Levofloxacin

LEVOFLOXACIN IS A NEW FLUROQUINOLONE ANTIMICROBIAL AGENT WITH POTENT ACTIVITY AGAINST A BROAD SPECTRUM OF GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA INCLUDING PS. ACRUGINOSA, ENTEROBACTERIACEAE AND STAPH AUREUS. IT DOES NOT DISTRUB NORMAL ANAEROBIC INTESTINAL FLORA AND HAS SIGNIFICANT POST-ANTIBIOTIC EFFECTS AND THUS PREVENTS REGROWTH OF BACTERIA. The mode of action of quinolones involves interactions with both DNA gyrase, the originally recognized drug target, a related type II topoisonnerase and topoisomerasc IV.

Dose:

THE USUAL DOSE :- 250-500 MG ONCE DAILY ORALLY OR I.V. MDR TUBERCULOSIS-750 MG OD OR 10-15 MG / KG DAILY

LEVOFLOXACIN Classification of Quinolones First Generation The first-generation agents include cinoxacin and nalidixic acid, which are the oldest and least often used quinolones. Because minimal serum levels are achieved, use of these drugs has been restricted to the treatment of uncomplicated urinary tract infections. Cinoxacin and nalidixic acid require more frequent dosing than the newer quinolones, and they are more susceptible to the development of bacterial resistance. These agents are not recommended for use in patients with poor renal function because of significantly decreased urine concentrations. Second Generation The second-generation quinolones have increased gram-negative activity, as well as some gram-positive and atypical pathogen coverage. Compared to first-generation drugs and considered as a group, these agents have broader clinical applications in the treatment of complicated urinary tract infections and pyelonephritis, sexually transmitted diseases, selected pneumonias and skin infections. Second-generation agents include ciprofloxacin, enoxacin, lomefloxacin, norfloxacin and ofloxacin. Ciprofloxacin is the most potent fluoroquinolone against P. aeruginosa. Because of its good penetration into bone, orally administered ciprofloxacin is a useful alternative to parenterally administered antibiotics for the treatment of osteomyelitis caused by susceptible organisms. Third Generation The third-generation quinolones currently include levofloxacin, gatifloxacin, moxifloxacin and sparfloxacin. These agents are separated into a third class because of their expanded activity against gram-positive organisms, particularly penicillin-sensitive and penicillin-resistant S. pneumoniae, and atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae. Although the third-generation quinolones retain broad gram-negative coverage, they are less active than ciprofloxacin against Pseudomonas species. Because of their expanded antimicrobial spectrum, third-generation quinolones are useful in the treatment of community-acquired pneumonia, acute sinusitis and acute exacerbations of chronic bronchitis, which are their primary PDA-labeled indications. Sparfloxacin carries a significant risk of phototoxicity. Grepafloxacin, sparfloxacin and moxifloxacin have been reported to cause prolongation of the QT interval; gatifloxacin has not. However,, the PDA recommends that all of these drugs should be avoided in patients who are taking drugs that are known to prolong the QT interval, such as tricyclic antidepressants, phenothiazines and class I antiarrhythmics. In contrast, levofloxacin does not affect the QT interval. Fourth Generation Trovafloxacin, currently the only member of the fourth-generation class, adds significant antimicrobial activity against anaerobes while maintaining the gram-positive and gram-negative activity of the third-generation quinolones. It also retains activity against Pseudomonas species comparable to that of ciprofloxacin. But, it has not yet introduced in India. The quinolones march started from Cinoxacin and has now come up to Trovafloxadi Major factors that are likely to determine a successful future for a specific class of therapeutic agents development of newer compounds that have, relative to earlier compounds in that class: Greater clinical efficacy Less toxicity and greater safety Lower propensity to induce resistance Better patient compliance Shorter effective duration of therapy Better cost-benefit ratio The first and key discovery in case of fluoroquinolones was the identification of the enzyme DNA topoisomerase II by Gellert and colleagues, which led to a better understanding of the molecular ba potent antibacterial effects of the newer quinolones. We now know that there are 4 DNA topoiso bacteria. Of these, topoisomerases I and III are not very sensitive to inhibition by the quinolones. I topoisomerase II and IV are the 2 major targets of the fluoroquinolones. The mechanism of action of the is that they inhibit DNA topoisomerases (gyrases), 4 subunits of which (2 A monomers and 2 B mono been identified in topoisomerase II. Topoisomerase II supercoils strands of bacterial DNA in the bai Thus topoisomerase II (nicking-closing enzyme) nicks double-stranded DNA, introduces negative supt seals the nicked DNA. The second major advancement contributing to the rapid expansion of the newer quinolones was thi chemically manipulate the nucleus at the N-l position, with different groups added to the (.'-6. C- positions. These modifications resulted in major changes in the antimicrobial activity, pharmacok metabolic properties of the quinolones. Modifications in the chemical structure of quinolones resulted in enhanced antimicrobial activity. INTRODUCTION TO LEVOFLOXACIN Levofloxacin, the optically pure levorotatory isomer of ofloxacin, is a fluoroquinolone antibacterial agent. Like other fluoroquinoloncs, it acts on bacterial topoisomerascs and has activity against a broad range of Gram- positive and Gram-negative organisms. Levofloxacin distributes well and achieves high levels in excess of plasma concentrations in many tissues (e.g. lung, skin, prostate). High oral bioavailability allows switching from intravenous to oral therapy without dosage adjustment. Levofloxacin, a broad spectrum fluoroquinolone antibacterial agent, is the active optical S (-)-isomcr of ofloxacin and has 2 to 4 times greater antibacterial activity than ofloxacin. CHEMISTRY Levofloxacin, a fluoroquinolone, is the optically active levo-isomer of Ofloxacin. Ofloxacin has an asymmetric center at position C-3 of its oxazine ring. Consequently, it exists as a racernic mixture of two optically active isomers (levo- and dextro-). Most of Ofloxacin's antibacterial activity is due to its levo-isomer that has greater affinity for the target molecule DNA gyrase and is 128 times more potent than the dextro-isomer. However, both isomers are equally responsible for the side effects of ofloxacin. When isolated, the levo-isomer has 2- to 4-times greater antibacterial activity than Ofloxacin and is associated with fewer side effects. Physical and chemical properties of this levo-isomer (levofloxacin) are enumerated in Table 1. The molecule exists as a zwitterion at the pH conditions in the small intestine and is stereochemically stable in humans. Chemical structure: 4-methyl piperazinyl group facilitates: - Increased oral absorption - Increased activity against some grain- negative bacilli - Increased half-life Oxazine ring facilitates: - Increased grann-ncgalivc coverage - Increased halt-life Levofloxacin is the levo-isomer of ofloxacin. PHARMACOLOGY Mechanism of Action The mode of action of quinolones involves interactions with both DNA gyrase, the originally recognized drug target, a related type II topoisonnerase and topoisomerasc IV. In a given bacterium these 2 enzymes often differ in their relative sensitivities to many quinolones, and commonly DNA gyrase is more sensitive in gram negative bacteria and topoisomerasc IV is more sensitive in Gram-positive bacteria. The recognition of