Emailing Quinolones-fluoroquinolones and Aminoglycosides-1.pdf

BROAD SPECTRUM ANTIBIOTICS AND MISCELLENOUS ANTIBACTERIAL AGENTS Akinola Olugbenga. PhD QUINOLONE & FLUOROQUINOLONES PHARMACOLOGY  QUINOLONES These are synthetic antimicrobials having a quinolone structure that are active primarily against gram-negative bacteria, though the...

BROAD SPECTRUM ANTIBIOTICS AND MISCELLENOUS ANTIBACTERIAL AGENTS Akinola Olugbenga. PhD QUINOLONE & FLUOROQUINOLONES PHARMACOLOGY  QUINOLONES These are synthetic antimicrobials having a quinolone structure that are active primarily against gram-negative bacteria, though the newer fluorinated compounds also inhibit gram-positive ones. The first member Nalidixic acid introduced in mid-1960s had usefulness limited to urinary and g.i. tract infections because of low potency, modest blood and tissue levels, restricted spectrum and high frequency of bacterial resistance. A breakthrough was achieved in the early 1980s by fluorination of the quinolone structure at position 6 and introduction of a piperazine substitution at position 7 resulting in derivatives called fluoroquinolones with high potency, expanded spectrum, slow development of resistance, better tissue penetration and good tolerability. Nalidixic acid It is active against gram-negative bacteria, especially coliforms: E. coli, Proteus, Klebsiella, Enterobacter, Shigella but not Pseudomonas. It acts by inhibiting bacterial DNA gyrase and is bactericidal. Resistance to nalidixic acid develops rather rapidly.  Nalidixic acid is absorbed orally, highly plasma protein bound and partly metabolized in liver: one of the metabolites is active. It is excreted in urine with a plasma t½ ~8 hrs. Concentration of the free drug in plasma and most tissues attained with the usual doses is nontherapeutic for systemic infections (MIC values for most susceptible bacteria just approach the ‘break- point’ concentration). However, high concentration attained in urine (20–50 times that in plasma) and gut lumen is lethal to the common urinary pathogens and diarrhoea causing coliforms.  Adverse effects These are relatively infrequent, consist mostly of g.i. upset and rashes. Most important toxicity is neurological—headache, drowsiness, vertigo, visual disturbances, occasionally seizures (especially in children). Photo toxicity is rare. Individuals with G-6-PD deficiency may develop hemolysis. Nalidixic acid is contraindicated in infants. Use Nalidixic acid is primarily used as a urinary antiseptic, generally as a second line drug in recurrent cases or on the basis of sensitivity reports. – Nitrofurantoin should not be given concurrently—antagonism occurs. It has also been employed in diarrhoea caused by Proteus, E. coli, Shigella or Salmonella, but norfloxacin/ciproloxacin are more commonly used now. FLUOROQUINOLONES  These are quinolone antimicrobials having one or more fluorine substitutions. The ‘first generation’ fluoroquinolones (FQs) introduced in 1980s have one fluoro substitution. In the 1990s, compounds with additional fluoro and other substitutions have been developed—further extending antimicrobial activity to gram-positive cocci and anaerobics and confering stability (longer t½). These are referred to as ‘second generation’ FQ  CLASSIFICATION First Generation - Nalidixic Acid Second Generation - Ciprofloxacin, Ofloxacin, Cinoxacin, Pefloxacin. Extended activities against gram +ve and -ve as well as atypical microbes. They hve better pharmacokinetic profile and more active than nalidixic. Third Generation - Getifloxacin, Levofloxacin,Spacfloxacin, Moxifloxacin. Similar to nd generation but with improved activities against atypical microbes. Fourth Generation - Tevofloxacin Exhibit greater activity G -ve and also have effects on anaerobic bacteria. Known to cause liver damage and therefore reserved for serious infections resistant to other agents. Mechanism of action The FQs inhibit the enzyme bacterial DNA gyrase (primarily active in gram negative bacteria), which nicks double stranded DNA, introduces negative supercoils and then reseals the nicked ends. This is necessary to prevent excessive positive supercoiling of the strands. The DNA gyrase consists of two A and two B subunits: The A subunit carries out nicking of DNA, B subunit introduces negative supercoils and then A subunit reseals the strands.  FQs bind to A subunit with high affinity and interfere with its strand cutting and resealing function. In gram-positive bacteria the major target of FQ action is a similar enzyme topoisomerase IV which nicks and separates daughter DNA strands after DNA replication. Greater affinityfor topoisomerase IV may confer higher potency against gram-positive bacteria.  The bactericidal action probably results from digestion of DNA by exonucleases whose production is signalled by the damaged DNA. In place of DNA gyrase or topoisomerase IV, the mammalian cells possess an enzyme topoisomerase II (that also removes positive supercoils) which has very low affinity for FQs— hence the low toxicity to host cells.  