OcPharm Antibiotics Lecture 3 PDF

Pharm II_2024 Antibiotics Drugs Affecting Intermediary Metabolism Pyrimethamine and Trimethoprim Diane T.Adamczyk, OD, FAAO Copyright © 2024 146 Pharm II_2024 Antibiotics Drugs Affec ting Intermediary Metabolism Pyrimethamine Pyrimethamine > Inhibits the enzyme dihydrofolic acid reductase which is p...

Pharm II_2024 Antibiotics Drugs Affecting Intermediary Metabolism Pyrimethamine and Trimethoprim Diane T.Adamczyk, OD, FAAO Copyright © 2024 146 Pharm II_2024 Antibiotics Drugs Affec ting Intermediary Metabolism Pyrimethamine Pyrimethamine > Inhibits the enzyme dihydrofolic acid reductase which is part of the pathway that leads to synthesize parasitic DNA > Use > Isa folic acid antagonist > > Oculartoxoplasmosis Can cause dose-related suppression of the bone marrow > Thisismitigated by concurrent administration of folinic acid (leucovorin). > Leucovorin protects the bone marrow from the toxic effects of pyrimethamine. Diane T.Adamczyk, OD, FAAO Copyright © 2024 147 Getting the end result but a diff MOA à coming into the pathway at a diff time - when using this drug only when sight threatening b/c using them has significant adverse effects - when using oral it basically effects the folic acid so can cause dose related suppression of bone marrow is using it to treat toxoplasmosis so better if you add in flic acid in the pts diet when using the drug to treat toxoplasmosis Pharm II_2024 Antibiotics AntibacterialsAffecting Intermediary Metabolism Pyrimethamine and Trimethoprim > Pharmacology > Inhibit folic acid synthesis > Block a sequential step in pathway > Trimethoprim:effective MRSA (KNOW THIS) Diane T.Adamczyk, OD, FAAO Copyright © 2024 Trimethoprim is broad spectrum and it is good to use for MRSA 148 Pharm II_2024 Antibiotics Drug s A ffe c ting Interme d ia ry M e ta b olism Trimethoprim > Trimethoprim/Polymyxin B (Polytrim): > Use:surface ocular infection > Spectrum: Gram(+), Gram(-); Haemophilus > Trime tho p rim=G ra m +, G ra m -, no t pseudomonas > With Po lymyxin B=G ra m - > Approved for infantstwo monthsand older > Diane T.Adamczyk, OD, FAAO Copyright © 2024 ADRs: Generally mild 149 Polytrim is one of the most commonly prescribed topical for babies with conjunctivitis à commonly used by pediatricians for red eye Pharm II_2024 Antibiotics > Trea tment option for MRSA > Dacryoadenitis, canaliculitis, dacryocystitis Treatment Example > Dac ryoc ystitis (MRSA ) > Trimethoprim/sulfamethoxazole 160/800 mg BID Diane T.Adamczyk, OD, FAAO Copyright © 2024 150 Pharm II_2024 Antibiotics AntibacterialsAffecting Intermediary Metabolism Sulfonamidesand Trimethoprim > > Sulfo na mid e Pha rma c o lo g y > Inhib it synthe sis o f fo lic a c id (c he mic a l re q uire d fo r synthe sis o f nuc le ic a c id a nd p ro te in) > Huma ns: a b so rb p re fo rme d fo lic a c id > M inima l e ffe c t o n ho st c e lls > Bacteriostatic Trime tho p rim Pha rma c o lo g y > Inhib it fo lic a c id synthe sis > Blo c k a se q ue ntia l ste p in p a thwa y > Diane T.Adamczyk, OD, FAAO Copyright © 2024 Summary! Effe c tivity M RSA 151 Pharm II_2024 Antibiotics > Treatment option for MRSA > Da c ryo a d e nitis, c a na lic ulitis, d a c ryo c ystitis > Treatment option for toxoplasmosis Treatment Example > Dac ryoc ystitis (MRSA) > Trim e tho p rim /sulfa m e tho xa zo le 160/800 m g BID Diane T.Adamczyk, OD, FAAO Copyright © 2024 152 Bactrim is the combo of sulfamethoxazole and trimethoprim - used for toxoplasmosis and MRSA and dacrocystitis - need to weigh risk and benefits for the sulfa aspect of it especially in the 