Ciprofloxacin is a fluoroquinolone and targets bacterial DNA gyrase and topoisomerase IV. For many gram-positive bacteria topoisomerase IV is the primary target. In contrast, DNA gyrase is the primary quinolone target for many gram-negative bacteria. Ciprofloxacin inhibits gyrase-mediated DNA supercoiling at concentrations that correlate with those required to inhibit bacterial growth (0.1 to 10 μg/ml). Ciprofloxacin is active against Proteus, Escherichia coli, Klebsiella, Salmonella, Shigella, Enterobacter, Campylobacter, Chlamydia, Mycoplasma, Legionella, Brucella, Mycobacterium tuberculosis, Mycobacterium fortuitum, and Mycobacterium kansasii. Ciprofloxacin is rapidly absorbed following oral administration and the mean elimination half-life of ciprofloxacin is 16.6, 6.2, 4.2, and 3.3 hours in newborns, infants, children, and adolescents, respectively. Ciprofloxacin is eliminated mainly by renal route and the renal function increases with infant maturation and child development. Ciprofloxacin has been found efficacy and safe in infants and children but can cause adverse-effects and the major adverse-effect is arthropathy which resolves with therapy. Ciprofloxacin interacts with drugs. Prophylaxis with ciprofloxacin prevents bacterial infections and ciprofloxacin treats bacterial infections in infants and children. Ciprofloxacin penetrates into the cerebrospinal fluid in significant amounts and successfully treats bacterial meningitis in infants and children and ciprofloxacin poorly crosses the human placenta and poorly penetrates into the beast-milk. The aim of this study is to review published data on ciprofloxacin dosing, efficacy and safely, adverse-effects, pharmacokinetics, interaction with drugs, prophylaxis, treatment, penetration into the cerebrospinal fluid, treatment of meningitis in infants and children and ciprofloxacin transfer across the human placental, and migration into the breast-milk.

Ciprofloxacin

The introduction of ciprofloxacin in the clinical use represents a particularly important therapeutic advance. Ciprofloxacin has a broad antimicrobial activity and is effective after oral administration for the treatment of a wide variety of infectious diseases [1].

Mechanism of action of ciprofloxacin

Ciprofloxacin targets bacterial DNA gyrase and topoisomerase IV. For many gram-positive bacteria, topoisomerase IV, which separates interlinked (catenated) daughter DNA molecules that are the product of DNA replication, is the primary target. In contrast, DNA gyrase is the primary quinolone target in many gram-negative microbes. The gyrase introduces negative supercoils into the DNA to combat excessive positive supercoiling that can occur during DNA replication. Ciprofloxacin inhibits gyrase-mediated DNA supercoiling at concentrations that correlate well with those required to inhibit bacterial growth (0.1 to 10 μg/ml). Mutation of the gene that encodes the A subunit of the gyrase can confer resistance to ciprofloxacin. Eukaryotic cells do not contain DNA gyrase. They do contain a conceptually and mechanistically similar type II DNA topoisomerase, but ciprofloxacin inhibits it only at concentrations (100 to 1,000 µg/ml) much higher than those needed to inhibit the bacterial enzyme [1].

Antimicrobial activity of ciprofloxacin

Ciprofloxacin is a potent bactericidal agent against most gram-negative pathogens when first introduced, including Proteus, Escherichia coli, Klebsiella, and various species of Salmonella, Shigella, Enterobacter and Campylobacter. Ciprofloxacin has sufficient activity against Pseudomonas species for use in systemic infections. Fluoroquinolones have good in-vitro activity against staphylococci, but they are less active against methicillin-resistant strains, and there is concern over development of resistance during therapy. Several intracellular bacteria are inhibited by ciprofloxacin at concentrations that can be achieved in plasma; these include species of Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium (including Mycobacterium tuberculosis). Ciprofloxacin has activity against Mycobacterium fortuitum, Mycobacterium kansasii, and Mycobacterium tuberculosis [1].

Absorption, distribution, metabolism and excretion of ciprofloxacin

Ciprofloxacin’s bioavailability is approximately 70%. Typically oral doses are 250 to 750 mg and intravenous doses are 200 to 400 mg twice-daily. The elimination half-life of ciprofloxacin is about 5 hours, and the drug is typically dosed twice-daily, with the exception an extended-release formulation, which can be doses once-daily. Most quinolones, thus ciprofloxacin, are well absorbed after oral administration. Peak serum concentrations of fluoroquinolones are obtained with 1 to 3 hours after oral dose. The distribution volume of quinolones is high, with concentration in urine, kidney, lung, and prostate tissue and stool, bile, and macrophages and neutrophils higher than in serum concentrations. Ciprofloxacin has been detected in breast-milk because of its excellent bioavailability; the potential exists for substantial exposure of nursing infant. Ciprofloxacin is cleared predominantly by the kidney, and dosages must be adjusted in renal failure [1].