Inhibition of cell wall synthesis: Inhibition of protein synthesis: Penlcllllns,cephalosporlns, Chloramplilenlcol,erythromycln, bacltra.cln, vancomycln tetracyclines,streptomycin ! Transcription Translation mRNA Replication Inhibition of Enzymatic nuclelc acid activity, replication and synthesis of transcription: essential Qulnolones, metabolites rlfampln Injury to plasma membrane: Inhibition of synthesis Polymyxln B of essential metabolites: Sulfanilamide,trfmethoprim  Dual MOA: 1. Inhibition of bacterial DNA Gyrase (Topoisomerase 11) i. Formation of quinolone-DNA-Gyrase complex ii. Induced cleavage of DNA 2. Inhibition of bacterial Topoisomerase IV Mechanism poorly understood Mechanism of DNA Gyrase StabUlzo Break Reseal broak positive node back segment on fronlside 1 2 3  Mechanism of resistance Because of the unique mechanism of action, plasmid mediated transferable resistance is less likely. Resistance noted so far is due to chromosomal mutation producing a DNA gyrase or topoisomerase IV with reduced affinity for FQs, or due to reduced permeability/increased efflux of these drugs across bacterial membranes.  In contrast to Nalidixic acid which selects single step resistant mutants at high frequency, FQ-resistant mutants are not easily selected. Therefore, resistance to FQs has been slow to develop. However, increasing resistance has been reported among Salmonella, Pseudomonas, staphylococci, gonococci and pneumococci. Ciprofloxacin (prototype) It is the most potent first generation FQ Active against a broad range of bacteria, the most susceptible ones are the aerobic gram-negative bacilli, especially the Enterobacteriaceae and Neisseria. The MIC of ciprofloxacin against these bacteria is usually < 0.1 µg/ml, while gram positive bacteria are inhibited at relatively higher concentrations. The spectrum of action is summarized below: Highly susceptible E. coli K. pneumoniae N. meningitidis Neisseria gonorrhoeae Enterobacter H. influenzae Salmonella typhi H. ducreyi Nontyphoid Salmonella Campylobacter jejuni Shigella Yersinia enterocolitica Proteus Cholerae Vibrio Moderately susceptible Pseudomonas aeruginosa Legionella Staph. aureus Brucella (including few MRSA) Listeria Staph. Epidermidis Bacillus anthracis Branhamella catarrhalis Mycobact. tuberculosis Organisms which have shown low/variable susceptibility are: Strep. pyogenes, Strep. faecalis, Strep. pneumoniae, Mycoplasma, Chlamydia, Mycobacteria. kansasii, Mycobact. avium. Notable resistant bacteria are: Bacteroides fragilis, Clostridia, Anaerobic cocci The distinctive microbiological features of ciprofloxacin (also other FQs) are: 1. Bactericidal activity and high potency: MBCs are close to MICs. 2. Relatively longpost-antibiotic effect on Enterobacteriaceae, Pseudomonas and Staph. 3. Low frequency of mutational resistance. 4. Low propensity to select plasmid type resistant mutants. 5. Protective intestinal streptococci and anaerobes are spared. 6. Active against many β-lactam and aminoglycoside resistant bacteria. 7. Less active at acidic pH. Pharmacokinetics Ciprofloxacin is rapidly absorbed orally, but food delays absorption, and first pass metabolism occurs. Ciprofloxacin (and other FQs) have good tissue penetrability: concentration in lung, sputum, muscle, prostate and phagocytes exceeds that in plasma, but CSF and aqueous levels are lower. It is excreted primarily in urine, both by glomerular filtration and tubular secretion. Urinary and biliary concentrations are 10–50 foldhigher than plasma. Adverse effects Ciprofloxacin has good safety record: side effects occur in ~10% patients, but are generally mild; withdrawal is needed only in 1.5%. Gastrointestinal: Nausea Vomiting, Bad Taste Anorexia. Because gut anaerobes are not affected Diarrhoea is infrequent. CNS: Dizziness Headache, Restlessness Anxiety, Insomnia Impairment of concentration and dexterity (caution while driving). Tremor and seizures Rare, occur only at high doses or when predisposing factors are present: possibly reflect GABA antagonistic action of FQs Skin/hypersensitivity: Rash Pruritus, Photosensitivity, Urticaria, Swelling Of Lips Serious Cutaneous Reactions Are Rare. Tendinitis and tendon rupture: A few cases have occurred. Risk of tendon damage is higher in patients above 60 years of age and in those receiving corticosteroids. The FQ should be stopped at the first sign of tendinitis.  