dual drug target enzymes also has important implications for the development of resistance. For resistance, mutations in the primary target enzyme is important. The increment in resistance may be limited by the level of sensitivity of the secondary target enzyme, which becomes the more sensitive when the primary target is resistant. Levofloxacin and other fluoroquinolones are rapidly acting bacterial antibiotics that selectively inl enzymatic activities of bacterial DNA gyrase, an essential type II topoisomerasc, that converts relax( to a supercoiled form. The bacterial chromosome of E. coli for example, consists of a circular double-stranded loop of D is approximately 1300 (J. in length. The E. coli cell is, however, only 2 [Ll in length. To fit inio the DNA is arranged as a loop around a ribonucleic acid (RNA) core; it is then further compact process called supercoiling. In this essential process, DNA strands are broken and released in a more form with the aid of enzyme DNA gyrase. The alpha-subunits of DNA gyrase arc concerned with the bacterial chromosome and resealing it after supercoiling. The beta-subunits arc concerned with inti negative supercoiling after initial resealing by alpha-subunits. Fluoroquinolones inhibit only the alpha- of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. Though type II topoisomerases are present in mammalian cells, the concentration of levofloxacin to inhibit 50% of its activity is over 3,500 times greater than that required to inhibit 50% ol' ac bacterial DNA gyrase. Hence, levofloxacin, like other fluoroquinolones, does not exert its action oi cells. Both, levofloxacin and ciprofloxacin showed similar in vitro activity against E. coli. P. ucú,-lcgilo.~ aureus, which correlated with their ability to inhibit DNA gyrase. However, the selectivity of lev(. for bacterial DNA gyrase is far greater than that of other fluoroquinolones such as olloxacin and cipro This probably accounts for the improved activity of levofloxacin against Gram-positive cocci corn older fluoroquinolones like ciprofloxacin. The fluoroquinolones have varying affinity for the two target enzymes depending on the type ol' infecting organism. Usually all the quinolones have higher affinity for the primary target enzyim chemical structure of levofloxacin allows it to have almost similar affinity for both the target ei as compared to the other quinolones. This dual target decreases the chances of resistance devel( due to target alteration. Owing to its unique mode of action, levofloxacin remains active against bacteria that resist actii beta-lactam antibiotics (penicillins and cephalosporins) by producing beta-lactamases. Further, unl some drugs with which killing requires much higher concentrations of antibiotic than those that inhibit or slow bacterial growth, there is little or no difference between concentrations of levoti that inhibits growth and that kills susceptible bacteria. ANTIBACTERIAL ACTIVITY Levofloxacin, like other fluoroquinolones, inhibits bacterial DNA gyrase, a type II topoisomerase and topol: IV. It is active against a broad range of bacteria, including Gram-positive and Gram-negative, atypical and intracellular pathogens, but may have less activity against Pseudomonas spp. and many anaerobes. Levofloxacin acts against DNA gyrase and Topoisomerase IV. Dual target decreases the chances of resistance development. Staphylococci Methicillin-or oxacillin-sensitive Stuphylococcus aureus, S. epidermidis and S. saprophylicus were susceptible to levofloxacin, with the highest median MIc 90 value being 1.25 mg/L for any of these strains. Against staphylococci, levofloxacin appears to have activity that is similar to or greater than that of some older fluoroquinolones (ofloxacin and ciprofloxacin). The activity of levofloxacin was similar to that of ciprofloxacin against methicillin-or oxacillin-susceptibic 5'. aureus and S. saprophylicus. MIC values for methicillin-resistant oxacillin-susceptible S. epidermidis were below the susceptibility breakpoint for levofloxacin (<2lng/L susceptible, median MI( 3 mg/L) or ciprofloxacin (< I mg/L susceptible, median MIC 1.5 nig/L). Mutations to both DNA topoisornerase II subunit A (gyr A) and DNA topoisomerase IV (grIA) subunits arc thought to be needed to produce high-level resistance of S. aureus to fluoroquinolones. Selection of I-step mutants appears to occur less often with levofloxacin or ofloxacin than with ciprofloxacin, sparfloxacin or pefloxacin. Streptococci and Enterococci Levofloxacin is active against penicillin-susceptible, -intermediate and -resistant strains of S. pneumoniae. Levofloxacin appears to be 2-fold more active than ofloxacin or ciprofloxacin against S pneumoniae. Active efflux is a mechanism of resistance of fluoroquinolones in S. pneumoniae . In one study, Levofloxacin appeared to be a less active substrate for a bacterial efflux pump in this pathogen. Levofloxacin also appeared to be less likely than ciprofloxacin or ofloxacin to select resistant strains of S. pneumoniae. The median MIG,, of levofloxacin against Enterococcus jaecalis was 2 mg/L, making it similar in activity ~\s to ciprofloxacin and sparfloxacin, but superior in activity to ofloxacin. Enterobacteriaceae Most Enterobacteriaceae were susceptible to levofloxacin. These included Enterobacter cloacae, Citrohacler freundii, C. diversus, Escherichiu coil, Klebsiella pneumoniac, K. oxyfoca, Morganella morganii, Proteus mirahilis and P. vulgaris, for which the highest median MIC~n was at the break-point for susceptibility to levofloxacin (2 mg/L). Other Gram-Negative Bacteria H. influenzae and Moraxella catarrhalis are susceptible to levofloxacin, with median MIG,,, values of 0.032 mg/L (776 isolates) and 0.06 mg/L (513 isolates), respectively. Both p-lactamase-positive and -negative H. influenzae and M. catarrhalis were susceptible to levofloxacin, and there were no major differences between the activity of levofloxacin, ofloxacin, ciprofloxacin, sparfloxacin or trovafloxacin against these pathogens. Levofloxacin is also active against Legionella pneumophila. MLC,, values for levofloxacin against /,. pneumophila ranged from 0.03 mg/L to 0.125 mg/L, with an overall range of MIC values from 0.003 to I mg/L. These MIC values were within 2-fold dilutions of those for ofloxacin (0.015 to 0.25 mg/L), ciprofloxacin (0.015 to 0.03 mg/L) and sparfloxacin (0.002 to 0.015 mg/L). Nonfermentative Bacteria Pseudomonas aeruginosa is, at best, moderately susceptible to levofloxacin, with a median MIC value of 4 mg/L against a total of 3332 isolates. Other fluoroquinolones examined do not appear to differ greatly from levofloxacin in activity against P. aeruginosa. Levofloxacin avoids the efflux mechanism of resistance. Anaerobes Clostridium perfringens is susceptible to levofloxacin, with MICQ, values of 0.5 to I mg/L against S6 i Atypical Palhogens Levofloxacin is active against C. pneumoniae and Mycoplasma pneumoniae. I I clinical isolates of C. pru'll were susceptible to levofloxacin (MIC,, 0.05 mg/L) in a study. Levofloxacin, ofloxacin and sparf were all active against M. pneumoniae isolates; MIC values were: levofloxacin 0.5 mg/L {n=43), of I mg/L (n=43) and sparfloxacin 0.063 mg/L. Levofloxacin demonstrates modestly improved ( two-fold) in vitro activity against most Gram-positive I bacteria, when compared to ofloxacin. Levofloxacin resistance is encountered for mcthicillin-i'ql Staphylococcus aureus, methicillin-resistant coagulasc-negative staphylococci, and multi-resistant enter Based on in vitro susceptibility data, Levofloxacin is likely to be no more efficacious than ofloxa vancornycin- susceptible enterococci, and is unlikely to be active against ciprofloxacin-resistant