Molecular structure of ciprofloxacin (molecular weight = 331.35 grams/mole)

The literature search was performed electronically using PubMed database as search engine. The following key words were used: “ciprofloxacin dosing infants, children”, “ciprofloxacin efficacy, safely infants, children”, “ciprofloxacin adverse-effects infants, children”, “ciprofloxacin pharmacokinetics infants, children”, “ciprofloxacin drug interaction”, “ciprofloxacin prophylaxis infants, children”, “ciprofloxacin treatment infants, children”, “ciprofloxacin CSF”, “ciprofloxacin meningitis infants, children”, “ciprofloxacin placental transfer”, and “ciprofloxacin breast-milk”. In addition, the books: The Pharmacological Basis of Therapeutics [1] and the British National Formulary for Children [2] have been consulted.

Administration schedules of ciprofloxacin to infants and children [2]

Oral or intravenous administration of ciprofloxacin to infants

Oral treatment of infants with severe respiratory-tract infections and gastrointestinal infections

Infants. Give: 15 mg/kg twice-daily.

Intravenous treatment of infants with severe respiratory-tract infections and gastrointestinal infections

Infants. Give: 10 mg/kg twice-daily, to be given over 60 min of infusion.

Oral treatment of complicated urinary-tract infections

Infants. Give: 10 mg/kg twice-daily.

Intravenous treatment of complicated urinary-tract infections

Infants. Give: 6 mg/kg twice-daily to be given over 60 min of infusion.

Oral prevention of secondary case of meningococcal meningitis

Infants. Give: 30 mg/kg (maximum per dose = 125 mg) for 1 dose.

Oral or intravenous administration of ciprofloxacin to children

Oral treatment for Fistulating Crohn’s disease

Children. Give: 5 mg/kg twice-daily.

Oral treatment of severe respiratory-tract infections and gastrointestinal infections

Children. Give: 20 mg twice-daily (maximum per dose = 750 mg).

Oral treatment of pseudomonal lower respiratory-tract infection in cystic fibrosis

Children. Give: 20 mg/kg twice-daily (maximum per dose = 750 mg).

Intravenous treatment of pseudomonal lower respiratory-tract infection in cystic fibrosis

Children. Give: 10 mg/kg thrice-daily (maximum per dose = 450 mg) to be given over 60 min of infusion.

Intravenous treatment of children with severe respiratory-tract infections and gastrointestinal infections

Children. Give: 10 mg/kg thrice-daily (maximum per dose = 750 mg).

Oral treatment of acute exacerbation of bronchiectasis

Children aged 1 to 17 years. Give: 20 mg/kg twice-daily (maximum per dose = 750 mg).

Intravenous treatment of acute exacerbation of bronchiectasis

Children aged 1 to 17 years. Give: 10 mg/kg thrice-daily (maximum per dose = 400 mg) to be given over 60 min of infusion.

Oral treatment for complicated urinary-tract infections

Children. Give: 10 mg/kg twice-daily, the dose should be doubled in severe infection (maximum per dose = 750 mg twice-daily).

Intravenous treatment for complicated urinary-tract infections

Children. Give: 6 mg/kg thrice-daily, increase the dose to 10 mg/kg thrice-daily in severe infection (maximum per dose = 400 mg twice-daily).

Oral treatment of uncomplicated gonorrhoea (when sensitivity is confirmed in combination with azithromycin).

Children aged 13 to 15 years. Give: 500 mg for 1 dose.

Oral treatment of uncomplicated gonorrhoea (genital and pharyngeal infection, when the sensitivity is confirmed).

Children aged 16 to 17 years. Give: 500 mg for 1 dose.

Intravenous treatment of disseminated gonococcal infection (when the sensitivity is confirmed)

Children aged 16 to 17 years. Give: 500 mg twice-daily for 7 days, the treatment may be switched for 24 to 48 hours after symptoms improve to a suitable oral antibacterial.

Oral treatment of anthrax (treatment and post-exposure prophylaxis)

Children. Give: 15 mg/kg twice-daily (maximum per dose = 500 mg).

