Clinafloxacin is an investigational

fluoroquinolone Quinolone antibiotics constitute a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They are used in human and veterinary medicine to treat bacterial infections, as well ...

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

. Despite its promising antibiotic activity, the clinical development of clinafloxacin has been hampered by its risk for inducing serious

side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...

Medical uses

Clinafloxacin has not been approved for any indication. The

investigational new drug The United States Food and Drug Administration's Investigational New Drug (IND) program is the means by which a pharmaceutical industry, pharmaceutical company obtains permission to start human clinical trials and to ship an experimental drug inte ...

application was withdrawn by the manufacturer in 1999, citing safety concerns.

Available forms

Clinafloxacin is available in both oral and intravenous formulations.

Specific populations

There is a warning against using clinafloxacin in pregnant patients, due to possible damage to the developing fetus.

Adverse effects

The use of clinafloxacin is associated with drug-induced light sensitivity (phototoxicity) and

low blood sugar Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

Diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

has also been reported. The phototoxicity with clinafloxacin has been more associated with oral dosing as compared to intravenous dosing, though the studies that described this were subject to

confounding In causal inference, a confounder is a variable that influences both the dependent variable and independent variable, causing a spurious association. Confounding is a causal concept, and as such, cannot be described in terms of correlatio ...

by study site (that is, patients that received intravenous clinafloxacin were less mobile, and thereby received less sunlight exposure). The mechanism for clinafloxacin's phototoxicity involves the

chlorine Chlorine is a chemical element; it has Symbol (chemistry), symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between ...

atom at position 8. In the presence of

ultraviolet light Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of th ...

, the chemical structure of clinafloxacin is degraded, resulting in the formation of toxic,

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

that can damage cellular structures—including

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

. For this reason clinafloxacin can also be classified as a

photocarcinogen A photocarcinogen is a substance which causes cancer when an organism is exposed to it, then illuminated. Many chemicals that are not carcinogenic can be photocarcinogenic when combined with exposure to light, especially UV. This can easily be un ...

(a chemical that can cause light-induced cancer), though the risk of developing cancer in humans taking the medication is small. The mechanism for clinafloxacin's effect on blood glucose is thought to involve stimulation of the pancreatic

beta cells Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vit ...

, which produce

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

(a hormone that lowers blood glucose levels). The symptoms of clinafloxacin overdose are unknown.

Interactions

Drug-drug interactions

Clinafloxacin inhibits multiple

CYP450 Cytochromes P450 (P450s or CYPs) are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for example, they have not been found in ''Escherichi ...

drug metabolizing enzymes, especially

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

. Clinafloxacin has induced the accumulation of CYP1A2 substrates, including

theophylline Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other met ...

, at therapeutic doses. This can also affect the metabolism of caffeine, another CYP1A2 substrate. Caffeine consumption must be limited while taking clinafloxacin to prevent caffeine accumulation and overdose. There is also a known interaction of clinafloxacin with

phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence se ...

, resulting in a decrease in the clearance of phenytoin from the body. The increase in INR seen in patients taking both clinafloxacin and the

anticoagulant An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...

warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...

has yet to be fully elucidated.

Food-drug interactions

There are no known food-drug interactions with clinafloxacin.

Pharmacology

Mechanism of action

Clinafloxacin's antibiotic mechanism of action, like other

fluoroquinolones Quinolone antibiotics constitute a large group of broad-spectrum antibiotic, broad-spectrum bacteriocidals that share a bicyclic molecule, bicyclic core structure related to the substance 4-Quinolone, 4-quinolone. They are used in human and ve ...

is derived from its activity against type II topoisomerases

DNA gyrase DNA gyrase, or simply gyrase, is an enzyme within the class of topoisomerase and is a subclass of Type II topoisomerases that reduces topological strain in an ATP dependent manner while double-stranded DNA is being unwound by elongating RNA-po ...

and

topoisomerase IV Topoisomerase IV is one of two Type II topoisomerases in bacteria, the other being DNA gyrase. Like gyrase, topoisomerase IV is able to pass one double-strand of DNA through another double-strand of DNA, thereby changing the linking number of DNA ...

. Clinafloxacin has been described as a

broad-spectrum antibiotic A broad-antimicrobial spectrum, spectrum antibiotic is an antibiotic that acts on the two major bacterial groups, Gram-positive and Gram-negative, or any antibiotic that acts against a wide range of disease-causing bacteria. These medications are ...

due to its activity against

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain is ...

and

Gram-negative bacteria Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the Crystal violet, crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelo ...

. In addition, clinafloxacin has antibiotic activity against

anaerobic bacteria An anaerobic organism or anaerobe is any organism that does not require molecular oxygen for growth. It may react negatively or even die if free oxygen is present. In contrast, an aerobic organism (aerobe) is an organism that requires an oxygenat ...

, including the

facultative anaerobe A facultative anaerobic organism is an organism that makes ATP by aerobic respiration if oxygen is present, but is capable of switching to fermentation if oxygen is absent. Some examples of facultatively anaerobic bacteria are ''Staphylococcus' ...

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common Bacterial capsule, encapsulated, Gram-negative bacteria, Gram-negative, Aerobic organism, aerobic–facultative anaerobe, facultatively anaerobic, Bacillus (shape), rod-shaped bacteria, bacterium that can c ...

''. Clinafloxacin's activity against anaerobic bacteria is higher than that of most other fluoroquinolones, including

ciprofloxacin Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra-abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin ...

levofloxacin Levofloxacin, sold under the brand name Levaquin among others, is a broad-spectrum antibiotic of the fluoroquinolone drug class. It is the left-handed isomer of the medication ofloxacin. It is used to treat a number of bacterial infections ...

, and

moxifloxacin Moxifloxacin is an antibiotic, used to treat bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It can be given by mouth, by injection into a vein, and as an eye drop. Common side effec ...

Pharmacokinetics

The time that it takes for

serum Serum may refer to: Biology and pharmacology *Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity *Serous fluid, any clear bodily fluid Places *Serum, Ind ...

concentrations of clinafloxacin to reach the maximum concentration (

Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose. It is a standard measurement in pharma ...

) in healthy volunteers after taking a dose by mouth is 0.7 hours. The elimination half-life in humans is 6.1 hours.

Steady state In systems theory, a system or a process is in a steady state if the variables (called state variables) which define the behavior of the system or the process are unchanging in time. In continuous time, this means that for those properties ''p' ...

levels of clinafloxacin are achieved in 3 days of twice daily dosing by mouth in healthy volunteers. About half of an administered clinafloxacin dose is found unchanged in the urine, meaning that the drug is cleared from the blood stream roughly equally by

hepatic metabolism The liver is a major metabolic organ exclusively found in vertebrates, which performs many essential biological functions such as detoxification of the organism, and the synthesis of various proteins and various other biochemicals necessary for ...

(liver-induced degradation) and renal elimination (kidney-mediated removal).

Chemistry

Clinafloxacin is a

, structurally related to other fluoroquinolones like

. It is soluble in methanol (about 2 mg/mL at 25 °C) and water.

History

In the 1990s, clinafloxacin showed promise as a novel, broad-spectrum fluoroquinolone antibiotic. However, further clinical trials raised serious concerns regarding its safety in humans, citing dangerously low blood sugar, drug-induced light sensitivity, and multiple drug-drug interactions.

Research

Clinical trials have been done to assess its efficacy in

sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...

and other serious and potentially life-threatening infections.

References

{{QuinoloneAntiBiotics Fluoroquinolone antibiotics Chloroarenes Pyrrolidines Cyclopropyl compounds Experimental drugs