3rd trimester à be careful during first trimester Pharm II_2024 Antibiotics Toxopla smosis Trea tment Diane T.Adamczyk, OD, FAAO Copyright © 2024 153 Pharm II_2024 Antibiotics Toxopla smosis Treatment > Antibiotic treatment is thought to eradicate the tachyzoite form of the parasite during the acu te inflammatory phase. > Antibiotics are not effective against the latent bradyzoite cyst fo rm o f the p a ra site. > Trip le d rug the ra p y: > Use d fo r mo re tha n 60 ye a rs > Pyrimethamine an d sulfadiazine: have a synergistic effect on different steps of the nucleic a c id synthesis in T. gondii > Pyrime tha mine inhib its d ihyd ro fo lic a c id re d uc ta se > Sulfadiazine is a competitive antagonist of pa mino b e nzo ic a c id (PABA). > > Corticosteroids Folinic a c id (leucovorin) 5-25 mg with e a c h dose of pyrimethamine; Diane T.Adamczyk, OD, FAAO Copyright © 2024 154 Take home is the use of folinic acid that MUST be used when using this drug to treat toxoplasmosis - may use corticosteroids too - recognize that the oral combos you need to use the folinic acid - antibiotic goes after the tachyzoite stage Pharm II_2024 Antibiotics > Fola te= is a B-vita min = Vita min B9 > It is na tura lly fo und in so me fo o d s > Huma ns c a nno t ma ke , it is re q uire d in the d ie t, ma king it a n e sse ntia l vita min > It is ne e d e d to ma ke DNA a nd RNA; > N e e d e d to form healthy cells, especially red blood cells > an d metabolize amino acids (required for cell division) Folic Ac id vs Folate vs Folinic Ac id > > Folic a c id is the ma n-ma d e fo rm o f fo la te. > It is a synthe tic fo rm o f vita min B9 > Folic acid is converted into folate by the body > It is used as a dietary supplement an d in food fortification an d a d d e d to p ro c e sse d fo o d s Folinic acid= is a medication used to decrease the toxic effects of methotrexate, an d antimicrobial dihydrofolate reductase inhibitors such as trimethoprim an d pyrimethamine > Also kno wn a s le uc o vo rin, > It may b e prescribed in the treatment of toxoplasmosis retinitis, in c o mb ina tio n with the fo lic a c id a nta g o nists p yrime tha mine a nd sulfa d ia zine. Diane T.Adamczyk, OD, FAAO Copyright © 2024 Folate is vitamin B9 ad needed in our diet to make DNA/RNA folic acid is manmade folate Folinic acid (leucovorin) is what is given when pt is given the combo meds 155 Pharm II_2024 Antibiotics Antibacterials Affecting Bacterial DNA Synthesis Fluoroquinolones Diane T.Adamczyk, OD, FAAO Copyright © 2024 156 Pharm II_2024 Antibiotics Antibacterials Affecting Bacterial DNA Synthesis Fluoroquinolones 4-Quinolones Adapted: Vogel/OcPharm Made Simple Diane T.Adamczyk, OD, FAAO Copyright © 2024 157 Pharm II_2024 Antibiotics Antibiotics Affecting Bacterial DNA Synthesis Fluoroquinolones Bacteria: DNA in Bacterial cells exists in supercoiled state Topoisomerases break and re-link strands of DNA chains Role in DNA replication, transcription and repair, and DNA supercoiling DNA gyrase=topoisomerase II à they uncoil the DNA to allow them to be replicated , the fluroquinolones come in and affect the way the DNA is replicated Topoisomerase IV Diane T.Adamczyk, OD, FAAO Copyright © 2024 158 Pharm II_2024 Antibiotics Antibiotics Affecting Bacterial DNA Synthesis Fluoroquinolones Pharm acology: Interfere with DNA synthesis during bacterial replication: By inhibiting bacterial DNA gyrase activity (topoisomerase ll) and topoisomerase lV Inability to unwind DNA helixfor replication/transcription Unwinding of DNA supercoils Results in: Cell death (Bactericidal) and Lossof