enter Levofloxacin activity against Gram-negative aerobic organisms is up to four-fold greater than ofloxacin to pathogens. In general, the in vitro MICs fall well under the levofloxacin resistance breakpoint of 8 mcg most Gram-negative pathogens except Pseudomonas species For Gram positive organism, Levofloxacin activity is 2-fold more than Ofloxacin while for Gram negative, it is 4-fold more. The MIC values for levofloxacin and ofloxacin were unaffected by the method of determination, except for one strain, where the MIC value for levofloxaein was one dilution lower when determined by microdilution than by agar dilution. For ciprofloxacin, the MIC" values determined by microdilution were lower for all strains (by one or two dilutions) and for sparfloxacin the results were variable. MBC values determined by microdilution were the same as MIC values for all the antibiotics against all strains, except for sparfloxacin against strain I where the MBC was higher. Antibacterial activity: Number of survivors at 18 h For all four strains, no viable bacteria remained (number of survivors <_ 10 CFLJ/ml) after 18-h exposure to either concentration of levofloxacin, ofloxacin and sparfloxacin. Levofloxacin showed more rapid anti-bacterial activity than ofloxacin and comparable activity to sparfloxacin. The results for ciprofloxacin varied according to the study strain. While, after 18 h exposure, no viable bacteria remained with strains 2 and 3, the number of survivors for strain I at 18 h was 2.0 and 1.2 log CFU/ml at the lower and higher concentrations, respectively, and 2.1 and 1.7 log CFU/ml at the lower and higher concentrations, respectively for strain 4. Comparative bacterial activity The anti-bacterial activity of levofloxacin was comparable for all four strains and similar to that of ofloxacin. The higher concentrations of levofloxaicn and ofloxacin showed greater anti-bacterial activity than the lower concentrations, although this difference was moderate and never greater than I log unit CFU/ml. Similar results were obtained for ciprofloxacin and sparfloxacin. Levofloxacin shows more rapid anti-bacterial activity than ofloxacin. Both MIC & MBC values are same with Levofloxacin. The mean minimum kill-times obtained with levofloxacin were 4.08 and 3.67 h at the lower and higher concentrations, respectively, and less than the minimum kill-times with ofloxacin (4.15 and 3.85 h, respectively). Ciprofloxacin had the longest kill times; 6.23 and 5.06 h at the lower and higher concentrations, respectively. For all antibiotics, the minimum kill-times were shorter at the higher antibiotic concentration studied: by 0.2-0.4 h for levofloxacin, ofloxacin and sparfloxacin and by 1.17 h for ciprofloxacin. BACTERICIDAL AND POSTANTIBIOTIC EFFECTS The minimum bactericidal concentration (MBC) of levofloxacin has been shown to be the same as the MIC for E. co/i, P. oeruginosa and S. aureus. The drug also had bactericidal effects against S. c~l,iclcrúmicll.vv E. faecalis, K. pneumoniae, S. pneumoniae, L. pneumophila and several anaerobes. Levofloxacin has been shown to have a post-antibiotic effect (PAE) against S. epidermidis, E. faecalis and E. coli. A PAE has now also been shown against B. fragilis, S. aureus and S. pneumoniae, and has been postulated against L. pneumophila on the basis of the ability of levofloxacin pretreatment to inhibit regrowth of the bacleriuiii. MECHANISM OF FLUOROQUINOLONE RESISTANCE In all species studied, mechanisms of fluoroquinolone resistance include alterations in the drug target, and/ or alterations in the permeation of the drug to reach its target. No specific quinolone-modifying or degrading enzymes have been found as a mechanism of bacterial resistance to fluoroquinoloncs. Alterations in Target Enzymes Most extensively studied have been alterations in target enzymes, which are generally localized to specific domains of each subunit type. These alterations arise from spontaneous mutations in the genes encoding the enzyme subunits and thus can exist in small numbers in large bacterial populations. With (iyrA and ParC subunits of resistant bacteria, amino acid changes are generally localized to a region of the enzyme in the amino terminus that contains the active site, a tyrosine that is covalently linked to the broken DNA strand during enzyme action. For the GyrB and ParE subunits of resistant bacteria, amino acid changes, when present (mutations in these subunits arc much less common than those in GyrA or ParC), arc usually localized to the mid-portion of the subunit in a domain involved in interactions with their complementary subunits (GyrA and ParC, respectively). Differences in Fluoroquinolone Targets and Resistance The interaction of a fluoroquinolone with the complexes of either DNA gyrase or topoisorncrase IV with DNA, may block DNA synthesis and result in cell death. The antibacterial potency of a quinolone is defined in part by its potency against the two enzyme targets, the more sensitive of the two enzymes within a cell is the primary target. Many fluoroquinolones have differing potencies against DNA gyrase and topoisoinerase IV. A general pattern for most quinolones has emerged. DNA gyrase is the primary drug target in gram- negative bacteria, and topoisomerase IV is the primary target in gram-positive bacteria. These differences correlate with relative drug sensitivities in several cases, the more sensitive of the two enzymes being the primary target defined by genetic tests. The first step in mutational resistance in the drug target usually occurs by amino acid changes in the primary enzyme target, with a rise in MIC of the cell predicted to be determined by the effect of the mutation itself or by the level of intrinsic sensitivity of the secondary drug target (whichever is lower). Levofloxacin exhibits post-antibiotic effect Alterations in Drug Permeation To reach their targets in the cell cytoplasm, fluoroquinolones must cross the cytoplasmic membrane and in gram-negative bacteria, the outer membrane as well. More recently, resistance caused by reduced accumulation has been shown to require the presence and enhanced expression of endogenous efflux system that actively pumps drug from the cytoplasm. In gram-negative bacteria, these systems typically have three components: the efflux pump located in the cytoplasmic membrane, an outer membrane protein, and a membrane fusion protein thought to link the two. Drug is actively extruded from the cytoplasm or cytoplasmic membanc across the periplasm and outer membrane to the cell exterior: the energy for this process is derived from the proton gradient across the membranes. Pumps of this type also exist in gram-positive bacteria, and increased amounts of these pumps have been associated with low levels of fluoroquinolone resistance. These efflux systems are typically capable of causing resistance to compounds of diverse structural types and thus are referred to as multidrug resistance (MDR) pumps. Although fluoroquinolones arc synthetic antimicrobial agents, a number of them are substrates for a range of efflux systems. Among pathogenic bacteria, E. coli, P. taeruginosa, S. aureus, and Streptococcus pneumoniae have been most extensively studied for efflux systems causing fluoroquinolone resistance. The structural features of a fluoroquinolone that determine whether it is affected by an efflux system are not fully defined, but correlate with hydrophilicity. Levofloxacin, being more lipophilic, is the least frequent substrate for the efflux pumps of the micro organisms. Resistance to Fluoroquinolones: Implications for the Future of Levofloxacin Two large-scale, multicenter surveillance studies compared the activity of various antimicrobial