Antibiotics Macrolides PDF

Pharm II_2024 Antibiotics Antimic robia ls Affec ting Protein Synthesis Macrolides Diane T.Adamczyk, OD, FAAO Copyright © 2024 109 Macrolides impact protein synthesis 109 Pharm II_2024 Antibiotics Antimic robialsAffec ting Protein Synthesis Macrolides > Pharmacology > Bind to 50Sribosomal subunit >i...

Pharm II_2024 Antibiotics Antimic robia ls Affec ting Protein Synthesis Macrolides Diane T.Adamczyk, OD, FAAO Copyright © 2024 109 Macrolides impact protein synthesis 109 Pharm II_2024 Antibiotics Antimic robialsAffec ting Protein Synthesis Macrolides > Pharmacology > Bind to 50Sribosomal subunit >inhibit bacterial protein synthesis > Low toxicity:do not bind to human ribosome > Bacteriostatic > Spectrum of activity can include: > Various:Gram positive, gram negative > Streptococci, Staphylococci, Chlamydia, Neisseria, Hemophilus influenzae > Clinical Use: > Chlamydial Infections > SebaceousGland Dysfunction Diane T.Adamczyk, OD, FAAO Copyright © 2024 110 Macrolides binds to the 50S subunit and this category of drugs is different from other category of drugs and when bonded to the 50S subunit it inhibits bacterial protein synthesis Overall low toxicity to humans as a group In contrast to tetracyclines, the spectrum of activity is better for pregnancy Spectrum of action is gram + and gram The biggest category of clinical use is chlamydial infection and meibomian gland type of problems like sebaceous gland dysfunction 110 Pharm II_2024 Antibiotics Drugs Affecting Protein Synthesis: Mac rolides Diane T.Adamczyk, OD, FAAO Copyright © 2024 The Drugs > Erythromyc in (Va rious) > Azithromyc in (Zithroma x) > Clarithromycin 111 The drugs in the macrolide category 111 Pharm II_2024 Antibiotics Macrolides: Erythromycin > Erythromycin > Pro to typ e m a c ro lid e , o b ta ine d fro m Streptom yces erythreus > A c tive a g a inst g ra m +, g ra m -, c hla m yd ia > O ra l a nd to p ic a l > Use: > Lid infec tion > Prophylaxis ophthalmia neonatorum > Gonoc oc c al c onjunc tivitis > C hlamydial infec tion > Sa fe r fo r p re g na nt w o m e n, nursing m o the rs, c hild re n < 8 ye a rs > Prior Designation: Pregnancy Category B Diane T.Adamczyk, OD, FAAO Copyright © 2024 112 This is a gonococcal keratoconjunctivitis infection - erythromycin is oral and topical - it is safer in pregnancy than tetracycline to use 112 113 Pharm II_2024 Antibiotics Drugs Affec ting Protein Synthesis Macrolides: Erythromycin > Erythromyc in O phtha lmic > Ointment only > Use:superficial bacterial ocular infection and ophthalmia neonatorum prophylactic > ADRs: Generally mild > Pregnancy > M a y use d uring p re g na nc y; > No human d ata available, though risk of fetal harm not expected based on expected limited systemic absorption > Prio r d e sig na tio n: C a te g o ry: B Diane T.Adamczyk, OD, FAAO Copyright © 2024 114 Ophthalmic erythromycin is safe to use for oral use à in comparison to ophthalmic, you need to weigh it to use it for pregnancy (weighing risk and benefit) used to be pregnancy category B the verbiage says “possible risk of fetal harm based on conflicting human data” so it is possible safe to use during pregnancy but as a clinician you may want to second check before using it on pregnant mom FDA wants you to be more specific so no longer just pregnancy category B but more details included 114 115 Pharm II_2024 Antibiotics Drugs Affec ting Protein Synthesis Macrolides: Erythromycin > Erythromyc in O phtha lmic Treatment Example: Superficial bacterial ocular infection: Erythromycin Ophthalmic Ointment:up to 6x/day x 7-10 days Diane T.Adamczyk, OD, FAAO Copyright © 2024 116 *this slide for completeness After baby goes through birth canal they use erythromycin instead now 116 Pharm II_2024 Antibiotics