Antibiotics In Obstetrics and Gynaecology Dr. Insaf Imthiyaz
Antibiotic or Antibacterial?The term antibiotic was first used in 1942 by Selman Waksman to describe anysubstance produced by a microorganism that is antagonistic to the growth of othermicroorganisms.What about drugs that “kill” microbes? A better term would be Antibacterials.This term includes the other antimicrobial agents such as antifungals, andsynthetic and semi synthetic agents.
AboutPenicillins are beta-lactam compounds which have a 4 membered beta-lactamring that is fused to a 5-membered thiazolidine ring. Side chain modifications ofthis structure confers:1) An improved spectrum of activity.2) Pharmacokinetic advantages.Six classes of penicillins are now available.
MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES1. Prevents cell wall synthesis by binding to enzymes called penicillin binding proteins (PBPs). These enzymes are essential for the synthesis of the bacterial cell wall.2. Bactericidal.3. Concentration-independent bactericidal activity.
Penicillin attacks bacterial cells by inactivating an enzyme that is essential forbacterial growth. The enzyme is peptidoglycan transpeptidase and it catalyses thecross-linking of the peptidoglycan, which forms the cell wall of the bacteria.The peptidoglycan transpeptidase enzyme is not needed in animals as their cellsdo not have cell walls.Therefore, the penicillin can safely disrupt the bacterial cell wall biosynthesiswithout harming existing cells in the body.The penicillin stops the growth of the bacterial cell wall, causing the pressureinside the cell to rise considerably until the cell lyses and thus the cell isdestroyed.
Penicillin G and V are only active against Gram Positive bacterial cells, whichhave an exposed layer of peptidoglycan around the outside of the cell wall,as shown below. Gram Negative bacteria have a more complicatedcomposition, which Penicillin G and V can not destroy, although there areother antibiotics that can.
Penicillin binds at the active site of the transpeptidase enzyme that cross-links the peptidoglycan strands. It does this by mimicking the D-alanyl-D-alanine residues that would normally bind to this site. The similarity between the structures of the residues and the penicillin molecule can be seen below:The labile β-lactam ring in penicillin reacts with a serine residue in the transpeptidaseas shown below.This reaction is irreversible and so the growth of the bacterial cell wall is inhibited. Theresulting complex is stable to water and remains attached to the polypeptide chain.
Sensitivity and Activity SPECTRUM OF ACTIVITY: Gram-positive aerobic cocci: Streptococci pyogenes (Group A strep), Streptococcus agalactiae (Group B strep), viridans streptococci, Enterococci. Staphylococci are usually resistant. Penicillin resistant S. pneumoniae with variable degrees of resistance (intermediately resistant, highly resistant) to penicillin is becoming a worldwide problem. Potential therapies for these resistant isolates include cefotaxime, ceftriaxone, vancomycin, imipenem. Gram-negative aerobes: Neisseria meningitidis, Pasteurella multocida. Anaerobes: Clostridium species, Fusobacterium species, Actinomyces israelii. Other: Treponema pallidum, Listeria monocytogenes.
Pharmacokinetics of PenicillinDistributes well into the urine; synovial, pleural, and pericardial fluids; cerebral spinal fluid(CSF).Elimination is primarily via the kidneys and dosage adjustment is necessary to minimizethe potential for seizures.Clinical Uses Useful for skin and soft tissue infections caused by Streptocccus pyogenes, meningitis caused by susceptible N. meningitidis and Streptococcus pneumoniae, oral or dental infections which frequently involve anaerobic streptococci, and syphilis which is caused by Treponema pallidum.
GENERAL SIDE EFFECTS/PRECAUTIONS:A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever,interstitial nephritis.B. Central nervous stimulation including myoclonic twitching and seizures. Risk factors include high doses, particularly when doses are not modified for renaldysfunction, lowered seizure threshold as may occur with meningitis.MISCELLANEOUS:A. Probenecid (usual dose of 500mg four times daily) blocks renal tubular transport ofpenicillin resulting in usually a 2-fold increase in penicillin blood levels.Useful in alternative regimens for syphilis in combination with amoxicillin; or incircumstances when higher blood levels of penicillin are desired.