agents against S. pneumoniae with that of penicillin. The studies demonstrated that, as the minimum inhibitory concentration (MIC) of penicillin increased, the proportion of strains that were resistant to four other comparator drugs - ceftriaxone, cefuroxime, erythromycin, and tetracycline - also increased. Increased resistance to levofloxacin, however, did not occur with rising penicillin MIC (Table 4). The dual targets of action and the more lipophilicity of levofloxacin confers upon it the property of less incidence of resistance by target mutation and the efflux mechanisms which preferably select other hydrophilic molecules. Due to high lipophilicity, Levofloxacin is not effluxed out. Levofloxacin by virtue of this & its dual action, avoids bacterial vesistance. PHARMACOKINETIC PROPERTIES The pharmacokinetics of levofloxacin has been studied in patients with various bacterial infections and both for healthy volunteers and volunteers with renal failure. Overview of Pharmacokinetic Properties Levofloxacin is 100% bioavailable after oral administration, making it possible to administer the drug at the same dosages either orally or intravenously. It exhibits linear pharmacokinetics over the dosage range from 50 to 100 mg, with an area under the plasma concentration - time curve (AUC) of 4.7 mg/L h alter a 50 mg oral dose and III mg/L h after a 1000 mg dose. With an elimination half-life of 6.S to 7.6 hours after single or multiple doses of levofloxacin 500 mg orally or intravenously, plasma concentrations reach steady state after about 3 days. The C of levofloxacin achieved after single 500 mg oral doses ranged from 4.5 to 5.2 mg/L. For comparator max agents examined, single dose C values were as follows: ofloxacin 400 mg, 4.8 mg/L; ciprofloxacin 750 mg, 2.0 to 3.4 mg/L: sparfloxacin 400 mg, I.I to 1.6 mg/L; trovafloxacin 200 mg, 2.9 mg/L. Renal excretion is primarily responsible for the elimination of levofloxacin. Following oral administration. 70.6% of the dose was recovered in the urine as unchanged drug within 24 hours, and 2% was recovered unchanged in faeces. Levofloxacin is metabolised in the liver to desmethyl-levofloxacin and levofloxacin- N-oxide. These metabolites make up ~ 5% of a dose excreted in the urine within 24 hours. Levofloxacin is very well distributed to body tissues and fluids, except that it penetrates poorly into the CNS. The drug is 24 to 38% bound to plasma protein. Levofloxacin, like ofloxacin, is thought to cross the placenta and be secreted into breast milk. It is taken up into polymorphonuclear leucocytes by a passive mechanism that rapidly results in cellular to extracellular ratios of about 6, making it suitable for use against intracellular organisms. There is excellent distribution of levofloxacin lo tissues and fluids of the respiratory tract and skin and it is found in large quantities in the urine. Tissue and fluid concentrations of levofloxacin exceed those in plasma at most sampling sites relevant to the infections. Levofloxacin concentrations in the lung, maxillary sinus, skin, sputum, and in alveolar macrophages and epithelial lining fluid exceed those in plasma by ratios of 1.14 to 11.6. Levofloxacin concentrations are also high in the urine. C :MIC max One therapeutic indicator used to assess the likely outcome of treatment is C relative to the antimicrobial MIC for a particular organism or organisms. A number of studies have shown that the scrum concentrations of antimicrobials (such as fluoroquinolones and aminoglycosides) related to the MIC correlate strongly with clinical response. In vitro studies have shown that a C ..:MIC ratio of>10 prevented the emergence ofantimicrobial- resistant micro-organisms (Blaser et al, 1987: Marchbanks et al, 1993: Michca-Hamzchpour et al, 1987). The most recent clinical trial data on levofloxacin suggest that a ratio of at least 12.2 correlates with favourable clinical and microbiological outcome (Preston ct al, 1998). AUIC concept and levofloxacin: The area under the inhibitory curve (AUIC), shown in Figure 1. predicts outcome. AUIC combines pharmacokinetics and pharmacodynarnics and is a measure of systemic bioavailability. With antimicrobials. not all of the drug is effective. There is no reliable activity below the minimum inhibitory concentration (MIC). Levofloxacin, taken orally, is 100% bioavailable. Tissue concentration. of the drug exceeds the plasma concentration in most places. The AUIC formula measures effective in vivo antibiotic exposure. It predicts outcome, but it is also intuitive. For example, consider a patient who has pneumococcal sepsis, bacteremic bilateral pneumonia, and is intlibated in the intensive care unit (ICU). Giving this patient ofloxacin PO twice a day would not be expected to achieve a satisfactory result. The area under the curve can be increased in several ways. Giving the patient a larger dose or giving the same dose to a smaller patient will raise drug concentration. Or the same dose can be given to a patient with impaired clearance mechanism. Finally, a patient infected with a bacterium which has a low MIC would obtain the active antibiotic through out the entire AUC. If patients receive a subpotent regimen, eg, an antibiotic that is subpotent, or an inadequate dose or dosing regimen, and if the AUIC is less than 125 (the least potent regimen), then only 40% of patients will have bacteria eradicated after one week. This leaves 60% of patients, who remain infected. If patients received a more potent regimen, with an AUIC of 125-250, virtually all will eradicate the bacteria by 2 weeks. Similarly, nearly all patients who receive the most potent regimen-with an AUIC exceeding 250 -will have the bacteria eradicated by the end of 2 weeks. The patients on the most potent regimen eradicate the bacteria about I week ahead of those receiving the regimen with AUIC 125-150. AUIC and Levofloxacin Flow do quinolones measure up? Table 5 compares the pharmacokinetics and phannacodynamics of four oral fluoroquinolone (quinolone) antibiotics against Streptococcus pneumoniae, the most common pathogen in the respiratory tract. Ciprofloxacin, at the high dose, has an MIC around 2, a peak:MIC ratio of 2.2, and an AUIC of 41. Levofloxacin has an MIC of I, a peak: MIC ratio of 5.7, and an AUIC of 48. Pharmacokinetics in Special Populations Dosage reductions should be considered for patients with renal impairment, but the drug is not substantially removed by dialysis, so no dose supplement should be given after haemo- or peritoneal dialysis. Peak plasma levofloxacin concentrations (C ) are unaffected by renal failure, but renal clearance of the drug is reduced max from 3.4 to 0.78 L/h (57 to 13 ml/min) as creatinine clearance decreases from a range of 3 to 4.8 L/h to < 1.14 L/h. CLINICAL USE Evidence for the efficacy of levofloxacin in patients with CAP, acute maxillary sinusitis, AECB, uncomplicated SSTIs and complicated UTIs (including pyelonephritis) comes from non-comparative and controlled comparative trials. Over 5600 patients were evaluated for efficacy in studies of levofloxacin. Therapeutic Uses: The efficacy of levofloxacin (250/500 ing) has been studied extensively in Europe and the US in the management of respiratory tract, genitourinary, skin, soft tissue, obstetric, gynaecological, intra-abdorninal, ear, nose and throat infections. Clinical efficacy was assessed in more than 5700 patients, while microbiological efficacy was tested against nearly 4200 pathogens. Levofloxacin has an MIC ,g of I, a peak: MIC ratio of 5.7, and an A UIC of 48 against Streptococcus pneumoniae. Levofloxacin has high clinical success & bacteriological eradication rates. Respiratory Infections Levofloxacin has been used extensively