Spectrum of Commonly used antibiotics Dr. Mahen Kothalawala MBBS, Diploma in Microbiology, MD, MPH(NZ) Consultant Clinical Microbiologist Teaching Hospital Kandy SriLanka
Line up• Antibiotics and Antibiosis• Antibiotic General• Classification of antibiotics• Different types of antibiotic – Penicillins – Cephalosporins – Other Cell-wall active drugs – Amino glycosides – Other Antibiotics – used in SL• Some pharmacokinetic and Pharmacodynamic Parameters
Antibiotics• Are types of medications that destroy or slow down the growth of bacteria.• anti bios (GREEK) – anti means "against", – bios means "life“• Any substance which used for this purpose is called an antibiotic
Antibiosis• Is a biological interaction between two or more organisms that is• detrimental to at least one of them – or• an antagonistic association between an organism and the metabolic substances produced by another(antibiotic)• Form of “Modified biological control” of organisms• The relationship between an antibiotic and an infectious organism is one form of antibiosis
An antibiotics are• Different to other drugs• Antibiotics- – Act on targets in the bacterial cell/organisms (Selectively toxic to bacteria/Organisms) – While no effective action on Human cell(Selective advantage)• All other drugs- – Act on targets in human cells/ Targets in human cells. Antibiotics – no useful action on human cells
Antibiotics• Are societal drugs – – Resistance occur not only within the person taking the antibiotic – Harmful effect may transfer to others as well – The resistance development is progressive and independent• “resistance gene passes very easily to other individuals”• Ingestion of one capsule of Amoxycillin – The selected resistant organisms shed in stools nearly three months- even after discontinuation of therapy
• No other category of drugs used in medicine demonstrate this quality
Activity of an Antibiotics• Desired Effect –Selective inhibition on bacterial cell –Which provide selective advantage• Undesired effects• Adverse effects – – Dose related (Predictable) • Renal Failure with Aminoglycosides • RF and oto-toxicity with Vancomycin – Non dose related(Un predictable) –Idiosynchratic reaction with chloramphenicol or Sulpha drugs – Hyper sensitivity reaction of –penicillin
Why antibiotics need so much of discussion?1. We have discovered almost all naturally occurring ones (No new ones)2. Organisms readily become resistant to the agents rendering them ineffective(Not tachyphylaxis or not through enhanced metabolism of drugs)3. The resistance is transferable The resistance mechanism/s readily become transferable to intra species or inter species
C. Broad Spectrum vs Narrow Spectrum •Carbepenams •Penicillin V and G •Chloramphenicol •Lincosamides(Clindamycin) •2nd 3rd 4th Gen Cephalosporiins •Glycopeptides(Vanco and Teicoplanin) •3rd Gen Fluoroquinolones •Streptogramins •Broad spectrum penicillins •Rifamycins •Tetracyclines •Daptomycin Broad Spectrum Coverage Narrow Spectrum Coverage
PenG,V, Nafcillin, Oxacillin, FluClox and Clox are bulky and less soluble in water Amph, Amoxy are more polardissolves readily inwater due to amine group attached Tic and Pip are made further polar by adding COOH and CO (NH)2 in to R group
Spectrum of penicillins• Narrow spectrum penicillin – Pen G,Pen V – Clox, Flu clox etc – Mecillinam• Broad Spectrum – All others• Extended Spectrum
Summary• Penicillin G and V are useful only for• Gram Positives and Anerobic Rods – (Clostridium tetany and Clostridium perfringens)• All gram negatives are resistant to penicillin G and V• Cloxacillins (Inclusive of Flu clox, DiClox, Oxa and Naf cillin) are exclusively for MSSA – DOC of MSSA – Are Above• Amphicillin and amoxycillin covers similar spectrum –only difference is dosage frequency and interference to absorption by food for amphicllin• Becampicillin – are amphicllin esters which were formed to overcome ↓of absorbtion due to food – No advantage over each other
Broad spectrum penicillins• Ticarcillin, Piperacillin, and Cabenicillin has anti psudomonal activity• Its spectrum is extended by adding Clav, Tazo and Sulbactam to withstand enzymetic degration• Piperacillin is more potent than ticarcillin against pseudomonas• Mecillinam is exclusive for gram negatives
Borad spectrum penicillins are• Need to be given high doses – Piperacillin – 4.5g -3 to 4 times – Ticarcillin as 3.2g- 3 to 4 times• May causes electrolyte imbalance
• Piperacillin has greater intrinsic activity against aerobic gram negative rods, than Ticarcillin• Adding Clavums will increase/expand the spectru of penicillins.