SPECIFIC AGENTS:A. Aqueous penicillin G. This formulation is usually used in patients who require intravenouspenicillin for more severe or complicated infections (eg: meningitis, pneumonia). 3.4 meq of K+accompany each 1 million unit (1MU) of penicillin G and hyperkalemia may occur particularlywhen high doses are give to patients with renal dysfunction.B. Procaine penicillin G. Repository, intramuscular formulation that provides prolonged bloodlevels of penicillin. May be used for treatment of uncomplicated pneumonia caused by penicillin-susceptible Streptococcus pneumoniae; syphilis."Procaine reaction" characterized by dizziness, palpitations, auditory or visual disturbances,fear of impending death. Symptoms usually resolve within 5-10 minutes.C. Benzathine penicillin G. Long acting intramuscular formulation that provides low, bloodlevels for 3-4 weeks. Used for syphilis (primary, secondary, latent); rheumatic fever prophylaxis;Streptococcal pharyngitis.D. Penicillin G/Penicillin VK. Oral forms of penicillin. Penicillin G is susceptible to breakdownby gastric acid which is why it has been largely replaced by penicillin VK which is stable in theacid environment of the stomach.
PENICILLINASE-RESISTANT PENICILLINSSide chain modification prevents destruction of beta-lactam ring by beta-lactamases produced by Staphylococci. Thus, unlike penicillin G, penicillinase-resistant penicillins are useful for Staphylococcal infections.SPECTRUM OF ACTIVITYGram-positive aerobic cocci: Methicillin-susceptible Staphylococcus aureus(MSSA); viridans streptococci; less potent than penicillin against Streptococcuspyogenes (Group A strep) and Streptococcus pneumoniae; not active againstEnterococci.Gram-negative aerobes: Not active.Anaerobes: Compared to penicillin, less active or inactive against penicillin-susceptible anaerobes.
GENERAL CLINICAL USES:Primarily used to treat infections involving MSSA such as bacteremiaassociated with:1) indwelling devices2) injection drug use3) skin and soft tissue infections; and endocarditis which may be acomplication of bacteremia.Sometimes used in combination with an aminoglycoside (usuallygentamicin) for their synergistic effect against Staphylococci.GENERAL SIDE EFFECTS/PRECAUTIONS:A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever, interstitial nephritis.
SPECIFIC AGENTS:A. Nafcillin. IV/IM/PO formulations . Phlebitis, neutropenia.B. Methicillin. IV/IM formulations. Less commonly used because of increased risk ofinterstitial nephritis; signs and symptoms which include eosinophilia, rash, renalfailure, proteinuria, fever.C. Oxacillin. IV/IM/PO. Hepatitis occurs more frequently than with nafcillin.D. Dicloxacillin and Cloxacillin. PO formulations. These oral formulations arepreferred over oral forms of nafcillin or oxacillin because their blood levels are higher.
Amino-PenicillinsSide chain modification (addition of amino group) to basic benzylpenicillin moleculeincreases spectrum of activity to include aerobic gram-negative bacilli.
ActivityGram-positive aerobic cocci: Same activity as for penicillin G but is moreactive than penicillin against Enterococci. Like penicillin G, Staphylococci areusually resistant to ampicillin.Gram-negative aerobes: Active against most beta-lactamase negativeHemophilus influenzae; Escherichia coli and Proteus mirabilis, particularly ifinvolved with community-acquired infections; Salmonella and Shigella species.Usually not active against aerobic gram-negative bacteria causing hospital-acquired infections.Anaerobes: Clostridium species, Fusobacterium species, Actinomyces israelii.Other: Listeria monocytogenes.