in the management of Respiratory Tract Infections (RTIs). Clinical isolates taken from both out-patients and in-patients with RTIs were found to be sensitive to the drug. Intracellular organisms isolated were also found to be sensitive to levofloxacin. Community-acquired pneumonia Pneumonia is a major cause of morbidity and mortality. Mortality varies from I to 5% for outpatients with community-acquired pneumonia to more than 25% amongst hospitalised patients. The incidence of Streptococcus pneumoniae ranges from 20 to 60%. //. influenzae is less common (3 to 10%) but increases in frequency in older patients; Staphylococcus aureus and Klebsiella pneumoniae (3 to 5%) and other gram negative bacilli (3 to 10%) are common in elderly, debilitated and immunocompromised patients. Intracellular micro-organisms, such as Chlamydia pneumoniae, Mycoplasma pneumoniae (3 to 6%) and Legionella pneumophila (2 to 8%) account for 10 to 20% of community-acquired pneumonia, the definitive etiology is never identified, thus making well chosen empirical therapy essential. Levofloxacin 500 to 1000 mg/day was effective in the management of mild to severe community - acquired pneumonia (CAP). Levofloxacin 500 mg/day was as effective as amoxicillin/clavulanic acid (1500/375 mg/day) and more effective than ceftriaxone 1000 to 2000 mg/day (with or without cefuroxime axetil 1000 mg/day). Levofloxacin 500 to 1000 mg/day was also as effective as ceftriaxone 4000 mg/day in patients with moderate to severe CAP. Increasing the dose of levofloxacin from 500 mg/day did not result in increased efficacy. Intravenous or oral levofloxacin 500 mg once or twice daily for 5 to 14 days produced clinical cure rates of 52 to 77.8% and clinical success rates of 87 to 96% in comparative and non-comparative trials in patients with mild to severe CAP (Table 8). Clinical relapse rates were low in levofloxacin and cefuroxime axetil/ceftriaxone groups (2.8 vs 1.9%). Relapse occured in similar percentages of levofloxacin recipients in this comparative trial and the noncomparative trial. Levofloxacin is effective as monotherapy in serious community-acquired pneumonia when compared with standard regimens. Overall eradication rates with oral or intravenous levofloxacin ranged from 87 to 100%. Only one-third to two- thirds of patients evaluable for clinical success were evaluable for bacteriological eradication. Rates ofbacteriological eradication ranged from 97.8 to 100% after oral levofloxacin 500 mg once or twice daily for 7 to 10 days and were similar to those after oral amoxicillin 500 mg plus clavulanic acid 125 mg 3 times daily for 7 to 10 days. When oral or intravenous levofloxacin 500 mg was administered once daily for 7 to 14 days, the bacteriological eradication rates in different studies were 95.1% and 98%. In the later study, the comparator agents oral cefuroxime axetil or intravenous ceftriaxone for 7 to 14 days produced bacteriological eradication in 85% of the subset of patients with typical pathogens and 90.4% across all pathogens. Superinfections were noted in a total of 9 levofloxacin recipients and 13 patients receiving the comparator agents in the 3 comparative trials. Levofloxacin has been used extensively in the management of Respiratory Tract Infections (RTIs). Acute Exacerbation of Chronic Bronchitis According to the World Health Organisation, acute exacerbation of chronic bronchitis (AECB) is the thirc major cause of mortality among men, following myocardial infarction and lung cancer. As defined by the American Thoracic Society guidelines, chronic bronchitis is a chronic respiratory disorder characterised b) the production of sputum for at least three consecutive months in each of 2 consecutive years. Rarely doc; chronic bronchitis occur alone, and there is nearly always some degree of emphysema present as well. Acute exacerbations are characterised by an increase in cough and worsening of dyspnea; in some cases, the presence of acute bacterial bronchitis is indicated by increased sputum production, greater purulence of sputum anc Levofloxacin is useful in community acquired pneumonia. Bacteriological eradication ranged from 97.8% to 100%. fever. The distinction between pneumonia and AECB may be difficult because they can be similar in clinical presentation, both have high rates of morbidity and mortality in patients with severe underlying chronic lung disease, and chest X rays may be difficult to interpret because of lung disease. The bacterial pathogens most commonly implicated in AECB include those that also cause typical community-acquired pneumonia, such as //. influenzae, S. pneumoniae and Moraxella catarrhalis. These pathogens cause 70% of all cases of AECB and 85% to 95% of all cases of bacterial AECB. Other bacteria implicated as causes of AECB include S. aweus, Pseudomonas aeruginosa and other opportunistic Gram-negative organisms, and Mycoplasma species. In patients with acute exacerbation of chronic bronchitis, levofloxacin 500 mg/day for 5 to 10 days was similar in efficacy to cefuroxime axetil 250 mg twice daily for 7 to 10 days or cefaclor 250 mg 3 times daily for 7 to 10 days. From the results of the two studies, it also appeared that levofloxacin achieved similar efficacy with shorter duration of therapy (5 to 7 days) than was used with comparator agents (7 to 10 days), although short-duration regimens with the comparators were not tested. In 2 studies, clinical success rates with levofloxacin 500 mg/day (94.6% and 92%) were similar to those for cefuroxime axetil (92.6%) and cefaclor (92%) groups. Bacteriological eradication rates were similar between all levofloxacin regimens (77% to 97%) and corresponding comparator agents cefuroxime axetil and cefaclor in treatment of 89 to 222 patients. Levofloxacin is useful in AECB. Bacterioloeical eradication is as high as 97ø/ Acute Maxillary Sinusitis Acute bacterial sinusitis is a common clinical condition complicating approximately 0.5% of common colgs ~v~ULFF VdL~IE;llal alllualllo lo a IrUIIIIIIUII CúIIIIICúil ~VIIIlIIIVIII ~vlllpll~arll~ applu~llliaLt-lyyyy u.J/u ui ~uilllliuil cuni~. Fewer than one fourth episodes of acute sinusitis appear to be directly caused by viruses. Most of the remainc er cases are the result of bacterial infection. The most prominent bacterial pathogen is S. pneumoniae. which is present in nearly half the cases, alone or with //. influenzae. Intracellular pathogens, such as C. pneumonine, may also cause acute sinusitis as well as chronic sinusitis. Less common respiratory pathogens such is At. catarrhalis, may be cultured in sinusitis and polymicrobial infections, other pathogens include S. aurenx. Streptococci, Gram-negative bacilli and anaerobes. The goals of antibiotic therapy are both symptomatic rel et and prevention of serious septic complications, such as meningitis, brain abscess, or epidural and subduial abscess. The prominence of beta-lactamase-producing strains of bacteria makes beta-lactam antibiotics, sii :h as cephalexin, penicillin or amoxicillin poor empirical choices. Because culturing sinuses in routine practice is impractical, antibiotic therapy must be empirical in nearly all cases. Levofloxacin has potent in vitro activity against all typical and intracellular pathogens found in acute and chronic sinusitis. In comparative trials in patients with acute maxillary sinusitis, oral levofloxacin 500 mg/day was similar in efficacy to oral amoxicillin / clavulanic acid 500 mg / 125 mg, 3 times daily or oral clarithromycin 500 mg twi :c daily. Rates of clinical cure with levofloxacin in comparative studies and noncomparative studies ranged from 88.3 to 96%. Clinical cure and clinical success rates for amoxicillin / clavulanic acid were 