Intravenous treatment of anthrax (treatment and post-exposure prophylaxis)

Children. Give: 10 mg/kg twice-daily (maximum per dose = 400 mg).

Oral prevention of secondary case of meningococcal meningitis

Children aged 1 month to 4 years. Give: 30 mg/kg (maximum per dose = 125 mg) for 1 dose.

Children aged 5 to 11 years. Give: 250 mg for 1 dose.

Children aged 12 to 17 years. Give: 500 mg for 1 dose.

Oral treatment of acute pyelonephritis or urinary-tract infection (catheter associated)

Children aged 16 to 17 years. Give: 500 mg twice-daily for 7 days.

Intravenous treatment of acute pyelonephritis or urinary-tract infection (catheter associated)

Children aged 16 to 17 years. Give: 400 mg thrice-daily or twice-daily for 7 days.

Efficacy and safely of ciprofloxacin in infants and children

Ciprofloxacin was administered orally at a daily dose of 15 mg/kg for 10 days to newborns with sepsis and this treatment effectively and safely treats the sepsis [3]. Ciprofloxacin was administered orally at a daily dose of 10 to 20 mg/kg for 12 days to 9 children with bacterial infection and this treatment effectively and safely treats the bacterial infection [4]. Ciprofloxacin administered orally at a daily dose of 20 mg/kg for 14 days to 56 burn children with bacterial infection effectively and safely treats the bacterial infection and does not cause arthropathy [5]. Ciprofloxacin administered orally at a daily dose of 15 to 25 mg/kg for 9 to 16 days to 58 children, aged 8 months to 13 years, with bacterial infection effectively and safely treats the bacterial infection and does not cause arthropathy [6]. Ciprofloxacin administered orally at a daily dose of 15 mg/kg for 10 days to children with bacterial infection effectively and safely treats the bacterial infection and the adverse-effects were noted in only 5% to 15% of children. The most common adverse-effects were: gastrointestinal, skin, and central nervous system reactions, and reversible arthralgia occurred in only 36 out of 1,113 children (3.2%) with cystic fibrosis, and no cartilage damage was demonstrated by radiographic procedures [7]. Six-hundred-thirty infants and children, aged 3 days to 17 years, with respiratory-tract infection and acute pulmonary acerbation received ciprofloxacin orally at a median daily dose of 25.2 mg/kg and the median duration of therapy was 22.8 days. This treatment effectively and safely treats infants and children and reversible arthralgia occurred in only 8 infants and children (1.3%) which resolved after cessation of treatment [8].

Adverse-effects caused by ciprofloxacin in infants and children

One-hundred-eight-four paediatric patients, aged ≤ 17 years, were treated with ciprofloxacin orally at a daily dose ranging from 3.1 to 93.8 mg/kg or intravenously at a daily dose ranging from 3.2 to 76.9 mg/kg. The most common adverse-effects were: musculoskeletal adverse-effects, abnormal liver function tests, nausea, changes in white blood cell counts and vomiting. Musculoskeletal adverse-effects occurred in only 1.4% of children and arthralgia accounted for 50% of the musculoskeletal adverse-effects and all cases of arthropathy resolved or improved with management [9]. A single oral dose of 500 mg of ciprofloxacin was administered to 5,236 infants, children, and adolescents, aged 5 days to 24 years, and the only adverse-effect noted is reversible cartilage toxicity [10]. Choonara [11] reviewed the adverse-effects caused by ciprofloxacin in children aged ≤ 17 years. One-hundred-five articles were reviewed and involved 16,184 paediatric patients. There were 1,065 adverse-effects (risk 7%, 95% confidence interval = 3.2% to 14.0%) and the most common adverse-effects were: musculoskeletal, abnormal liver function test, nausea, change in white cell count, and vomiting. Ciprofloxacin related death occurred in only a newborn infant. The musculoskeletal adverse-effects were 258 which occurred in 232 paediatric patients (1.4%). Arthralgia accounted for 50% of the musculoskeletal adverse-effects and the age of occurrence of arthropathy ranged from 7 months to 17 years (median, 10 years) and all cases of arthropathy resolved or improved with management.