Clinical UsageUsed as empiric therapy in many community-acquired infections involving therespiratory tract(eg: bronchitis, sinusitis, otitis media) where frequent pathogens includeStreptococcus pneumoniae, Hemophilus influenzae; urinary tract infections causedby susceptible Escherichia coli.A high prevalence of beta-lactamase producing aerobic gram-negative bacteria maypreclude the empiric use of amino-penicillins for these community-acquired infections.Side EffectsA. Hypersensitivity reactions manifested by rashes, eosinophilia, fever, interstitialnephritis.B. Ampicillin rash is a generalized erythematous, maculopapular rash that occurs inpatients taking ampicillin and who have a concurrent viral illness (eg: mononucleosis,cytomegalovirus, viral respiratory tract infection).
Specific AgentsA. Ampicillin. IV/IM/PO formulations. More effective than Amoxicillinagainst Shigella.B. Amoxicillin. PO formulation. More active than ampicillin againstSalmonella. Favored over ampicillin because: 1) better absorption, 2) food does not interfere with absorption, 3) less frequent dosing (8Hourly vs 6Hourly for Ampicillin).
Carboxy-Penicillins Side chain modification (substitution of amino group with a carboxy group and others) increases spectrum of activity to include other aerobic gram-negative bacilli.
SPECTRUM OF ACTIVITYGram-positive aerobic cocci:Less active than ampicillin against Enterococci, Streptococcus pneumoniae,Streptococcus pyogenes. Not active against methicillin-susceptibleStaphylococcus aureus (MSSA).Gram-negative aerobes:Active against many hospital-acquired pathogens such as Pseudomonasaeruginosa, Enterobacteriaceae (indole positive Proteus, Enterobacter,Morganella). Similar activity to ampicillin against Hemophilus species,Escherichia coli, Proteus mirabilis. Inactive against Klebsiella.Anaerobes:Bacteroides fragilis (at high concentrations)
Clinical Use Usually in combination with another antibiotic (generally an aminoglycoside) for aerobic gram- negative infections (especially P. aeruginosa).
Specific AgentsA. Carbenicillin indanyl sodium. PO formulation. An indanyl ester whichreleases active carbenicillin after breakdown in the liver. Low blood levelspreclude its use for infections outside the urinary tract.B. Ticarcillin. IV/IM formulations. Similar spectrum to carbenicillin exceptthat it is 2-4 times more active than carbenicillin against Pseudomonasaeruginosa.Side effects include occasional bleeding due to platelet dysfunction. Eachgram of ticarcillin is accompanied by 5.2meq of sodium. .
Spectrum of Activity Gram-positive aerobic cocci: More active than carboxy- penicillins against Enterococci, Streptococcus pneumoniae, Streptococcus pyogenes. Gram-negative aerobes: Active against many hospital-acquired pathogens such as Pseudomonas aeruginosa (more active than carboxy-penicillins); Enterobacteriaceae (eg: Klebsiella, indole positive Proteus, Enterobacter, Morganella). More active than ticarcillin against Hemophilus influenzae.
Specific AgentsA. Mezlocillin (MezlinR). IV/IM formulations. Similar spectrum of activityto ticarcillin including comparable activity against Pseudomonasaeruginosa; invitro may be more active against Klebsiella pneumoniae.Each gram contains 1.85meq of sodium.B. Piperacillin (PipracilR). IV/IM formulations. It is 4-fold moreactive than mezlocillin against Pseudomonas aeruginosa.
Penicillin/ Inhibitor CombinationsIn order to overcome resistance due to beta-lactamase enzymes, variouspenicillins have been combined with beta-lactamase inhibitors that irreversiblyinhibits beta-lactamases. Unfortunately, not all beta-lactamase enzymes can beneutralized by the currently available beta-lactamase inhibitors.These inhibitors generally do not have any clinically useful antibacterial activity.Currently available products combine ampicillin, amoxicillin, ticarcillin, orpiperacillin with a beta-lactamase inhibitor.The intrinsic antibacterial activity of the penicillin is an important factor in theeffectiveness of the penicillin/inhibitor combinations.