ability of cell to replicate Diane T.Adamczyk, OD, FAAO Copyright © 2024 159 Pharm II_2024 Antibiotics Netter 1st Ed Diane T.Adamczyk, OD, FAAO Copyright © 2024 160 Start with bacterial cell and they have supercoiled DNA and add DNA gyrase and it helps to relax the supercoiled DNA and then the DNA is replicated and then topoisomerase comes in and let them separate The fluroquinolones prevents replication of the bacteria Pharm II_2024 Antibiotics Fluoroquinolones: M ec ha nisms of Ac tion a nd Resista nc e > https://www.youtube.com/watch?v=IkKZ_gxAOXI Diane T.Adamczyk, OD, FAAO Copyright © 2024 161 Pharm II_2024 Antibiotics Antibiotics Affecting Bacterial DNA Synthesis Fluoroquinolones > Fluoroquinolone Advantages: Broad spectrum Bactericidal Rapid killing of organisms Resistance developsslowly à resistance dtarted to develop Therapeutic levelsachieved in oculartissues Minimal toxicity No significant systemic absorption/toxicity from ocular use Diane T.Adamczyk, OD, FAAO Copyright © 2024 162 Pharm II_2024 Antibiotics Antibiotic sAffec ting Bac terial DNA Synthesis Fluoroquinolones > Use: > Topical: > Conjunctivitis > Keratitis > C o rne a l ulc e r > Pre /p o st o p > Systemic: > UTI > GI > Re sp ira to ry a nd skin infections Diane T.Adamczyk, OD, FAAO Copyright © 2024 163 The fluroquinolones have allowed to manage corneal ulcers - a loading dose is first given to the pt and so every 15 mins the pt puts in drops into the eye and then they do this for many hours so done even throughout the night à no changed to 30 mins and can be done at home Pharm II_2024 Antibiotics > Resistance Antibiotics Affecting Bacterial DNA Synthesis Fluoro q uino lo ne s Diane T.Adamczyk, OD, FAAO Copyright © 2024 > Mechanism > Reduced cellular accumulation of quinolones: > Decreased passive transport of quinolones into cells > Increased active transport of quinolones out of cells > Efflux pumps > Sing le Ste p M uta tio n/Ste p wise muta tio n (a lte r): > DNA gyrase > Topoisomerase lV 164 Single step mutation means one aspect of the process the bacteria got smart with and formed resistance - so bacteria gyrase the bacteria got resistant and smarter Pharm II_2024 Antibiotics > Resistance > Olderfluoroquinolones Antibiotics Affecting Bacterial DNA Synthesis Fluoro q uino lo ne s > Single-step mutations in topoisomerase IV (involved in bacterial chromosome replication) > New fluoroquinolones > Better activity against single-step mutations > Gatifloxacin an d moxifloxacin resistance reported with S. aureus, coagulase negative staphylococci, Pseudomonas aeruginosa > Ciprofloxacin:10%resistant S. pneumoniae > Increasing resistance to methicillin-resistant S. Aureus Diane T.Adamczyk, OD, FAAO Copyright © 2024 165 Older fluroquinolones had single step mutation and for newer ones they had resistance to that so they have multistep mutations Pharm II_2024 Antibiotics Mechanisms of Resistance Fluoro q uino lo ne s > M ulti-step M uta nts > High level fluoroquinolones > 2 or more mutations needed Diane T.Adamczyk, OD, FAAO Copyright © 2024 166 - the later fluoroquinolones that came out addressed that bacteria got smarter like affecting one fo the enzymes or the efflux pumps and they make an antibiotic the bacteria needs to be smart enough so there is two ways of forming resistance à they go after one of the enzymes and one of the efflux mechanisms à when later drugs came out the though was that bacteria are not smart enough to form a two step process to form resistance but the bacteria were smart! - Early generation of fluroquinolones meant bacteria only needed to be