58.6 and 87.3% and the rate of clinical success with clarithromycin was 93.3%. Bacterial eradication rates in non-comparative studies were from 88.6 and 92%. Relapse rates were similar between levofloxacin and amoxicillin/ clavulanic acid group Relapse rates were 3.7% and 7.9% in the 2 noncomparative studie Levofloxacin is useful in acute maxillary sinusitis. Bacteriological eradication rate was upto 92' Skin and soft tissue infections S. aureus and S. pyogenes are the main pathogens responsible for primary (or uncomplicated) skin and soft tissue infections (SSTI) such as impetigo, folliculitis, furuncles and cellulitis as well as for secondary (or complicated) SSTI such as diabetic foot ulcers, pressure sores, traumatic and surgical wounds. Enterobacteriaceae, non-fermenting Gram-negative bacilli (such as P. aeruginosa) and anaerobes can occasionally cause SSTI. in vitro studies have shown that levofloxacin is active against nearly all organisms commonly involved in SSTI. In clinical studies, levofloxacin 500 mg once daily for 7-10 days was found to be not only efficacious and well tolerated, but also it had the added benefit of being given once daily. Furher, it was associated with fewer side effects as it does not cause the gastrointestinal side effects encountered with amoxicillin/clavulanate. In two multicentric double-blind parallel group studies involving patients with uncomplicated SSTI, 97.8% and 96.1% clinical success rates were observed with levofloxacin, while rates with ciprofloxacin were 94.3% and 93.5%. Bacteriological eradication rates were 97.5% and 93.2% for levofloxacin and 88.8% and 91.7% with ciprofloxacin. There were no statistically significant differences between the two treatments. Levofloxacin is useful in SSTI. Bacteriogical eradication rate was upto 97.5%. Urinary Tract Infections Urinary tract infections (LJTI) are divided into three categories: uncomplicated UTI, complicated U'l'l and pyelonephritis. Uncomplicated UTI is commonly seen in young sexually active women. Complicated UTI is seen in both men and women due to anatomical or functional predisposing factors such as benign hypertrophy of the prostate gland (in men), pregnancy (in women) and bladder catheter patients (in both). Pyelonephritis can occur in patients with either complicated or uncomplicated UTI. While E. coli is primarily responsible for uncomplicated UTI, complicated UTI can be caused by a variety of Enterobacteriaccac such as Kk'hsiylhi. Proteus and Pseudomonas aeruginosa. While many of these organisms have developed resistance to commonly used antimicrobials such as amino- penicillins, first generation cephalosporins and cotrimoxazole, in vitro studies have shown that lcvofloxacin is active against nearly all organisms commonly involved in UTI and pyelonephritis. In clinical studies, levofloxaciii 250 mg once daily for 10 days was equivalent in efficacy to ciprofloxacin 250 mg twice daily lor 10 days or lomefloxacin 400 mg once daily for 14 days. Clinical success was seen in 92% and 92.9% of patients with complicated urinary tract infections or acute pyelonephritis receiving levofloxacin in two randomized, muticentric studies, compared with SS% receiving ciprofloxacin and 88.5% receiving lomefloxacin. Bacteriological eradication rates of 93.6% and 95.3% observed with levofloxacin were similar to the 97.5% with ciprofloxacin and 92.1% with lomefloxacin. Rates of relapse were not reported. In addition, levofloxacin had similar clinical success (93%) and bacteriological eradication (100%) rates to those seen in a combined group (95 and 97.75 respectively) of ciprofloxacin or lomefloxacin Levofloxacin is useful in UTI. Bacteriological eradication rate was as high as 97.5%. Obstetric and Gynaecological infections In a noncornparative trial fo 197 women with various obstetric and gynaecological infections including intrauterinc infection, Bartholinitis, Bartholin's abscess and mastitis, levofloxacin 200 to 300 mg/day in divided doses for 3 to 14 days improved symptoms in 93% of patients. The most frequently isolated pathogen in this study was C. trachomatis (n=28) from women with cervicitis; 93% of these isolates were eradicated. Eradication rates of >95% were observed for the other commonly isolated organisms which includes E. coli, S. aureus, Streptococcus spp. and Peptostreptococcus spp. Ear, Nose and Throat infections The efficacy of levofloxacin has been demonstrated in patients with ear, nose and throat infections. In 3 noncomparative studies, levofloxacin 100 to 200 mg 2 to 3 times daily resulted in overall clinical efficacy rates of 74 to 97%. Organisms isolated most frequently were Staphylococcus spp. (n = 133), Streptococcus spp.(n = 42), P. aeruginosa (n = 27), H. mfluenzae (n = 18) and M. catarrhalis (n =\\). Levofloxacin exhibited good antibacterial activity with overall eradication rates of 100% for //. mfluenzae and M. catarrhulis. 97% for Streptococcus spp., 93% for MSSA and MRSA, and lower rates observed for coagulase-negative Staphytococci (75%) and P. aeruginosa (67%). Genitourinary infections Levofloxacin was effective in eradicating N. gonorrhoeae and Chlamydia trachomalis in patients with uncomplicated urethritis. Clinical and bacteriological efficacy rates of 100% were observed for levofloxacin 200 to 400 mg/day administered for 3 days to patients with gonococcal urethritis and 14 (Jays to patients with nongonococcal (chlamydial) urethritis. Levofloxacin 200 to 600 mg/day for 3 to 14 days achieved moderate or excellent responses in the treatment of acute or chronic prostatitis and acute or chronic epididymitis. Other infections Levofloxacin was effective in the treatment of a variety of other infections, including ocular, odontogenic infections and bacterial enteritis. In 108 patients with ocular infection, clinical and bacteriological efficacy rates of 92% and 88%i were obtained. Levofloxacin 200 to 300 mg/day for 3 to 14 days was effective in treating 83% of 203 patients with odontogeme infections caused primarily by Streptococcus spp. and Gram-positive anaerobes. Using a regimen of levofloxacin 200 to 300 mg/day for 5 to 7 days, Murata et al. (1992) reported a clinical cure rate of 97% in 114 patients with bacterial enteritis. Bacteriological eradication rates of 99% for Shigella spp. (n 1 83) and 71% for C. jejuni (n = 17) and Salmonella (n ~ 15) were reported. Levofloxacin is also useful in 0&G infections, ENT infections, Genitourinary infections & other infections like ocular & odontogenic infections and bacterial enteritis. Indian Studies Studies were conducted in Indian set-ups to study the safety and clinical efficacy of once daily administralio of Levofloxacin 500 mg IV/PO in comparison with twice daily administration of ciprofloxacin 400 mg IV 500 mg PO in treatment of adult patients with lower respiratory tract inlection. In a study conducted in the Chest Medicine department of K.H.M. Hospital, Mumbai by Dr. A. A. Mahashu 51 patients-21 male and 30 female, aged 18-60 years, with lower respiratory tract infection were enrolle into the study. Of the 58 patients, 7 were lost to follow-up, so that 51 were evaluabic (26 in levofloxaci group & 24 in ciprofloxacin group). The clinical success rate (cured + improved) with levofloxacin was superic to that of the ciprofloxacin group (100% and 80% respectively). The bacteriological efficacy was also signifieanti superior in the levofloxacin group compared to the ciprofloxacin group (satisfactory response 100% and 56" respectively). Tolerability was rated as excellent by all 51 patients (100%). No adverse events were observe in haematological, hepatic or renal function tests. In another study, conducted in the Medicine department of SSG