Clinical UseAs monotherapy for mixed aerobic/anaerobic infections caused bysusceptible bacteria (eg: intraabdominal/gynecologic infections, skinand soft tissue infections such as diabetic ulcers).For serious infections or infections in which resistant gram-negativebacteria are suspected a second agent (eg: aminoglycoside) can beadded.
A. Ampicillin/sulbactam (UnasynR). IV/IM formulations.Has the spectrum of ampicillin plus beta-lactamase producing organisms such asHemophilus influenzae, Moraxella catarrhalis, Bacteroides fragilis, Escherichia coli(although susceptibilities to Escherchia coli is variable), Proteus species,Klebsiella species, Enterobacter aerogenes, Acinetobacter calcoaceticus,methicillin-susceptible Staphylococcus aureus (MSSA). Useful for infections due tothese beta-lactamase producing bacteria (sinusitis, otitis); mixedaerobic/anaerobic infections, bite wounds.B. Amoxicillin/clavulanate (AugmentinR). PO formulation. Similar toampicillin/sulbactam with respect to spectrum of activity and clinical usefulness.
C. Ticarcillin/clavulanate (TimentinR). IV/IM formulations.Has the spectrum of ticarcillin plus beta-lactamase producing bacteria such as`Staphylococcus aureus, Escherichia coli, Klebsiella species, Proteus, Hemophilusspecies, Bacteroides fragilis.Clavulante does not increase the activity of ticarcillin against gram-negativebacteria that produce Class 1 Richmond-Sykes beta-lactamases (eg:Pseudomonas, Serratia, Citrobacter, Enterobacter).D. Piperacillin/tazobactam (ZosynR). IV/IM formulations.Has the spectrum of piperacillin plus beta-lactamase producing bacteria such asEscherichia coli, Enterobacter, Citrobacter, Providencia, methicillin-susceptibleStaphylococcus aureus, Bacteroides fragilis, Hemophilus species.
Dosage and AdministrationAqueous penicillin G 1-4 million IV 4-6Penicillin G units PO 6Pencillin VK 250-500 mg PO 6 250-500 mgAmpicillin 1-2 gm IV/IM 4-6 250-500 mg PO 6Ampicillin/sulbactam 3 gm IV/IM 6Ticarcillin/clavulanate 3.1 gm IV 4-6Piperacillin/tazobactam 3.75/ 4.5gm IV 4-6Amoxicillin/clavulanate 375mg / PO 8h - 12h 625mg
Structure of CephalosporinsCephalosporins are structurally related to Penicillins, they contain a B-lactamase ringattached to a dihydrothiazaline ring.
Classification of CephalosporinsCephalosporins have been divided in 5 generations depending on there antibacterial activity. Generation Range of Activity Aerobic gram-positive organisms and some 1 Generation st community-acquired gram-negative organisms (Cephalexin, Cephradine, and Cefadroxil) (P mirabilis, Escherichia coli, Klebsiella species) 2nd Generation Extended Gram negative coverage, (Cefuroxime,Cefprozil,Cefeclor,) (Indole-positive Proteus ,Klebsiella M catarrhalis and Neisseria species) 3rd Generation Active against staphylococci, Serratia (Cefexime,Cefpodoxime,Cefotaximem marcescens, Providencia, Haemophilus, and Ceftriaxone) Neisseria, including -lactamase–producing strains 4th Generation Effective against pseudomonas aeroginosa (Cefepime) 5th Generation
Mechanism of Action1. Cephalosporins are bactericidal and have the same mode of action as otherbeta-lactam antibiotics (such as penicillins)2. but are less susceptible to penicillinases.3. Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterialcell walls. The peptidoglycan layer is important for cell wall structural integrity. 4. The final transpeptidation step in the synthesis of the peptidoglycan isfacilitated by transpeptidases known as penicillin-binding proteins (PBPs).5. PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycanprecursors) to crosslink the peptidoglycan.6. Beta-lactam antibiotics mimic the D-Ala-D-Ala site, thereby competitivelyinhibiting PBP crosslinking of peptidoglycan.