G Nafcillin Oxacillin CloxacillinAmphi-sul Amphicillin Amoxycillin Flucloxacillin Penicillin V & Co-amoxyclav BecamphicillinX X X X O Streptococcus PyogenesX X X X O Streptococcus pneumoniae(DSSP) Streptococcus pneumonia(DRSP)O X O X O X O X O O Enterococcus X Staphylococcus(MSSA)O O O O O O O O O Staphylococcus MRSAX X X Gram Positive RodsX X X O X O O Neisseria MenicngitidisO O O O O Neiseeria gonorhoeaX X X O O Gram Negative rods(Sensitive)X X O O O Gram Neg Rods(βlactamase+)O O O O O Gram Negative –KPC ProducersO ) O O O O Gram Negative ESBL(O O O O O PseudomonasX O O O O Acinetobacter spX O O O O Atypical organismsX X X X O Spirochaetes(Lepto,, Treponema)O O O O O Spirochaete(Borrelia)
TicarcillinMero/Ime Amoxy-clv Mezlocillin Piperacillin Aztreonam Mecillinam Piptaz-TacClav Clavulinic AcidX X X X O O O Streptococcus PyogenesX X X X O O O Streptococcus pneumoniae(DSSP)X X X X O Streptococcus pneumonia(DRSP)X X X X O O O O EnterococcusX X X Staphylococcus(MSSA)O O O O O O O O O Staphylococcus MRSAX X X X Gram Positive RodsX X X X O O O O Neisseria MenicngitidisX X X X O O Neiseeria gonorhoeaX X X X X X O Gram Negative rods(Sensitive)X X X X O O Gram Neg Rods(βlactamase+)O O O O O O Gram Negative –KPC Producers ) #X O O O O O Gram Negative ESBL(X X X X O O PseudomonasO O O O O O Acinetobacter spO O O O O O Atypical organisms- X X O O O Spirochaetes(Lepto,, Treponema)- O O O O O Spirochaete(Borrelia)
Hypersensitivty reaction to penicillin• Major Ractions – Rare 1 in 10,000 doses• Common reactions- MP rash with amphicillin, sometimes subsequent exporsure may not result rash• 100% patients with IM, develop amphicillin rash, if amp is given• Should be very careful when labelling a patient penicillin hypersensitive –Degree of reaction should be noted down
Major hypesrsensitivity• Anaphylaxis – 1/10000 patients – Hives, angioedema, rhinitis, asthma, and anaphylaxis. – 10% mortality rate. – Anaphylaxis possible after negative skin testing. – Avoid all other B-lactams. – Mainly occur within first hour of exposure Even with the first exposure to pen can get major HS reactions Should be given in diagnosis card For true HS patients –No beta lactam should be given
Cephalosporins• Are semi-synthetic antibiotics derived from 7- Amino cephalosporanic acid (7-ACA (cephem nucleus).• Similar to penicillins in – mechanism of action, – chemical structure, and – toxicities
Traditionally divide into• Generations• On• 1. Availabile form –IV or oral• 2. Coverage• 3. Ability withstand degradation by ᵦ Lactamases
Gram Negative activity Improves Gram Positive Activity Improves First Second Third ForthGeneration Generation Generation Generation Increasing activity against gram-negative bacterial and anaerobes Increasing activity against Pneumococcus Increasing ability to reach cerebrospinal fluid
First generation cephalosporinsClinical uses• To treat gram-positives.• Usually for non life threatening infections• IV form is used to treat infections of mild mild to moderate severe infection by sensitive bacteria.
Agents• Cephalexin• Cephalothin• Cephradine• Cefazolin• Cefadroxil• Cefazolin- Main surgical prophylactic agent in west (t ½ is 2 hrs)
Second generation cephalosporinsPharmacological propertiesThey exhibit• enhanced activity against gram-negatives • First Gen< Second Gen < Third Gen • but less than that of Third Gens• More stability to bacterial β-lactamase• Renal friendly than First Gen
Second generation cephalosporinsClinical uses• first choice drugs for gram-negative bacteria• other indications are similar with First Gens• In SL – Surgical prophylaxis (t1/2 is 80 min)
Second generation cephalosporins• Cefuroxime,• Cefamandole,• Cefaclor• Ceforanide
Cephamycins• Classified with second gen – Cefoxitin – Cefotitan• Has anaerobic coverage and second gen coverage
Third generation cephalosporinsPharmocological properties – least activity on gram-positive • First Gen > Second Gen < Third Gen – most active on Gram Negs • First Gen < Second Gen < Third Gen – high stability with β-lactamase; (Not to ESBL) – Easily penetrate to different tissues (Including CSF) – little kidney toxicity. – Some third Gens are active against Pseudomonas (CAZ)
Third generation cephalosporinsClinical uses• Severe gram-negative resistant bacilli infection.• Other complex infection• Community acquired pneumonia and meningitis• SSTI
Fourth generation cephalosporins – Cefepime – Cefpirome• have similar antibacterial activity with third generation on most gram-negatives,• more stable to β-lactamase.