smart once but later generations they had to be smart twice Pharm II_2024 Antibiotics Drugs Affec ting Bac terial DNA Synthesis Fluoroquinolones Diane T.Adamczyk, OD, FAAO Copyright © 2024 167 Pharm II_2024 Antibiotics Drugs Affecting Bacterial DNA Synthesis Fluoroquinolones Fluoroquinolones Ocular Systemic Norfloxacin Chibroxin (d/c) Noroxin/generic (d/c) Ofloxacin Ocuflox Ofloxacin Ciprofloxacin Ciloxan Cipro Levofloxacin Quixin (d/c), Iquix (d/c) Levofloxacin Gatifloxacin Zymar (d/c); Zymaxid Gatiloxacin(d/c) Moxifloxacin Vigamox, Moxeza (d/c) Moxifloxacin (d/c) Besifloxacin Besivance None Diane T.Adamczyk, OD, FAAO Copyright © 2024 168 - Levofloxacin in certain concentrations are no longer available - the brands are gone but generics are still for some of these drugs - only besifloxacin does not have a systemic counterpart à it is a new topical fluoroquinolone and b/c it has no systemic counterpart hopefully there is no resistance to this fluoroquinolone like the others have Pharm II_2024 Antibiotics Systemic Fluoroquinolones Diane T.Adamczyk, OD, FAAO Copyright © 2024 169 Pharm II_2024 Antibiotics Drug s A ffe c ting Ba c te ria l DNA Synthe sis Fluoroquinolones > Fluoroquinolones (systemic drugs): Adverse reactions: Common: > Gastrointestinal tract (nausea and diarrhea) > CNS (HA and dizziness) Uncommon > Inc reased risk of tendon rupture (happens more frequently than reported) > Prolongation of QTinterval > Arthroplasty > Idiosyncratic reactions (hepatitis) May be related to chemical moiety of the molecular structure of the FQ Diane T.Adamczyk, OD, FAAO Copyright © 2024 170 Antibiotics Diane T.Adamczyk, OD, FAAO Copyright © 2024 Pharm II_2024 171 The Achilles tendon is most commonly affected for fluroquinolones Runners should not be on fluroquinolones any of the ligaments can get torn but the Achilles tendon is the most common to be torn Ciprofloxacin of the fluoroquinolones in particular increases expression of the enzyme MMP9 in the tendons Pharm II_2024 Antibiotics Fluoroquinolone (O ra l) a nd Tendon Pathology > Mean time following FQ use to symptoms:2 weeks to months > Risk fac tors >60 yo C o nc o mita nt ste ro id the ra p y Re na l d ise a se M ales M a g ne sium d e fic ie nc y Hyperthyroidism Gout Syste mic d ise a se e.g. DM , RA > Most c ommon: levofloxac in and c iprofloxac in use Diane T.Adamczyk, OD, FAAO Copyright © 2024 172 So can be affected with ligament being torn even without any of these risk factors Thought to be because of ischemia, degradation of tendon matrix, or alteration of tenocyte activity (proposed hypotheses Pharm II_2024 Antibiotics VS Diane T.Adamczyk, OD, FAAO Copyright © 2024 173 If you read the literature, the use of oral fluroquinolones can result in retinal detachments - there is controversy in the literature about this! Pharm II_2024 Antibiotics Drug s A ffe c ting Ba c te ria l DNA Synthe sis Fluoroquinolones: Ocular > > 2 nd Generation > O flo xa c in (O c uflo x) > C ip ro flo xa c in (C ilo xa n) > No rflo xa c in (C hib ro xin) (d /c ) 3rd Generation > Le vo flo xa c in (Q uixin) (Iq uix) > C he mic a l struc ture simila r 2nd g e ne ra tio n > 4th Generation > M o xiflo xa c in (Vig a mo x)(M o xe za – d /c ) > G a tiflo xa c in (Zyma xid ) > Be siflo xa c in (Be siva nc e ) Note: Ophthalmic topicals safe to use pregnancy and lactation Diane T.Adamczyk, OD, FAAO Copyright © 2024 174 4th gen antibiotics are the ones that require the bacteria to do the two step and people seem to be using those than the earlier ones Pharm II_2024 Antibiotics 2nd Generation Ocular Fluoroquinolones