1st Generation Of CephalosporinsAntimicrobial ActivityGram-positive: Activity against penicillinase-producing, methicillin-susceptible staphylococci and streptococci(though they are not the drugs of choice for such infections). No activity against methicillin-resistantstaphylococci or enterococci.Gram-negative: Activity against Proteus mirabilis, some Escherichia coli, and Klebsiella pneumoniae("PEcK"), but have no activity against Bacteroides fragilis, Pseudomonas, Acinetobacter, Enterobacter, indole-positive Proteus, or Serratia
Drug, Route and Dosage (1st Gen) Name Route of Administration Dosage Cefadroxil Oral Cefradine Oral Cephalexin Oral Cefazolin IV (Preferred) /IM Cefalonium Cefaloridine
Clinical Use Oral drugs : 1. Urinary tract infections, 2. Minor skin and soft tissue infections (eg, cellulitis, soft tissue abscess). Intravenous : 1. Most clean surgical prophylaxis The second-generation cephalosporins cefoxitin and cefotetan have expanded anaerobic activity and are superior to first-generation agents as prophylaxis for colorectal surgery or for hysterectomy. N.B : First-generation cephalosporins do not adequately penetrate into cerebrospinal fluid and are less potent than second- and third-generation agents and cannot be used to treat meningitis.
2nd Generation of Cephalosporins Gram-positive: Less than first-generation. Gram-negative: Greater than first-generation: HEN (Haemophilus influenzae, Enterobacter aerogenes and some Neisseria + the PEcK described above
Drug, Route and Dosage (2nd Gen) Name Route of Administration DosageCefaclor OralCefonicidCefuroxime Oral/IV O : 12h IV : 8HCefmetazole AntianaerobicCefotetanCefoxitin
Clinical Use Because of their activity against -lactamase–producing H influenzae and M catarrhalis, cefprozil and cefuroxime axetil have a role in the treatment of sinusitis and otitis media in those patients unresponsive to amoxicillin. Because of their activity against B fragilis, cefoxitin and cefotetan can be used to treat mixed anaerobic infections, eg, peritonitis and diverticulitis. Cefoxitin and cefotetan are useful as prophylaxis in colorectal surgery, vaginal or abdominal hysterectomy, and appendectomy due to their moderate to strong activity against B fragilis.
3rd Generation CephalosporinsGram-positive: Some members of this group (in particular, thoseavailable in an oral formulation, and those with antipseudomonal activity)have decreased activity against Gram-positive organisms.Gram-negative: Third-generation cephalosporins have a broadspectrum of activity.They may be particularly useful in treating hospital-acquired infections.They are also able to penetrate the CNS, making them useful againstmeningitis caused by pneumococci, meningococci, H. influenzae, andsusceptible E. coli, Klebsiella, and penicillin-resistant N. gonorrhoeae.Since 2007, third-generation cephalosporins (ceftriaxone or cefixime)have been the only recommended treatment for gonorrhea in the UnitedStates.
Drug, Route and Dosage (3nd Gen) Name Route of Administration DosageCefotaximeCeftriaxoneCeftazidimeCefiximeCefpimizole
Clinical UseBecause of their penetration into the cerebrospinal fluid and potent in vitroactivity, intravenous third-generation cephalosporins are useful to treatmeningitis due to susceptible pneumococci, meningococci, H influenzae, andsusceptible enteric gram-negative rods.In meningitis in older patients, third-generation cephalosporins should becombined with ampicillin or trimethoprim-sulfamethoxazole until Lmonocytogenes has been excluded as the etiologic pathogenCeftazidime has been used to treat meningitis due to Pseudomonas. Thedosage for meningitis should be at the upper limits of the recommended range,because cerebrospinal fluid levels of these drugs are only 10–20% of serumlevels.Ceftazidime is frequently administered empirically in the febrile neutropenicpatient.