New Cephalosporins• Classified as “Fifth Generation”• Ceftibiprole and Ceftibuten
Ceftobiprole• Activity against – MRSA, – DRSP, – Pseudomonas aeruginosa, and – Enterococci• Shown statistically non-inferiority to Vancomycin and Ceftazidime combination
(PO Cefoxitin cEFIPIME Ceftrixone Cephalexin Amoxycillin CefuroximeCeftibiprole Ceftazidime Cefazolin (IV); X X X X X XX O Streptococcus Pyogenes X X X X XX O O Streptococcus pneumoniae(DSSP) X X XX Streptococcus pneumonia(DRSP)X O O O O O O O O O O O Enterococcus X X X X XX Staphylococcus(MSSA) O XX O O O O O O O Staphylococcus MRSA X X X X X XX Gram Positive Rods X O X XX O O O O Neisseria Menicngitidis X X X X XX O O Neiseeria gonorhoea X X X X XX O Gram Negative rods(Sensitive) X XX O O X* O Gram Neg Rods(βlactamase+)? O O O O X* O O X* O Gram Negative –KPC Producers? ) O O O O O O O Gram Negative ESBL( X XX O O O O O Pseudomonas O O O O O O O Acinetobacter sp X O O O O O OO Atypical organisms X O O O O O OO Spirochaetes(Lepto,, Treponema) 0 X X XX O O O Anerobes
Other β-lactams• Carbapenems – Imipenem – Meropenem – Panipenem – Ertepenam• Has super broad antibacterial spectrum• Resistant to activity of many bacterial enzymes• Nearly all gram-negative and gram-positive bacteria are treatable –EXCLUSION -Atypicals• Carbapenems are one of the antibiotics of last resort for many bacterial infections
Emerging issues – Acinetobacter, – Metalo betal lactamases producing organisms and – Carbepenamases producing organisms Are resistant to carbepenems• Carbepenem resistance – An emerging grave concern• NDM-1 – Rapidly spreading resistant gene
• One case of KPC –Klebsiella pneumoniae reported in THK recently• Options for treatment?
• Rate of Carpepenem usage = Poor Infection control activities• Sorry state prevails in THK,( and in all around SL) • From here to where?
Other β-lactamsMonobactams – Aztreonam – Carumonam• highly resistant to ß-lactamases.• Effective in treating – Gram-negative urinary tract infections, – lower respiratory tract, – skin, intra abdominal, – gynecologic infections and septicemia.
Other β-lactamsβ-lactamase inhibitors• This kind of drug include – clavulanic acid, – sulbuctam and – tazobactam.• They are potent inhibitors of many kind of ß- lactamases• It increases the spectrum of penicillins• Sulbactam has Acinetobactor coverage
VancomycinOnly effective against gram-positive bacteriaUsed to be the “Magic bullet” for methicillin- resistant (MRSA)Slowly bactericidal – agaist StaphIf, Staph are sensitive to Clox, DOC for that become Clox (Not Vanc)Poor oral absorption => Therefore available only in IV formFor psudomembranous colitis (PMC) – oral form available –NA in SL
Vanco• Given for Penicillin allergic patients• DOC for surgical prophylaxis in patients with a history of severe penicillin allergy• I have came across – 5 patients who developed “allergic Reactions” to Vanc (Which is highly unlikely• Could be “Rate related Anaphylactoid Reaction” – For three patients treated well with Low rate vacomycin (RMS)
Vanc• Adverse effects. – Fever, chills, phlebitis and red man syndrome. • Slow injection and prophylactic antihistamines. – Ototoxic – may potentiate known ototoxic agents.• Renal excretion (90-100% glomerular filtration). – Normal half-life 6-10 hours. – Half life is over 200 hours in pts with ESRD
Teicoplanin• Teicoplanin is similar to Vanc in action and structure• No RMS• Can be given as a iv push• Renal failure –Can give few doses safetly
Side effects• Tinnitus and high tone deafness• Dose related Renal toxicity• Potentiating of activity of other renal toxic drugs• Red man Syndrome – Never to give as a injection or as a bolus
Aminoglycosides• Broad spectrum antibiotics (bactericidal)• Penetration into cell requires an oxygen-dependent transport => anaerobes are resistant• Poor oral absorption (very polar) => parenteral administration• Narrow therapeutic range - severe side effects: – Ototoxicity: destruction of outer hair cells in organ of Corti – Nephrotoxicity: killing of proximal tubular cells – Neuromuscular toxicity: blockage of presynaptic ACh release => respiratory suppression• Elimination almost completely by glomerular filtration (impaired kidney function => concentration of AG increases => toxicity)Drug Interaction with other antibiotics• Chloramphenicol blocks this transport => inhibits AG uptake into bacteria;• Penicillins weaken the cell wall => promote AG uptake)
• Adverse effects: – Ototoxic – associated with high peak levels and prolonged therapy. Pts on loop diuretics, vancomycin and cisplatin are at higher risk. • Cochlear and vestibular. • Concentrates in endolymph and perilymph. – Nephrotoxic. • Proximal tubule damage.