Pharmacokinetics of ciprofloxacin in infants

Zhao et al. [12] studied the pharmacokinetics of ciprofloxacin in 60 infants with a median postmenstrual age of 36.5 weeks (range, 24.9 to 47.9), a postnatal age of 27.0 days (range, 5.0 to 121), and a body-weight of 1,115 grams (range, 540 to 3,850). Ciprofloxacin was administered intravenously at a dose of 7.5 mg/kg twice-daily to infants with a postmenstrual age ≥ 34 weeks (84%) and at a dose of 12.5 mg/kg twice-daily to infants with longer postmenstrual age (16%). The median dose was 9.7 mg/kg (range, 9.7 to 11.0) and the median duration of treatment was 5 days (range, 1 to 17). Ciprofloxacin was administered to infants infected by Enterobacter species resistant to standard treatment and also to infants at risk of meningitis. Table 1 summarizes the pharmacokinetic parameters of ciprofloxacin.

Central DV = central distribution volume. Peripheral DV = peripheral distribution volume. Q = intercompartmental clearance. TBC = total body clearance. F inotrope = scaling factor applied for infants co-administered with inotropic agents.

Table 1. Pharmacokinetic parameters of ciprofloxacin which have been obtained in 60 infants with median postmenstrual, postnatal ages, body-weight and serum creatinine of 27.9 weeks, 27.0 days, 1,955 grams, and 42 µmol/L, respectively. Ciprofloxacin was administered intravenously at a dose of 7.5 mg/kg twice-daily to infants with a postmenstrual age ≥ 34 weeks (84%) and at a dose of 12.5 mg/kg (16%) in infants with longer postmenstrual age. Values are by Zhao et al. [12].

This table shows that the central distribution volume is higher than the water volume and is similar to the peripheral volume indicating that ciprofloxacin distributes into the whole body and there is a remarkable interindividual variability in the pharmacokinetic parameters. This variability is accounted by the wide variation in postmenstrual age, postnatal age, and body-weight of infants included in the study.

Pharmacokinetics of ciprofloxacin in infants and young children

Peltola et al. [13] studied the pharmacokinetics of ciprofloxacin in 7 infants, aged 5 to 14 weeks, and in 9 children aged 1 to 5 years. A single oral dose of 15 mg/kg of ciprofloxacin was administered to all subjects who were infected by Salmonella typhi. Table 2 summarizes the pharmacokinetic parameters of ciprofloxacin.

*Student t test for unimpaired data. AUC = area under the concentration-time curve.

Table 2. Pharmacokinetic parameters of ciprofloxacin which have been obtained in 7 infants and in 9 young children. A single oral dose of 15 mg/kg of ciprofloxacin was administered to all subjects. Values are the mean+SD, by Peltola et al. [13].

This table shows that the peak concentration, the time to reach the peak concentration, and the absorption half-life of ciprofloxacin are similar in infants and in young children. In contrast, the elimination half-life, the area under the concentration-time curve, and the mean residence time of ciprofloxacin are higher in infants suggesting that ciprofloxacin is more slowly eliminated in infants than in young children. Ciprofloxacin is eliminated mainly by renal route and the renal function increases with infant maturation and child maturation thus the elimination half-life of ciprofloxacin is longer in infants than in young children and consequently 

the area under the concentration-time curve and the mean residence time of ciprofloxacin are higher in infants than in young children.

Pharmacokinetics of ciprofloxacin in infants, children, and adolescents

Payen et al. [14] investigated the pharmacokinetics of ciprofloxacin in 3 newborns aged 1.4 days (range, 1.1 to 2.2) and weighing 2.1 kg (range, 1.7 to 3.5), in 17 infants aged 0.5 years (range, 28 days to 23 months) and weighing 5.5 kg (range, 0.75 to 9.2), in 27 children, aged 5.6 years (range, 2 

to 11) and weighing 18.6 kg (range 8 to 13), and in 8 adolescents, aged 16.4 years (range, 12 to 24) and weighing 42.3 kg (range, 28 to 58). Thirteen children (48.1%) and 7 adolescents (87.5%) were suffering from cystic fibrosis. Fifteen children (63.0%) had dysuria or polyuria and the strains isolated were: Pseudomonas aeruginosa, group D streptococci, Enterobacter cloacae, Escherichia coli, Klebsiella species, Pseudomonas pickettii, and Enterococcus faecalis. The fever was caused by Klebsiella species, Pseudomonas cepacia, Serratia, and Escherichia coli. A single intravenous infusion of 10 mg/kg of ciprofloxacin was administered to all subjects and it was followed by ciprofloxacin administered orally at a dose of 15 mg/kg twice-daily to subjects with cystic fibrosis, a second group of subjects, aged 2 days to 8 years, received 5 to 17 mg/kg of ciprofloxacin intravenously twice-daily, a third group of subjects, aged 1 to 13 years, received ciprofloxacin intravenously at a dose 7.5 to 30 mg/kg twice-daily, and the fourth group of subjects, aged 1 day to 4 years, received ciprofloxacin intravenously at a dose of 8 to 15 mg/kg twice-daily. Table 3 summarizes the pharmacokinetic of ciprofloxacin obtained in infants, children, and adolescents.