Ceftriaxone is indicated for gonorrhea, chancroid, and more seriousforms of Lyme disease.Because of its long half-life and once-daily dosing requirement,ceftriaxone is an attractive option for the outpatient parenteraltherapy of infections due to susceptible organisms..Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are thebest third-generation oral agents against pneumococci and Saureus.Cefixime is available in an oral suspension and 400-mg tablets.This latter dosage form is important because it is the only oral agentrecommended by the Centers for Disease Control and Prevention(CDC) for the treatment of uncomplicated urogenital or rectalgonorrhea.
4th Generation CephalosporinsGram-positive: They are extended-spectrum agents with similaractivity against Gram-positive organisms as first-generationcephalosporins.Gram-negative: Fourth-generation cephalosporins arezwitterions that can penetrate the outer membrane of Gram-negative bacteria.They also have a greater resistance to beta-lactamases than thethird-generation cephalosporins. Many can cross the blood–brainbarrier and are effective in meningitis. They are also usedagainst Pseudomonas aeruginosa.
Drug, Route and Dosage (4th Gen) Name Route of Administration DosageCefclidineCefepimeCefozopranCefpirome
5th Generation Cephalosporins Ceftobiprole has powerful antipseudomonal characteristics andappears to be less susceptible to development of resistance.
Drug, Route and Dosage (5th Gen) Name Route of Administration DosageCeftobiproleCeftaroline
Clinical Use Ceftaroline is a novel cephalosporin that has activity against MRSA with phase III clinical trials for complicated skin and skin structure infections with reported non-inferior efficacy against MRSA compared to vancomycin and aztreonam
Mechanism of ActionSimiliar to the other B-lactamases.It has a wide spectrum of activity that includes that includesmost gram-negative rods (including P aeruginosa) and gram-positive organisms and anaerobes, with the exception ofBurkholderia cepacia,Stenotrophomonas maltophilia,Enterococcus faecium,and methicillin-resistant S aureus and Staphylococcusepidermidis.
Drug Route of Dosage AdministrationImepenam IV 1 - 2g 8hourlyMerapenam IV 1 - 2g 8hourlyErtapenam IV 1 g every 24 hours
Clinical Use In patients hospitalized for a prolonged period with presumed infection with a multidrug-resistant organism. Not used alone for serious pseud.infections Not used for MRSA infections
QuinolonesThe quinolones are synthetic analogs of nalidixic acid with a broad spectrum of activity against many bacteria.
Mechanism Of ActionQuinolones inhibit the action of DNA gyrase and topoisomerase IV andkill bacteria by binding to these enzyme-DNA complexes, therebydisrupting DNA replication.
Spectrum Of ActivityEnterobacteriaceaeHaemophilusNeisseriaMoraxella Fluoroquinolones are lessBrucella potent against gram-positiveLegionela than against gram-negativeSalmonella organismsShigellaCampylobacterYersiniaVibrioand Aeromonas organisms
Gemifloxacin, levofloxacin, and moxifloxacin have the bestgram-positive activity, including against streptococci,pneumococci and S aureus and S epidermidis, and somemethicillin-resistant strains.T pallidum and Nocardia are resistant to all fluoroquinolones.Moxifloxacin also provides the most reliable coverage of M tuberculosis.
Pharmacokinetics and AdministrationsAfter oral administration, the fluoroquinolones are well-absorbed and widely distributed in body fluids and tissuesand are concentrated intracellularly.Fluoroquinolones bind some heavy metals; thus, absorptionis inhibited when administered concomitantly with iron,calcium, and other multivalent cations.Optimal oral bioavailability is achieved if fluoroquinolones aretaken 1 hour before or 2 hours after meals.