Amikacin NetilmIicin Gentamicin0 0 0 Gram PositivesX X X Staphylococcus(MSSA)0 0 0 Staphylococcus MRSA0 0 0 Gram Positive Rods0 0 0 Neisseria Menicngitidis0 0 0 Neiseeria gonorhoeaX X X Gram Negative rods(Sensitive)X X X Gram Neg Rods(βlactamase+) xX X Gram Negative –KPC ProducersX X X ) Gram Negative ESBL(X X XX Pseudomonas X X Acinetobacter sp Aminoglycosides0 0 0 Atypical organisms0 0 0 Spirochaetes(Lepto,, Treponema)0 0 0 anerobes 0 0X Tuberculosis(MDR)
Macrolides• Antibacterial spectrum: – Erythromycin: • Gram positives: Staph.(Not MRSA), Strep., Bordetella, Treponema, Corynebacteria. • DOC to Atypicals: Mycoplasma, Ureaplasma, Chlamydia – Clarithromycin: • Similar to erythromycin. • Increased activity against gram negatives (H. flu, Moraxella) and atypicals – Azithromycin: • Decreased activity against gram positive cocci. • Increased activity against H. flu and M. cat • Salmonella typhi.
• Adverse effects. – 10-15% of pts do not finish the prescribed course of erythromycin because of GI distress. – Jaundice – Ototoxic (high doses)• Drug interactions – Oxidized by cytochrome p-450. – Inhibits other substrates and increases their serum concentrations. • Theophylline, warfarin, astemizole, carbemazepine, cyclosporine, digoxin, terfenadine
Clindamycin• Used for deep neck space infections, chronic tonsillo-pharyngitis, odontogenic abscesses, and surgical prophylaxis in contaminated wounds.• Concomitant use of macrolides or Chloramphenicol adds no benefit.• Resistance: MLSB – ribosomal alteration.
Clinda• Pseudomembranous colitis – clindamycin > cephalosporins (Ceftin) > aminopenicillins. – Abdominal pain, fever, leukocytosis, bloody stool… – Diarrhea commonly develops on days 4-9 of treatment. – Typically resolves14 days after stopping the antibiotic. – Treat with Flagyl (PO or IV). – Life threatening cases can be treated with oral Vancomycin.
FQ• Ciprofloxacin (Cipro; IV $103.75/day; PO/Topical; Restricted use @ UTMB), Ofloxacin (Floxin; Topical $60.90), Levofloxacin (Levaquin; IV 15.62/day; Oral $6.72/day).• Synthetic derivatives of nalidixic acid.• Inhibits DNA gyrase, causing permanent DNA cleavage.• Resistance: – DNA Gyrase mutations – Cellular membrane efflux mechanisms. – Decreased number of porins in target cells.• Wide distribution - CSF, saliva, bone, cartilage
Coverage FQ• Effective vs. gram +, gram -, atypicals, and Pseudomonas.• Decreased activity against anaerobes.• Respiratory quinolones (levofloxacin). – Active against Strep (including penicillin-resistant forms), S. aureus (including MRSA), H. flu, M. cat (including penicillin-resistant strains), and atypicals. – Used in AOM, sinustiis, pharyngitis…• Antipseudomonas quinolones (ciprofloxacin/ofloxacin) – Active against Pseudomonas, H. flu, M. cat. – Strep pyogenes, Strep pneumoniae, and MRSA are resistant. – Used in children with Cystic Fibrosis. – Topicals used for otitis media.• Levofloxacin and Moxifloxacin have increased Staph activity even against cipro-resistant strains.
How shall one select an antibiotic for treatment• Ten rules in antibiotic prescription
Ten Rules in antibiotic prescriptions1. Antibiotics indicated on Clinical Grounds?2.Have appropriate investigations performed?3.What organisms are likely cause?4.Which Agent is best?5.Is an appropriate combinations best?6.Is any host factors relevant?7.What is the best route of Administration?8.What is the appropriate dose?9.Can therapy be modified when lab results are available?10.What is the optimal duration of therapy? 81