Table 3. Pharmacokinetic parameters of ciprofloxacin which have been obtained in 3 newborns, 17 infants, 27 children, and 8 adolescents. Values are the minimum, the maximum, and the %coefficient of variation, by Payen et al. [14].

This table shows that the total body clearance and the distribution volume of ciprofloxacin increase with increasing the subject age whereas the elimination half-life of ciprofloxacin decreases with increasing the subject age. Ciprofloxacin is eliminated mainly by renal route and the renal function increases with infant maturation and child development thus the elimination half-life of ciprofloxacin decreases with increasing the subject age. Ciprofloxacin distributes in the whole body (see table 1) thus the distribution volume of ciprofloxacin increases with increasing the body-weight. In addition, there is a remarkable interindividual variability in the pharmacokinetic parameters and this variability is accounted by the wide variability in subject age and body-weight.

Interaction of ciprofloxacin with drugs

Ciprofloxacin interacts with mycophenolate mofetil and ciprofloxacin reduces the area under the concentration-time curve of mycophenolate mofetil as ciprofloxacin improves the elimination of mycophenolate mofetil [15]. Ciprofloxacin interacts with diclofenac and reduces the availability of diclofenac drops at ocular level [16]. The co-administration of atorvastatin with ciprofloxacin leads to the formation of a charge-transfer complex which depletes the binding of these drugs to their respective receptors [17]. The co-administration of ciprofloxacin with nonsteroidal anti-inflammatory drugs reduces the binding of the neurotransmitter GABA in brain causing an epileptogenic effect [18]. Ciprofloxacin inhibits the metabolism of caffeine, theophylline and antipyrine [19]. Ciprofloxacin interacts with theophylline and ciprofloxacin reduces the clearance of theophylline [20]. Ciprofloxacin interacts with theophylline and ciprofloxacin increases the blood concentration of theophylline [21]. Probenecid reduces the renal elimination of ciprofloxacin by inhibiting the tubular secretion of ciprofloxacin [22]. The absorption of ciprofloxacin is significantly reduced when ciprofloxacin is co-administered with antacids containing magnesium and/or aluminium and this concomitant administration must be avoided [23].

Prophylaxis with ciprofloxacin in children

The prophylaxis with ciprofloxacin reduces pneumonia, lung exacerbations, length of hospital stay and mortality in high-risk children [24]. The prophylaxis with ciprofloxacin reduces the occurrence of fever in children with leukaemia and lymphoma [25]. The prophylaxis with ciprofloxacin is particularly helpful in preventing multidrug-resistant infections which do not respond to standard antibiotic therapy in immunocompromised children [26]. The prophylaxis with ciprofloxacin administered orally at a dose of 10 mg/kg thrice-daily prevents sepsis in severely malnourished children [27]. The prophylaxis with ciprofloxacin reduces the length of hospital stay in children with gam-negative bacteraemia [28].