Drug Route Of Dosage AdministrationNorfloxacin PO 400mg /12 HrlyCiprofloxacin PO 250 – 750 mg / 12hrly IV 200 – 400 mg / 12hrly Ofloxacin PO 200 – 400 mg / 12hrly IV 200 – 400 mg / 12hrlyLomefloxacin PO 400mg / 24 hrly
Clinical Use Urinary tract infections: Uncomplicated, complicated urinary tract infections,prostatitis. Only ofloxacin and ciprofloxacin are approved for prostatitis. Sexually transmitted diseases : Neisseria gonorrhea. single doses of ciprofloxacin and ofloxacin can be used for uncomplicated urethritis, cervicitis, or rectal infections. Reports of fluoroquinolone-resistant gonococci are emerging. Chlamydia trachomatis : Ofloxacin is the only approved quinolone. Chancroid : Ciprofloxacin approved. Community-acquired (eg: pneumonia, bronchitis, otitis). Should not be used alone as empiric therapy because of their inadequate activity against Streptococcus pneumoniae, one of the common pathogens in these infections. Quinolones would be effective alternatives when infections are caused by gram- negative bacteria such as Hemophilus influenzae, and Moraxella catarrhalis that are resistant to agents such as amoxicillin, trimethoprim/sulfamethoxazole.
Contd...Hospital-acquired (eg:pneumonia). Have been effective for gram-negative pneumonia.Aspiration pneumonia. Should not be used because of their lack of activityagainst anaerobes.Atypical pneumonia (eg: Mycoplasma, Chlamydia, Legionella). Furtherstudies are needed to determine the role of quinolones in these infections.Bone and Joint. Gram-positive bacteria. Although data exists todemonstrate their effectiveness, quinolones are not the drugs of choicebecause of their moderate activity against Staphylococci, and tendency forresistance to develop.
Contraindicated in Pregnancy (1st trimester for trichomoniasis).
Metronidazole is an antiprotozoal drug, active against mostanaerobic gram-negative bacilli (ie, Bacteroides, Prevotella,Fusobacterium) as well as Clostridium species but hasminimal activity against many anaerobic gram-positive andmicroaerophilic organisms.It is well absorbed after oral administration and is widelydistributed in tissues.It penetrates well into the cerebrospinal fluid, yielding levelssimilar to those in serum.The drug is metabolized in the liver, and dosage reduction isrequired in severe hepatic insufficiency or biliary dysfunction.
Mechanism Of ActionMetronidazole is cytotoxic to facultative anaerobic bacteriaFour Step Process of Action1. Entry into the microorganism — Metronidazole is a low molecularweight compound that diffuses across the cell membranes of anaerobic andaerobic microorganisms. However, antimicrobial activity is limited toanaerobes.2. Reductive activation by intracellular transport proteins — Metronidazole isreduced by the pyruvate:ferredoxin oxidoreductase system in the mitochondria ofobligate anaerobes, which alters its chemical structure. Pyruvate:ferredoxinoxidoreductase normally generates ATP via oxidative decarboxylation of pyruvate.With metronidazole in the cellular environment, its nitro group acts as an electronsink, capturing electrons that would usually be transferred to hydrogen ions in thiscycle. Reduction of metronidazole creates a concentration gradient that drivesuptake of more drug, and promotes formation of intermediate compounds and freeradicals that are toxic to the cell.