Hospital, Vadodara, Gujarat, by Dr. K...I. 1'atlialj 50 LRTI patients were enrolled into the study with 25 receiving levofloxacin and 25 receiving ciprolloxacii The clinical success rate (cured + improved) with levofloxacin was superior to that of the ciprofloxacin grou (100% and 84% respectively). The bacteriological efficacy was also significantly superior in the levofloxaei group compared to the ciprofloxacin group (satisfactory response 100% and 48% respectively). Tolei-abilit was rated as excellent by all 50 patients (100%). In 2 patients on levofloxacin and 4 patients in the ciprofloxaci group, mild adverse events occured, comprising: nausea in 4, giddiness & skin reaction in I each. No advers events were observed in haematological, hepatic or renal function tests. In both studies, both drugs were well tolerated orally and intravenously. Once daily levolloxacin 500 mg, either IV or as sequential IV / oral therapy, was superior to IV / oral twice daily ciprofloxacin therapy in the treatment of hospitalised / outdoor patients with LRTI and offers the advantage of sequential therapy. SAFETY PROFILE General Tolerability Levofloxacin is generally well tolerated and most adverse events are transient in duration and mild to moderati in seventy. With oral levofloacin, the most frequently reported adverse events were gastrointestinal symptom; including nausea, anorexia, abdominal discomfort and diarrhoea. With intravenous lcvofloxacm, phlebitis an reddening at the infusion site has been reported. Drug-related adverse events ranged in incidence from 4 to 4.3% with levofloxacin 250 mg/day, from 5.3 1)1 26.9% for levofloxacin 500 mg/day. The most common adverse events were diarrhoea (1.1 to 2.8%), nausea (I.I to 3%), abdominal pain (I I 1.1%), flatulence (1.6%), insomnia (1.1%) and somnolence (2.2%) In the comparative studies, levofloxacin was reported to be tolerated as well as cefaclor and ciprofloxacii In I trial it was similar in tolerability to amoxicillin/clavulanic acid, but it was associated with fewer advers events than amoxicillin/clavulanic acid or lomefloxacin in other studies. Although the tolerability profile of levofloxacin is generally typical of a fluoroquinolonc agent, there appeall to be some differences between levofloxacin and other drugs of this class in the overall incidence of udvcrs events. A review of fluoroquinolone tolerability reported that adverse events occurred in 3.3% of ofloxaci recipients, 5.5 to 10.2% of ciprofloxacin and 8% of pefloxacin recipients. Withdrawals from clinical trial occured in 1.3% of patients receiving levofloxacin versus 1.5 to 2.2% of ciprofloxacin, ofloxacin and pcfloxaci recipients. In Indian studies, Levofloxacin was very useful in LRTI. Serious Adverse Events With regard to serious adverse events, product labelling for levofloxacin, in common with other fluoroquinolones, urges that patients take care to avoid photosensitisation and discontinue levofloxacin if tendinitis, pseudomembranous colitis or haemolytic reactions (in those with glucose-6-phosphate deficiency) are suspected. During levofloxacin use, tendinitis is rare (<0.1% incidence), pseudomembranous colitis is very rare (<0.01%) and haemolytic reactions occur only in isolated cases. The safety and efficacy of levofloxacin in patients less than 18 years of age has not been established. However, the ability of levofloxacin to cause ostcochondrosis and arthropathy in juvenile animals of several species is similar to that of other fluoroquinolones. As a class, fluoroquinolones are contraindicated for use in children and adolescents for this reason. The phototoxic potential of levofloxacin has been reported to be similar to that of ofloxacin and lower than that of lomefloxacin, sparfloxacin or nalidixic acid. CNS events may occur in smaller proportions with levofloxacin compared to ofloxacin events. Seizures have been linked to fluoroquinolone overdose or following interaction between fluoroquinolones and theophylline (see section nonsteroidal anti-inflammatory drugs [NSAIDs]). However, seizures have been reported only with levofloxacin (<0.1%) and may be less common with levofloxacin that with some other fluroquinolones. During the primary Phase 11/111 clinical trials, the safety and tolerability of levofloxacin was assessed in more than 5388 patients. Of the patients treated with levofloxacin, 3.8% discontinued therapy due to adverse events as compared to 4.5% patients who discontinued therapy following adverse events due to comparison drugs. In comparative studies, levofloxacin was reported to be tolerated as well as cefaclor and ciprofloxacin. In one trial it was similar in tolerability to amoxicillin / clavulanic acid, but it was associated with fewer adverse events than amoxicillin / clavulanic acid or lomefloxacin in other studies. The reported incidence of adverse events with levofloxacin was similar to that of ceftriaxone and cefuroxime axetil in some studies, but ceftriaxone and/or cefuroxime axetil appeared to be less tolerated than levofloxacin in one trial. Levofloxacin and Fluoroquinolone-related adverse events fluoroquinolones are known to be associated with some typical adverse events, such as photosensitivity, tendinitis, pseudomembranous colitis and hemolytic reactions. Photosensitivity is infrequent with levofloxacin. Its phototoxic potential is similar to ciprofloxacin and ofloxacin, but much lower than that of lomefloxacin, enoxacin or nalidixic acid. While the incidence of phototoxicity with levofloxacin is < 1%, it is nearly 8% with sparfloxacin, whose use has, as a result, been severely restricted in several countries. A recent study found no difference in dermal reactions to UVA light or solar simulating radiation between healthy volunteers receiving levofloxacin 500 mg once daily for 5 days (n = 24) or those receiving placebo (n=b). The low potential for phototoxicity demonstrated by levofloxacin was confirmed by a significantly lower reporting incidence of adverse reactions compared with the pooled rate for fluoroquinolone comparison agents. Levofloxacin has the least reported adverse events among various fluoroquinolones. Animal studies have shown that in high doses lcvofloxacin can induce articular damage. In the cartilage ol'juveni e rats or rabbits, oral or intra-articular lcvofloxacin produced chondrocyte necrosis and erosion with some cavi y formation, believed to occur through inhibition of glycosaminoglycan and DNA synthesis and disruplion il mitochondrial function. These effects appear to affect both joints and tendons and were similar to those induced I y ciprofloxacin. Tendon disorders were reported for only 8 of almost 9000 patients treated with levofloxaein; l'ive p these were receiving corticosteroids. No case of tendon rupture was reported. Incidence of seizures, tendinitis, pseudomembranous colitis, hemolytic episodes and arrhythmias lollowii administration of lcvofloxacin is rare to none. During levofloxacin use, incidence oftendinitis is rare (< 0.1%), pseudoinembranous colitis is very rare ( 0.01 and liemolytic reactions occur only in isolated cases. Lcvofloxacin must be used with caution in patients with history of seizures, tendinitis, pseudo-membranois Gastrointestinal toxicity Nausea,diarrhea, colitis, hemolytic episodes (related to glucose-6-phosphatc deficiency) Central Nervous System Toxicity (irritability, insomnia, drowsiness, dizziness) Rashes/Skin Toxicity (all types) Phototoxicity or Photosensitivity Effects on Laboratory Indices There are no clinically significant changes in laboratory tests in patients treated with levolloxacin incilnii liver function and renal function tests, blood glucose, and haematological tests. Drug Interactions Absorption of