Treatment of bacterial infections with ciprofloxacin in infants and children

Kaguelidou et al. [29] reviewed the literature about the treatment of bacterial infection with ciprofloxacin in infants and children. A study showed that the bacterial infection was treated with ciprofloxacin in 64% of infants, another study showed that ciprofloxacin treats bacterial infection in 91% of infants, and another study showed that ciprofloxacin treats bacterial infections in 83% of infants. Fourteen reports indicate that ciprofloxacin treats bacterial infections in infants and no serious adverse-effects, particularly joint toxicity, were observed. Thirty infants developed nosocomial infection caused by Pseudomonas aeruginosa and were treated with ciprofloxacin intravenously at an initial dose of 10 mg/kg and the daily dose was increased to 40 mg/kg according to the clinical response. Two infants (6.6%) died due to the infection and in the remaining 28 infants (93.4%) the infective agent was eradicated. No laboratory abnormality related to ciprofloxacin was observed after one week of follow-up. Ciprofloxacin administered orally at a dose of 15 mg/kg twice-daily for 10 days effectively treats life-threatening infections caused by a multidrug-resistant Pseudomonas aeruginosa in infants [30]. Forty-one children with cystic fibrosis, aged 2 to 14 years, were treated with ciprofloxacin orally at a dose of 20 mg/kg twice-daily for 10 days to treat an infection caused by Pseudomonas aeruginosa and this treatment eradicated the infective agent [31]. Ciprofloxacin is the drug recommended by WHO for treatment of dysentery. Ciprofloxacin administered intravenously at a dose of 20 mg/kg twice-daily for 10 days successfully treats dysentery in children reducing the clinical and bacteriological signs and symptom of dysentery thus ciprofloxacin decreases the mortality due to dysentery [32]. The Centers for Disease Control and Prevention recommends a single oral dose of ciprofloxacin for the treatment of gonorrhoea. Adolescents, aged 15 to 19 years, were treated with a single oral dose of 500 mg ciprofloxacin for the treatment of uncomplicated gonorrhoea which was cured but irreversible cartilage toxicity was observed [33]. Twenty-one children, aged 6 months to 10 years, were suffering from acute diarrhoea and were treated with ciprofloxacin intramuscularly at a dose of 10 mg/kg twice-daily for 10 days. Stool cultures revealed the presence of Shigella, Salmonella, Campylobacter species, and diarrheagenic Escherichia coly and ciprofloxacin cures or improves all children [34]. Eighteen children had positive cultures for Salmonella typhi and 3 children had positive cultures for Salmonella paratyphi A and all children received ciprofloxacin intravenously at a median daily dose of 15 mg/kg and the treatment lasted 10 days. Ciprofloxacin was well-tolerated and effectively treats of typhoid fever and the few adverse-effects that were recorded left no permanent sequelae and were likely to be caused by the disease itself [35]. Ciprofloxacin administered intravenously at a dose of 20 mg/kg twice-daily for 15 days has been found to be a safe and efficacious treatment of shigellosis cholera and Escherichia coli gastroenteritis in children living in developing countries [36].

Penetration of ciprofloxacin into the human cerebrospinal fluid (CSF)

A patient with meningitis caused by Pseudomonas aeruginosa was treated with ciprofloxacin intravenously at a dose of 400 mg thrice-daily for 12 days. At the end of therapy, the peak concentration of ciprofloxacin was 10.3 µg/ml in plasma and 0.9 µg/ml in the CSF. After one week of treatment the microorganism was eradicated from the CSF and this treatment was found effective [37]. The penetration of ciprofloxacin into the CSF has been investigated in 25 patients with non-inflamed meninges (group A) and in 9 patients with inflamed meninges (group B) and all patients received ciprofloxacin intravenously at a dose of 200 mg twice-daily for 10 days. In patients of group A, CSF specimens were sampled from 1 to 10 hours after the second dose of ciprofloxacin and in patients of group B specimens of CSF were sampled 1, 2, 3, 5, 7 and 9 hours after the second dose of ciprofloxacin. In patients of group A, ciprofloxacin concentrations in the CSF ranged from 0.073 to 0.106 µg/ml and in patients of group B, ciprofloxacin concentration ranged ranged from 0.089 to 0.260 µg/ml. These results indicate that ciprofloxacin penetrates into the CSF in concentration which exceeds the minimum inhibitory concentration (MIC) of Neisseria meningitides and gram-negative aerobic bacilli which were the bacteria that cause the meningitis [38]. Nine patients with external ventriculostomy received ciprofloxacin by intravenous infusion at a dose of 200 mg twice-daily for 10 days. The CSF concentration of ciprofloxacin peaked at 60 to 120 min after the end of the infusion. Ciprofloxacin elimination half-life ranged from 260 to 430 min in the CSF and from 145 to 170 min in serum. At 60 min post-dose the ciprofloxacin concentration in CSF ranged from 0.042 to 0.223 μg/ml (median, 0.110). This concentration is lower than the MIC90 of bacteria involved in central nervous system infections (CNS) thus this concentration is inadequate to treat bacteria which cause infection in the CNS [39]. Of 23 hospitalized patients, 20 patients (86.9%) had purulent meningitis and 3 patients (13.1%) had ventriculitis and all patients and were treated with ciprofloxacin intravenously at a dose of 200 mg twice-daily for 14 days. Ciprofloxacin concentration in CSF was measured on four occasions ranging from 60 to 480 min after dosing and ranged from 0.35 to 0.56 µg/ml. These concentrations were equal or higher the MICs of enterobacteria causing the meningitis or the ventriculitis [40].