Ciprofloxacin and other FQs are contraindicated during pregnancy and in children However, under pressing situations like Pseudomonas pneumonia in cystic fibrosis and multi-resistant typhoid, ciprofloxacin has been administered to millions of children in India and elsewhere. Though a few cases of joint pain and swelling have been reported, cartilage damage has not occurred. Caution, nevertheless, is needed while using FQs in children. Interactions Plasma concentration of theophylline, caffeine and warfarin is increased by ciprofloxacin (also by norfloxacin and pefloxacin) due to inhibition of metabolism: CNS toxicity can occur by concurrent use of theophylline and a FQ. NSAIDs may enhance the CNS toxicity of FQs; seizures are reported. Antacids, sucralfate and iron salts given concurrently reduce absorption of FQs. Uses Ciprofloxacin is effective in a broad range of infections. Because of wide-spectrum bactericidal activity, oral efficacy and good tolerability, it is being extensively employed for empirical therapy of any infection, but should not be used for minor cases or where gram positive organisms and/or anaerobes are primarily causative. In severe infections, therapy may be initiated by i.v. infusion and then switched over to oral route Urinary tract infections: High cure rates, even in complicated cases or those with indwelling catheters/prostatitis, have been achieved. Comparative trials have reported higher successrates than with cotrimoxazole. Chronic Pseudomonas infections respond less completely. Gonorrhoeae: – Initially a single 500 mg dose was nearly 100% curative in non-PPNG as well as PPNG infections – But cure rate has declined due to emergence of resistance, and it is no longer a first line drug; may be used if strain is sensitive. Bacterial gastroenteritis: – Currently, it is the most commonly used drug for empirical therapy of diarrhoea. – However, it should be reserved for severe cases due to EPEC, Shigella, Salmonella and Campy. jejuni infection. – Ciprofloxacin can reduce stool volume in cholera Typhoid: – Ciprofloxacin is one of the first choice drugs in typhoid fever since chloramphenicol, ampicillin and cotrimoxazole have become unreliable due to development of resistance. – In India andelsewhere up to 95% S. typhi isolates were sensitive to ciprofloxacin. – However, increasing number of nonresponsive cases are being reported. – Ceftriaxone (or cefotaxime/cefoperazone) are more commonly used. Being bactericidal the advantages of ciprofloxacin Quick defervescence: fever usually subsides in 4–5 days but may take longer now. Early abetment of symptoms; low incidence of complications and relapse. Prevention of carrier state due to cidal action, good penetration into infected cells, high biliary and intestinal mucosal concentration. It can also be used to treat typhoid carriers (750 mg BD for 4– 8 weeks). This has been found to achieve 92% eradication rate compared to 50% by ampicillin. Bone, soft tissue, gynecological and wound infections: – Caused by resistant Staph. and gram-negative bacteria respond to ciprofloxacin. – High cure rates have been obtained in osteomyelitis and joint infections but prolonged treatment (6–8 weeks) with high doses (750 mg BD) is required. – Used along with clindamycin/ metronidazole (to cover anaerobes) it is a good drug for diabetic foot. Respiratory infections: – Ciprofloxacin should not be used as the primary drug because pneumococci and streptococci have low and variable susceptibility. – However, it can treat Mycoplasma, Legionella, H. influenzae, Branh. catarrhalis and some streptococcal and pneumococcal infections besides gram-negative ones. – Several 2nd generation FQs have now become available for the treatment of pneumonias and chronic bronchiti. Tuberculosis – It is a second line drug which can be used as a component of combination chemotherapy against multidrug resistant tuberculosis. – Recently, even FQ-resistant TB (extensively drug resistant or XDR-TB) have arisen. Gram-negative septicaemias: – Parenteral ciprofloxacin may be combined with a third generation cephalosporin or an aminoglycoside. Meningitis: Though penetration in CSF is not very good, ciprofloxacin has been successfully used in bacteria gram-negative meningitis, especially occurring in immuno compromised patients or those with CSF shunts. Prophylaxis: – Of infections in neutropenic/ cancer and other susceptible patients Conjunctivitis: – By gram-negative bacteria: topical therapy is effective.  Norfloxacin – It is less potent than ciprofloxacin: MIC values for most gram-negative bacteria are 2–4 times higher. – Many Pseudomonas and gram-positive organisms are not inhibited. – Moreover, it attains lower concentration in tissues which are non-therapeutic. – Unchanged drug as well as metabolites are excreted in urine. Norfloxacin is primarily used for urinary and genital tract infections.  Given for 8–12 weeks, it can treat chronic UTI. It is also good for bacterial diarrhoea, because high concentrations are present in the gut, and anaerobic flora of the gut is not disturbed. Norfloxacinis not recommended for respiratory and other systemic infections. Pefloxacin It is the methyl derivative of norfloxacin which is more lipid soluble, completely absorbed orally, penetrates tissues better and attains higher plasma concentrations. Passage into CSF is greater than other FQs— preferred for meningeal infections. It is highly metabolized—partly to norfloxacin which contributes to its activity.  