Drug s A ffe c ting Protein Synthesis M a c rolid e s: A zithromyc in > Azithromycin (Zithromax) > Semisynthetic derivate of erythromycin > Use:c hlamydia, gonoc oc c al c onjunc tivitis, oc ular rosac ea > Pregnancy: > May use during pregnanc y; > Prior pregnanc y Category B > Drugs.com: lactation-distributed in milk;use with c aution > Side Effec t: GIupset, skin rash > May take with or without food Diane T.Adamczyk, OD, FAAO Copyright © 2024 117 If looking at oral macrolides then more likely using azithromycin it is coming from erythromycin May be used during pregnancy but diff from erythromycin where you have to weigh risk and benefits azithromycin oral is safer than erythromycin usage during pregnancy GI upset is more of an issue 117 Pharm II_2024 Antibiotics Drugs Affecting Protein Synthesis Macrolides: Azithromycin > Azithromycin (Zithromax) > Dosage: C a n take with/out food > Note:food helpsto tolerate better > Exception:Azithromycin Zmax extended-release suspension/liquid should be taken 1 hour before or 2 hoursaftera meal 1000mg single dose (c hlamydia) > Extended half life >QD Diane T.Adamczyk, OD, FAAO Copyright © 2024 118 - tetracycline yo1000 mg single dose of azithromycin with or without food (with food makes it easier to tolerate) for chlamydia treatment (KNOW THIS) u cant use during pregnancy but azithromycin you can - if you have a pt with chlamydia and with chlamydial conjunctivitis - sometimes the topical no matter how much you use wont be enough and so you have to take it orally 118 Pharm II_2024 Antibiotics C DC : 2021 G uideline C hla mydia l Infec tions Diane T.Adamczyk, OD, FAAO Copyright © 2024 > Azithrom ycin vs doxycycline for urogenital c hla m yd ia l infe c tio n ha d hig he r tre a tm e nt fa ilure a m o ng m e n fo r a zithro m yc in à w hich is w hy doxy is # 1 > D oxycycline m ore efficaciou s for rectal infe c tio n fo r m e n a nd w o m e n > Sex partners during 60 days p re c e d in g onset of sym ptom s or dx should b e tested (o r la st c o nta c t if >60 d a ys)à so if you have chlamydia you need to get in touch with who you have been in this time frame > D oxycycline d e la y e d release 200 m g Q D is a s e ffe c tive a s d o xyc yc line 100m g b id x 7d a ys fo r uro g e nita l C tra c ho m a tis, w ith lo w e r G I A DR, b ut m o re c o stly 119 The CDC helps to delineate the accepted protocol for many infectious diseases it tells you that the first choice to treat chlamydia in adolescents and adults is doxycycline à used to be azithromycin alternative to doxy you can use azithromycin or levofloxacin Azithromycin can be used but doxy is preferred Azithromycin is best for pregnant moms with chlamydial infections and amoxicillin can also be used (know this) 119 Pharm II_2024 Antibiotics Azithromyc in Drug Intera c tion Considerations > Antiarrhythm ics (e.g. am iodaron e, quinidine, sotalol) > M ay cause QT prolongation (dangerous, irregular, fast heartbeat) > Azithromycin – carries risk of QT prolongation; higher in elderly an d those with hx of heart arrythmia > Combination: increase risk of QT prolongation an d cardiac arrhythmias > Antacids (those with alum inum , m agnesium or c a lc iu m salts) (e.g. Rolaids, M ild of M ag n e sia) > Sta tins (e.g. a to rva sta tin=Lip ito r, sim va sta tin=Zo c o r) > > Sta tins ma y re sult in rha b d o myo lysis > With a zithro myc in ma y inc re a se risk o f rha b d o myo lysis W a rfa rin (C o um a d in) > Diane T.Adamczyk, OD, FAAO Copyright © 2024 Bind to azithromycin, affecting absorption, resulting in less effectiveness > With azithromycin potential risk of increased bleeding 120 Azithromycin is a very safe drug but you need to consider the drug interactions - so you can end up with an irregular fast heartbeat or any