Treatment of bacterial meningitis with ciprofloxacin in infants and children

Three-hundred-sixty-seven infants, aged from 1 month to < 12>

In-vitro transfer of ciprofloxacin across the human placenta

In literature there is only one study on the transfer of ciprofloxacin across the human placenta and has been reported by Polachek et al. [49]. The ratio of the concentration of ciprofloxacin in the foetal compartment to that in the maternal compartment is only 3.2+0.7% indicating that ciprofloxacin is poorly transferred across the human placenta.

Penetration of ciprofloxacin into the beast-milk

Ten lactating women received 3 oral doses of 750 mg twice-daily of ciprofloxacin and the highest average concentration of ciprofloxacin in milk is 3.79 μg/ml at two hours after dosing. The concentration of ciprofloxacin in milk is 0.20 and 0.02 μg/ml 12 and 24 hours, respectively, after dosing [50]. A lactating woman received a single oral dose of 500 mg of ciprofloxacin and the concentration of ciprofloxacin in milk is: 9.1, 9.1, 9.1, and 6.0 µmol/L at 4, 8, 12, and 16 hours after dosing, respectively [51]. These results indicate that ciprofloxacin poorly migrates into the breast-milk.

Ciprofloxacin is a fluoroquinolone and its introduction in clinical use represents a particularly important therapeutic advance. Ciprofloxacin has a broad antimicrobial activity and is active after oral administration for treatment of a wide variety of infectious diseases. Ciprofloxacin targets bacterial DNA gyrase and topoisomerase IV. For many gram-positive bacteria, topoisomerase IV, which separates interlinked (catenated) daughter DNA molecules that are the product of DNA replication, is the primary target. In contrast, DNA gyrase is the primary quinolone target in many gram-negative microbes. The gyrase introduces negative supercoils into the DNA to combat excessive positive supercoiling that can occur during DNA replication. Ciprofloxacin inhibits gyrase-mediated DNA supercoiling at concentrations that correlate well with those required to inhibit bacterial growth (0.1 to 10 μg/ml). Eukaryotic cells do not contain DNA gyrase. They do contain a conceptually and mechanistically similar type II DNA topoisomerase, but ciprofloxacin inhibits it only at concentrations (100 to 1,000 μg/ml) much higher than those needed to inhibit the bacterial enzymes. Ciprofloxacin is a potent bactericidal agent against most gram-negative pathogens including Proteus, Escherichia coli, Klebsiella, and various species of Salmonella, Shigella, Enterobacter, Campylobacter, and Pseudomonas. Several intracellular bacteria are inhibited by ciprofloxacin at concentrations that can be achieved in plasma; these include species of Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium (including Mycobacterium tuberculosis). Ciprofloxacin has activity against Mycobacterium fortuitum, Mycobacterium kansasii, and Mycobacterium tuberculosis [1]. The administration schedules of ciprofloxacin have been reported in infants and children, ciprofloxacin may be administered orally and intravenously, and following oral administration is rapidly absorbed. Ciprofloxacin is usually administered twice-daily or thrice-daily for the treatment of different infections whereas a single oral dose is used to prevent secondary case of meningococcal meningitis in infants and to treat uncomplicated gonorrhoea in children [2]. The efficacy and safely of ciprofloxacin have been reviewed in infants and children. Ciprofloxacin was administered orally at a daily dose of 15 mg/kg for 10 days to newborns with sepsis and this treatment effectively and safely treats the sepsis [3], ciprofloxacin was administered orally at a daily dose of 10 to 20 mg/kg for 12 days to 9 children with bacterial infection and this treatment effectively and safely treats the bacterial infection [4], ciprofloxacin administered orally at a daily dose of 20 mg/kg for 14 days to burn children with bacterial infection effectively and safely treats the bacterial infection and does not cause arthropathy [5], ciprofloxacin administered orally at a daily dose of 15 to 25 mg/kg for 9 to 16 days to children with bacterial infection effectively and safely treats the bacterial infection and does not cause arthropathy [6], ciprofloxacin administered orally at a daily dose of 15 mg/kg for 10 days to children with bacterial infection effectively and safely treats the bacterial infection and the adverse-effects were noted in only 5% to 15% of children. The most common adverse-effects are: gastrointestinal, skin, and central nervous system reactions and reversible arthralgia occurs in only 3.2% of children with cystic fibrosis and no cartilage damage is observed [7], infants and children, aged 3 days to 17 years, with respiratory-tract infection and acute pulmonary acerbation received ciprofloxacin orally at a median daily dose of 25.2 mg/kg for a median duration of 22.8 days. This treatment effectively and safely treats the children and reversible arthralgia occurs in only 1.3% of infants and children [8]. These results indicate that ciprofloxacin effectively and safely treats bacterial infections in infants and children and induces few adverse-effects. The adverse-effects caused by ciprofloxacin have been reviewed. Ciprofloxacin was administered orally at a daily dose ranging from 3.1 to 93.8 mg/kg or intravenously at a daily dose ranging from 3.2 to 76.9 mg/kg to children aged ≤ 17 years and the most common adverse-effects are: musculoskeletal adverse-effects, abnormal liver function tests, nausea, changes in white blood cell counts and vomiting. Musculoskeletal adverse-effects occurs in only 1.4% of children and arthralgia accounts for 50% of the musculoskeletal adverse-effects and all cases of arthropathy resolve or improve with management [9], a single oral dose of 500 mg of ciprofloxacin was administered to infants, children, and adolescents and the only adverse-effect noted is reversible cartilage toxicity [10]. Choonara [11] reviewed the adverse-effects caused by ciprofloxacin in children aged ≤ 17 years and the most common adverse-effects are: musculoskeletal, abnormal liver function test, nausea, change in white cell count, and vomiting. Death related to ciprofloxacin treatment occurred in only a newborn and musculoskeletal adverse-effects occur in only 1.4% of children. Arthralgia accounts for 50% of the musculoskeletal adverse-effects and the age of occurrence of arthropathy ranged from 7 months to 17 years (median, 10 years) and all cases of arthropathy resolve or improve with management. Zhao et al. [12] studied the pharmacokinetics of ciprofloxacin in 60 infants with a median postmenstrual age of 36.5 weeks, a postnatal age of 27.0 days and a body-weight of 1,115 grams and ciprofloxacin was administered intravenously at a dose of 7.5 mg/kg twice-daily to infants with a postmenstrual age ≥ 34 weeks (84%) and at a dose of 12.5 mg/kg twice-daily to infants with longer postmenstrual age (16%). Ciprofloxacin was administered to infants infected by Enterobacter species resistant to standard treatment and also to infants at risk of meningitis. The median central and peripheral distribution volume of ciprofloxacin is 1.82 and 1.97 L, respectively, indicating the ciprofloxacin distributes into the whole body. In addition, there is a remarkable interindividual variability in the pharmacokinetic parameters and this variability is accounted by the wide variation in postmenstrual age, postnatal age, and body-weight of infants included in the study. Peltola et al. [13] studied the pharmacokinetics of ciprofloxacin in 7 infants, aged 5 to 14 weeks, and in 9 children, aged 1 to 5 years, and a single oral dose of 15 mg/kg of ciprofloxacin was administered to all subjects who were infected by Salmonella typhi. Ciprofloxacin is rapidly absorbed following oral administration, the absorption half-life is 0.40 and 0.29 hours (P-value > 0.05) in infants and in young children, respectively, and ciprofloxacin is rapidly eliminated as the elimination half-life is 2.73 and 1.28 hours (P-value < 0>

