sometimes ciprofloxacin can cause stomach upset and abdominal pain.
4. Nervousness, anxiety and agitation may be occurred.
5. Sleep problems and rash are also common side effects of ciprofloxacin.(Common Side Effects of Cipro (Ciprofloxacin) Drug Center – RxList, no date)

Indications:

1. The treatment of urinary tract infection (UTI), including acute uncomplicated cystitis and pyelonephritis .
2. For the treatment of lower respiratory tract infections. Such as, bronchitis, community-acquired pneumonia (CAP), and nosocomial pneumonia.
3. Acute exacerbations of chronic bronchitis can be treated.
4. Can be used to treat skin and skin structure infections, including diabetic foot ulcer, surgical incision site infections, animal bite wounds, and necrotizing infections.
5. Enteric infections, including acute gastroenteritis and infectious diarrhea can also be treated with it.
6. The treatment of uncomplicated gonorrhea (e.g., cervicitis and urethritis) and mild to moderate acute sinusitis
7. For the treatment of prostatitis caused by susceptible organisms. Like bacterial conjunctivitis.
8. It can be used for anthrax prophylaxis after exposure to Bacilus anthracis (postexposure prophylaxis, PEP)(Cipro Oral Suspension and Tablets (ciprofloxacin hydrochloride) dose, indications, adverse effects, interactions… from PDR.net, no date)

Ten Brand Name (Bangladesh)

NEOFLOXIN (Ciprofloxacin 250mg, 500mg & 750mg/tablet) Beximco Pharmaceuticals Ltd.
ORLEV IV (Ciprofloxacin 500mg in 100ml bottle) Orion Infusion Ltd.
QUINOX (Ciprofloxacin 250mg, 500mg & 750mg/tablet) Eskayef Bangladesh Ltd.
ROCIPRO (Ciprofloxacin 500mg & 750mg/tablet) Healthcare Pharmaceuticals Limited
FLONTIN (Ciprofloxacin 250mg/5ml suspension) Renata Ltd.
FLOXABID (Ciprofloxacin 250mg, 500mg & 750mg/tablet) ACI Limited
CIPROZ (Ciprofloxacin 500mg & 750mg/tablet) Ziska Pharmaceuticals Ltd.
CIPROCIN (Ciprofloxacin 250mg, 500mg & 750mg/tablet) Square Pharmaceuticals Ltd.
CIPRO-A (Ciprofloxacin 250mg, 500mg & 750mg/tablet) ACME Laboratories Ltd.
BEUFLOX (Ciprofloxacin 250mg, 500mg & 750mg/tablet) Incepta Pharmaceuticals Ltd.
(Ciprofloxacin – Brand Names – BDdrugs.com – First Online drug index of Bangladesh, no date)

Ten Brand Name (Foreign):

NAME DOSAGE STRENGTH ROUTE LABELLER
Act Ciprofloxacin Tablet 750 mg Oral Teva (Canada)
Ciloxan Ointment 0.3 % Ophthalmic Novartis(Canada)
Cipro Kit 5 g/100mL Bayer HealthCare Pharmaceuticals Inc.(USA)
Cipro IV 10mg/ml Liquid 10 mg Intravenous Miles Inc. Pharmaceutical Division (Canada)
Ciprofloxacin Solution / drops 3 mg/1mL Topical Directrx (USA)
Ciprofloxacin Intravenous Infusion BP Solution 2 mg Intravenous Sandoz Canada Incorporated
Ciprofloxacin Tablets USP – 100 mg Tablet 100 mg Oral Dr Reddy’s Laboratories
(Canada)
Otiprio Suspension 6 mg/6mg Intratympanic Alliance Medical Products Inc. (dba Siegfried Irvine) (USA)
Proquin XR Tablet, film coated, extended release 500 mg/1 Oral Depomed (USA)
Sandoz Ciprofloxacin Tablet 250 mg Oral Sandoz Canada Incorporated
(Karkare et al., 2013)(Long et al., 2008)(Ohta et al., 2009)(Preissner et al., 2010)(Tanihara et al., 2007)(Surivet et al., 2013)(Ohta et al., 2009)

Reference:

Aldred, K. J., Kerns, R. J. and Osheroff, N. (2014) ‘Mechanism of Quinolone Action and Resistance’. doi: 10.1021/bi5000564.
‘Bangladesh National Formulary (BDNF)’ (2015). Directorate General of Drug Administration.
Cipro Oral Suspension and Tablets (ciprofloxacin hydrochloride) dose, indications, adverse effects, interactions… from PDR.net (no date). Available at: https://www.pdr.net/drug-summary/Cipro-Oral-Suspension-and-Tablets-ciprofloxacin-hydrochloride-2273 (Accessed: 10 November 2018).
Ciprofloxacin – Brand Names – BDdrugs.com – First Online drug index of Bangladesh (no date). Available at: http://www.bddrugs.com/product5.php?page=1;idn=321;prev1=;prev=;prev2= (Accessed: 10 November 2018).
Class, A. et al. (no date) ‘Ciprofloxacin’.
Common Side Effects of Cipro (Ciprofloxacin) Drug Center – RxList (no date). Available at: https://www.rxlist.com/cipro-side-effects-drug-center.htm (Accessed: 10 November 2018).
Fàbrega, A. et al. (2008) ‘Mechanism of action of and resistance to quinolones’. doi: 10.1111/j.1751-7915.2008.00063.x.
Karkare, S. et al. (2013) ‘The Naphthoquinone Diospyrin Is an Inhibitor of DNA Gyrase with a Novel Mechanism of Action’, Journal of Biological Chemistry, 288(7), pp. 5149–5156. doi: 10.1074/jbc.M112.419069.
Long, F. et al. (2008) ‘Functional Cloning and Characterization of the Multidrug Efflux Pumps NorM from Neisseria gonorrhoeae and YdhE from Escherichia coli’, Antimicrobial Agents and Chemotherapy, 52(9), pp. 3052–3060. doi: 10.1128/AAC.00475-08.
Ohta, K. -y. et al. (2009) ‘Functional Characterization of Multidrug and Toxin Extrusion Protein 1 as a Facilitative Transporter for Fluoroquinolones’, Journal of Pharmacology and Experimental Therapeutics, 328(2), pp. 628–634. doi: 10.1124/jpet.108.142257.
Preissner, S. et al. (2010) ‘SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions’, Nucleic Acids Research, 38(suppl_1), pp. D237–D243. doi: 10.1093/nar/gkp970.
Surivet, J.-P. et al. (2013) ‘Design, Synthesis, and Characterization of Novel Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Potent Anti-Gram-Positive Activity’, Journal of Medicinal Chemistry, 56(18), pp. 7396–7415. doi: 10.1021/jm400963y.
Tanihara, Y. et al. (2007) ‘Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H + -organic cation antiporters’, Biochemical Pharmacology, 74(2), pp. 359–371. doi: 10.1016/j.bcp.2007.04.010.