Diane T.Adamczyk, OD, FAAO Copyright © 2024 175 Pharm II_2024 Antibiotics Drug s A ffe c ting Ba c te ria l DNA Synthe sis Fluoroquinolones 2nd Generation > Norfloxacin, ciprofloxacin, ofloxacin: > Betteractivity common ocularpathogens(these were found to be better than) than: > Aminoglycosides (tobramycin, gentamicin) > Chloramphenicol > Tetracycline > Erythromycin Diane T.Adamczyk, OD, FAAO Copyright © 2024 2nd generation ones were actually the first to be used for ophthalmic purposes 176 Pharm II_2024 Antibiotics Ocular Fluoroquinolones: 2nd G enera tion: C ompa rison > O floxa c in (O c uflox®) > Highest aqueousconcentration > 1 year old > Use: > C o rne a l ulc e r > Ba c te ria l c o njunc tivitis > Ciprofloxacin (Ciloxan®) > Corneal precipitates(17%) > Solution, ung > 1 year old > Use: > C o rne a l ulc e r > Ba c te ria l c o njunc tivitis > Diane T.Adamczyk, OD, FAAO Copyright © 2024 Norfloxacin (Chibroxin®) > No longeravailable US 177 - Not all the ophthalmic/topical fluoroquinolones were approved for corneal ulcers - some are used but used off label and that is ok if the eye car practitioners all agree that these are good drugs to use but the FDA did not specifically use it for corneal ulcers - especially 4th generation ones are used off label - one of the things that happens is that corneal precipitates are formed Pharm II_2024 Antibiotics Figure 9.8 Ciprofloxacin corneal precipitates Diane T.Adamczyk, OD, FAAO Copyright © 2024 178 Here the corneal precipitates (maybe from tears) usually doesn’t effect vision but this is dramatic so the VAs are effected Pharm II_2024 Antibiotics 3rd Generation Ocular Fluoroquinolones Diane T.Adamczyk, OD, FAAO Copyright © 2024 179 Pharm II_2024 Antibiotics Drug s A ffe c ting Ba c te ria l DNA Synthe sis Fluoroquinolones: Levofloxacin > Third genera tion > Maintained excellent gram-negative coverage > Improved gram-positive activity à this means with each generation of fluroquinolones the gram (-) activity stays equivalent but here is improved gram (+) activity b/c less resistance > Lessresistance > Ineffective against organisms resistant to cipro and ofloxacin > Drugs: > Levofloxacin 0.5% (QUIXIN ) > Le vo flo xa c in 1.5%(IQ UIX) Diane T.Adamczyk, OD, FAAO Copyright © 2024 180 Cipro and ofloxacin were the original Even though called second generation for ophthalmic purposes they were the first fluoroquinolones Called second b/c in relation to systemic drugs levofloxacin are the middle Very quickly after it came along the next generation came out Pharm II_2024 Antibiotics Drug s A ffe c ting Ba c te ria l DNA Synthe sis Fluoroquinolones: Levofloxacin > Levofloxacin 0.5%(Quixin): > L-isomerof racemate, ofloxacin > Clinical indication: Bacterial conjunctivitis > not keratitis > 1 year old > Levofloxa c in 1.5%(IQ UIX) > pH 6.5 > Indication:corneal ulcer Diane T.Adamczyk, OD, FAAO Copyright © 2024 181 Levofloxacin has an L isomer so it is a mirror image of ofloxacin - if used for corneal ulcers then done off label so the high concentration came out but the lower conc is the FDA approved Pharm II_2024 Antibiotics C ompa rison 2nd vs 3rd Generation Fluoroquinolones Diane T.Adamczyk, OD, FAAO Copyright © 2024 182 Pharm II_2024 Antibiotics Fluoroquinolones: Comparisons 2nd and 3rd Generation > Overall activity: > Levofloxacin >ofloxacin, ciprofloxacin > Gram + > Levofloxacin superior (esp Streptococcus) >ofloxacin, ciprofloxacin Diane T.Adamczyk, OD, FAAO Copyright © 2024 183 Each subsequent generation ha better Gram + activity but the gram – activity stays the same throughout the generations