Pefloxacin has longer t½: cumulates on repeated dosing achieving plasma concentrations twice as high as after a single dose. Because of this it is effective in many systemic infections as well. Dose of pefloxacin needs to be reduced in liver disease, but not in renal insufficiency. It is less effective in gram-positive coccal and Listeria infections. Ofloxacin This FQ is somewhat less active than ciprofloxacin against gram-negative bacteria, but equally or more potent against gram-positive ones and certain anaerobes. Good activity against Chlamydia and Mycoplasma has been noted.  It is an alternative drug for nonspecific urethritis, cervicitis and atypical pneumonia caused by Chlamydia trachomatis. It also inhibits M. tuberculosis; can be used in resistant cases of TB. High activity is exhibited against M. leprae, and it is being used in alternative multidrug therapy regimens  Ofloxacin is relatively lipid soluble; oral bioavailability is high, and higher plasma concentrations are attained. Food does not interfere with its absorption. It is excreted largely unchanged in urine; dose needs to be reduced in renal failure. Ofloxacin is comparable to ciprofloxacin in the therapy of systemic and mixed infections. Levofloxacin It is the active levo(s) isomer of ofloxacin having improved activity against Strep. pneumoniae and some other gram- positive and gram-negative bacteria. Anaerobes are moderately susceptible. Oral bioavailability of levofloxacin is nearly 100%; oral and i.v. doses are similar. It is mainly excreted unchanged, and a single daily dose is sufficient because of slower elimination and higher potency.  Theophylline, warfarin, cyclosporine and zidovudine pharmacokinetics has been found to remain unchanged during levofloxacin treatment. The primary indication of levofloxacin is community acquired pneumonia and exacerbations of chronic bronchitis High cure rates have been noted in sinusitis, pyelonephritis, prostatitis and other UTI, as well as skin/soft tissue infection Lomefloxacin It is a second generation difluorinated quinolone, equal in activity to ciprofloxacin but more active against some gram- negative bacteria and chlamydia. Because of longer t½ and persistence in tissues, it is suitable for single daily administration. However, due to higher incidence of phototoxicity and Q-T prolongation, it has been withdrawn in USA and some other countries, but is available in India, though infrequently used. Sparfloxacin Another second generation difluorinated quinolone which has enhanced activity against gram-positive bacteria (especially Strep. pneumoniae, Staphylococcus, Enterococcus), Bacteroides fragilis, other anaerobes and mycobacteria. Its major indicationsincludepneumonia, exacerbations of chronic bronchitis, sinusitis and other ENT infections. However, it has frequently caused phototoxic reactions: recipients should be cautioned not to go out in the sun.  Prolongation of QTc interval has been noted in 3% recipients. Fatal arrhythmias have occurred in patients taking other QT prolonging drugs concurrently. It has been discontinued in many countries including USA, but not yet in India. Dose: 200–400 mg OD oral. Gatifloxacin This 2nd generation FQ with higher affinity for bacterial topoisomerase IV was frequently used for gram positive coccal (mainly respiratory and ENT) infections. However, it caused Q-T prolongation, arrhythmias, phototoxicity, and unpredictable hypoglycaemia, because of which it was discontinued in most countries and has been banned in India since March 2011. Moxifloxacin A long-acting 2nd generation FQ having high activity against Str. pneumoniae, other gram-positive bacteria including β- lactam/ macrolide resistant ones and some anaerobes. It is the most potent FQ against M. tuberculosis. Bacterial topoisomerase IV is the major target of action. Moxifloxacin is primarily used for pneumonias, bronchitis, sinusitis, otitis media, in which efficacy is comparable to β- lactam antibiotics.  However, it is not good for urinary tract infections. It is primarily metabolized in liver; should not be given to liver disease patients. Side effects are similar to other FQs. It should not be given to patients predisposed to seizures and to those receiving proarrhythmic drugs Gemifloxacin Another broad spectrum FQ, active mainly against aerobic gram positive bacteria, especially Strep. pneumoniae, H. influenzae, Moraxella, Mycoplasma pneumoniae, Chlamydia pneumophila, Klebsiella including some multidrug resistant strains. Some anaerobes are also inhibited. It is rapidly absorbed, undergoes limited metabolism, and is excreted in urine as well as faeces, both as unchanged drug and as metabolites. Dose needs to be halved if creatinine clearance is 60 years age and in those with kidney damage. Do not mix aminoglycoside with any drug in the same syringe/infusion bottle. Ref: https://tmedweb.tulane.edu/pharmwiki/doku.php/aminoglycosides; last assessed on 04/05/2022 THANK YOU