fluoroquinolones can be adversely affected due to chelation by metal cations (such as aluminium and magnesium present in antacids, zinc-containing rnultivitamin preparations). Administration of ferrous sulphate, magnesium oxide and aluminium hydroxide significantly reduced the relative bioavailability of levofioxacin 100 mg by 81, 78 and 56% in healthy volunteers compared with controls, while mean reductions in Cmax ranged from 40 to 65%. Hence, levofioxacin should not be administered with medications containing metal cations; it should be given 2 hours before or 2 hours after the treatment. Xanthine derivatives such as theophylline are commonly used in patients with respiratory tract infections and several fluoroquinolones are known to inhibit the metabolism of theophylline. Serious adverse effects associated with elevated plasma theophylline concentrations, including nausea and vomiting or central nervous sytem effects such as dizziness and seizures, have been observed in patients receiving concomitant theophylline and fluoroquinolones. Although the mechanism of the interaction between some fluoroquinolones and xanthines has yet to be fully elucidated, levofioxacin does not appear to significantly alter the clearance of theophylline. Results from studies in healthy volunteers have shown that oral levofloxacin has minor effect on the steady state pharmacokinetics of theophylline 200 mg twice daily. Increases in theophylline C and AUC were observed with concurrent administration of enoxacin (41 to 98%) or ciprofloxacin (17 to 28%) to healthy volunteers. Interactions between levofioxacin and theophylline, NSAIDs, antihyperglycaemic drugs, cimetidine, digoxin, calcium carbonate, probenecid, cyclosporin are clinically insignificant and does not warrant dose adjustment. The potential of levofloxacin to interact with NSAIDs and antihyperglycaemic drugs is assumed on the basis of interactions between these agents and other fluoroquinolones although there are no published data suggesting that this interaction occurs with levofloxacin. Interactions with some other agents have been characterized and are known to be minor or clinically insignificant. Table 14 Drug interaction profile of levofloxacin Antacids containing magnesium or aluminium Ferrous sulphate or multivitamins should be taken 2 hrs before or after with iron/zinc levofloxacin Sucralfate NSAIDs increases plasm levels of levofloxacin and may increase Calcium carbonate risk of cns stimulation. Cimetidine Probenecid Theophylline no clinically significant action. Digoxin Glibenclamide Cyclosporin Warfarin Should be taken 2 hours before or after levofloxacin administration Increases plasma levels of levofloxacin and may increase risk of CNS stimulation in susceptible patients Levofloxacin bioavailability is affected due to chelation by metal cations Overdosage In animal toxicity studies, the most important signs that may be expected to follow overdos.ige of lcvofloxacin are neurological symptoms such as confusion, dizziness, impairment of consciousness and seizures, and gastrointestinal tract reactions such as nausea and mucosal erosions. No specific antidot exists. Management should involve hydration, gastric lavage and symptomatic treatment. Antacids may be used to protect gastric mucosa. Levofloxacin is not efficiently removed by hemodialysis and peritoneal dialysis. DOSAGE AND ADMINISTRATION Indications and Dosage Recommendations Levofloxacin is indicated for oral or intravenous administration to adults with mild-to-moderate acute sinusitis AECB, CAP, complicated UTIs including pyelonephritis and SSTIs Indications :- levofloxacin is indicated for the treatment of adults with Skin infections,community acquired pneumonias,sinusitis,u.t.i. and pyelonephritis. Levofloxacin is a once daily drug. Use in Special Populations The safety and efficacy of levofloxacin in children and adolescents below the age of 18 years has not been established. Fluoroquinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. Levofloxacin should not be used in patients with epilepsy or a history of tendon disorders related to fluoroquinolone use, or during pregnancy, or breast feeding. In patients with impaired renal clearance (creatinine clearance <3L/h or <50 ml/min), dosages of levofloxacin should be adjusted on the basis of creatinine clearance. No dosage adjustment is necessary when levofloxacin is used in patients with liver impairment or in the elderly. Levofloxacin Dosing in Renal Impairment (CrCI: 50 or more ml/min) crcl: 20-49 ml/min crcl: 19 orless than ml/min 500 mg q 24 hours' 500 mg, then 250 mg 500 mg, then 250 mg q 24 hours 48 hours 250 mg q 24 hours' No Change 250 mg q 48 hours Levofloxacin dose remains unaltered in the elderly and hepatic-impaired patients. PLACE OF LEVOFLOXACIN IN THE MANAGEMEN~ -OF INFECTIOUS DISEASE- Levofloxacin and other newer fluoroquinolones are now recommended as first line therapy lor CAP and respiratory tract infections caused by S. pneumoniac, H. influenzac, Legionella spp., M pncuinoniac aiii pneumoniae. In particular, median MIC values for lcvofloxacin against S. pneumoniae, regardless of the penicillin scusil of this bacterium are I mg/L, i.e. 2- fold lower than those of both ofloxacin and ciprofloxacin. Predictably, levofloxacin consistently achieved eradication rates of>90% for other respiratory pathogens, iiiclu atypical agents. In comparative clinical trials, levofloxacin achieved efficacy rates similar to those ofsevei'iil P-lactams agents (amoxicillin/clavulanic acid, ceftriaxone cefuroxime axetil and cefaclor) in the treatmci lower respiratory tract infections, and amoxicillin and clarithromycin in acute maxillary sinusitis. Another important aspect of the clinical profile of levofloxacin is the degree of experience with regai tolerability of the agent. An overview of trials, suggests that levofloxacin (3.3%) may be associated with f drug-related adverse events than either ciprofloxacin (5.5 to 10.2%) or ofloxacin (4.3%),and that some interactions may be less common with levofloxacin than other fluoroquinolones. Lcvofloxacin differs fron newer agents in having been well tested and appears to be at least as well tolerated as the older, estahli fluoroquinolones such as ciprofloxacin and ofloxacin, while also appearing to have fewer significant interactions. In addition, levofloxacin has the advantage of being 100% orally available such that it can be used sequential intravenous followed by oral administration without any adjustment in dosage. Levofloxacin also ma administered in once-daily regimens, which may aid compliance. The efficacy oflevofloxacin in the treatment of complicated LIT Is, including acute pyclonephritis makes it a i\ alternative to other fluoroquinolones in these infections. Fluoroquinolones also may be a good choice tor use ii treatment ofSSTIs because of their wide distribution to the sites of infection. When a fluoroquinolonc is indic for use in complicated SSTIs, levofloxacin appears to be a good alternative. In conclusion, levofloxacin can be administered in a once-daily regimen for the treatment ofARCB, CAP. ,: maxillary sinusitis, complicated urinary tract infections including pyelonephritis and uncomplicated Sr Levofloxacin is distinguished by a well-characterised tolerability and enhanced activity against pneurn compared with ciprofloxacin or ofloxacin. Clinicians should consider the relative merits of improved activity against S. pneumoniae versus known tolerability profile when choosing between levofloxacin and other newer fluoroquinolone agents for the treatment of respiratory tract infection Levofloxacin is an effective drug in the treatment of AECB, CAP, Acute maxillary sinusitis, complicated UTI, and SSTI.