In conclusion, ciprofloxacin is a fluoroquinolone and targets bacterial DNA gyrase and topoisomerase IV. For many gram-positive bacteria, topoisomerase IV is the primary target. In contrast, DNA gyrase is the primary quinolone target for many gran-negative organisms. The gyrase introduces negative supercoils into the DNA to combat excessive positive supercoiling that can occur during DNA replication. Ciprofloxacin is active against Proteus, Escherichia coli, Klebsiella, Salmonella, Shigella, Enterobacter, Campylobacter, Chlamydia, Mycoplasma, Legionella, Brucella, Mycobacterium tuberculosis, Mycobacterium fortuitum, and Mycobacterium kansasii. Ciprofloxacin may be administered orally and intravenously and following oral administration is rapidly absorbed. Following oral administration, the absorption half-life of ciprofloxacin is 0.40 and 0.29 hours (P-value > 0.05) in infants and children, respectively, and the elimination half-life of ciprofloxacin is 2.73 and 1.28 hours, (P-value < 0>

The authors declare no conflicts of financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employments, gifts, and honoraria.

This article is a review and drugs have not been administered to men or animals.

The author thanks Dr. Patrizia Ciucci and Dr. Francesco Varricchio, of the Medical Library of the University of Pisa, for retrieving the scientific literature.