3. Reduced intermediate particle interacts with intracellular targets —Cytotoxic intermediate particles interact with host cell DNA, resulting in DNAstrand breakage and fatal destabilization of the DNA helix.4. Breakdown of cytotoxic intermediate products — The toxic intermediateparticles decay into inactive end products
Clinical Use Vaginitis caused by Trichomonas vaginalis : Single dose of either metronidazole or tinidazole (2 g) or 500 mg orally three times daily for 7 days. Bacterial vaginosis 500 mg twice daily for 7 days. Metronidazole vaginal cream (0.75%) applied twice daily for 5 days is also effective. Anaerobic infections, Metronidazole can be given orally or intravenously, 500 mg three times daily (30 mg/kg/d). Metronidazole is active against virtually all of B fragilis isolates.
Clinical Use Contd: Preparation of the colon before bowel surgery. Therapy of brain abscess, often in combination with penicillin or a third-generation cephalosporin. In combination with clarithromycin and omeprazole for therapy of H pylori infections.
Adverse ReactionsSeizures, peripheral neuropathy, GI upset, anorexia, constipation,headache, metallic taste, dysuriaHigh doses and/or long-term systemic treatment withmetronidazole is associated with the development of leukopenia,neutropenia, increased risk of peripheral neuropathy and/orCNS toxicity.
Mechanism of ActionErythromycins inhibit protein synthesis by binding to the50S subunit of bacterial ribosomes.Which causesdissociation of t-RNA from the ribosome inhibits proteinsynthesis.They generally are bacteriostatic and sometimes bactericidalfor gram-positive organisms, including most streptococci andcorynebacteria
Spectrum Of ActivityGram positive aerobes - Active against streptococcuspneumoniae and other streptococci, staphylococci, andcorynebacterium diphtheriae.Gram negative aerobes - Active against Legionellapneumophila, Neisseria gonorrhoeae, Moraxella catarrhalis,Bordetella pertussis.Enterobacteriaceae are resistant.Anaerobes - Bacteroides fragilis are usually resistant.Other - Mycoplasma pneumoniae, chlamydiatrachomatis/pneumoniae, Treponema pallidum.
Clinical UseCommunity-acquired Pneumonias - where atypicalpathogens such as Mycoplasma pneumoniae and Legionellapneumophilia are common.Chlamydial infections (ie. chlamydia pneumoniaepneumonia or chlamydia trachomatis pelvic infections,especially in pregnancy.)Bordetella pertussis
Streptococcal infections in patients with Penicillin allergyMinor staphylococcal skin infectionsCampylobacter gastroenteritisSyphilis in pregnancyProphylaxis of bacterial endocarditis
Dosage Oral - Several oral preparations are available: Available as capsules and film-coated tablets. Dose is 250-500 mg po q6 hours, 500 mg po q12h depending on the severity of illness and the indication. Parenteral - Used for patients with serious infections or patients unable to take oral medications. Dose is 250-1000 mg iv q6h. Must be given as an intravenous infusion.
Clarithromycin and AzithromycinGram positive aerobes - Clarithromycin is 2-4 times more active in vitrothan erythromycin against most streptococci and staphylococci.Azithromycin is 2-4 times less active against the gram positives comparedto erythromycin.Gram negative aerobes - Azithromycin has greater activity than botherythromycin and clarithromycin against Moraxella catarrhalis andHemophilus influenzae.
Clinical Use Upper and lower respiratory tract infections (ie. pharyngitis,sinusitis, bronchitis and pneumonia) - to cover pathogens usuallyseen in these infections such as S. pneumoniae, H. influenzae,M. pneumoniae, M. catarrhalis.Skin infections – uncomplicatedNon-gonococcal urethritis and cervicitis due to Chlamydiatrachomatis (Azithromycin only).Mycobacterium Avium Complex in patients with AIDS -Clarithromycin is approved for treatment, and must be used incombination with at least one other drug. Both clarithromycin andazithromycin are approved for MAC prophylaxis.Helicobacter pylori - Clarithromycin
DosageClarithromycinDose is 250-500 mg po q12 hours depending on infection beingtreated, usually upto 7 daysAzithromycin500 mg once daily for 3 days or500 mg on first day and 250mg once daily for 4 days