other arrythmia à higher in elderly and those treated for it - antacids can reduce the effectiveness of the drug - statins effects and breaks down the muscles and with azithromycin this can happen more (you can have muscle cramping but with azithromycin you end up with muscle breaking down) - warfarin + azithromycin can increase risk of bleeding 120 Pharm II_2024 Antibiotics Drugs Affec ting Protein Synthesis Mac rolides:Azithromyc in > A zithro m yc in 1% o p htha lm ic (A za Site ) > Durasite-vehicle > G ro w ing re sista nc e > Pregnancy: > M a y use d uring p re g na nc y; > no hum a n d a ta a va ila b le , tho ug h risk o f fe ta l ha rm no t e xp e c te d b a se d o n insig nific a nt syste m ic absorption > Prio r C a te g o ry: B > Diane T.Adamczyk, OD, FAAO Copyright © 2024 A g e : 1 ye a r 121 There is a topical version of azithromycin - durasite is a stand alone ophthalmic lubricants which can be a vehicle à the durasite is the vehicle for azithromycin - the topical isn’t as concerning 121 Pharm II_2024 Antibiotics Drugs Affec ting Protein Synthesis Mac rolides:Azithromyc in > Azithromycin 1%ophthalmic (AzaSite) > For Bacterial Conjunctivitis: > Dosage:BID X 2 days, QD X 5 days Diane T.Adamczyk, OD, FAAO Copyright © 2024 120 122 Pharm II_2024 Antibiotics > Some antibiotics with anti-inflammatory effects may help: Oral azithromycin vs doxycycline in meibomian gland dysfunction: a randomised double masked open label clinical trial (BJO 2015;99:199– 204/2014 on line) > to control bacterial colonization and > lid inflammation > Tetracyclines decrease inflammation and inhibit matric metalloproteinases > Doxycycline treats MGD through its antimicrobial, antiinflammatory and antimetalloproteinase properties > Ha s fe we r sid e e ffe c ts tha n te tra c yc line. > Azithromycin inhibits pro-inflammatory cytokines > Topical and oral azithromycin reported to improve the sign and symptomsof MGD and posteriorblepharitis. > With ocular surface, the inflammatory circle is what we want to reduce > Topical azithromycin can help with posterior blepharitis and DED which is counter intuitive b/c not getting into the gland yet it works Diane T.Adamczyk, OD, FAAO Copyright © 2024 121 Tetracyclines get in the with meibomian gland issues and resolve them and some of them have anti-inflammatory effects - some of the antibiotics control the bacteria but they are nice for their anti-inflammatory effect b/c it decreases inflammation and its effect on MMP9 à doxy is better in the tetracycline group to use 123 Pharm II_2024 Antibiotics Oral Azithromycin vs Doxycycline in Meibomian Gland Dysfunction: Received either: 5-day azithromycin (200mg/day) Or 1 month doxycycline (200 mg/day) Conclusion: 5 day course of oral azithromycin is recommended for its: better effect on improving the signs, better overall clinical response and shorter duration of treatment 5 day treatment course may need to be repeated because MGD is chronic Diane T.Adamczyk, OD, FAAO Copyright © 2024 122 It is a randomized double masked trial so a good study Don’t need to know dosage The least amount of drug is the azithromycin (5 day vs 1 month of doxy) the azithromycin is recommended after comparing the two 124 Pharm II_2024 Antibiotics Oral azithromycin vs doxycycline in meibomian gland dysfunction: a randomized double masked open label clinical trial (BJO 2015;99:199– 204/2014 on line) Diane T.Adamczyk, OD, FAAO Copyright © 2024 > Results: > Both oral doxycycline and azithromycin have beneficial effect > Azithromycin group better symptom effect (statistically insignificant) > Azithromycin group better sign scores (statistically significant) > Azithromycin fewer side effects > Azithromycin lowercost than doxycycline 123 Azithromycin was better than doxy 125 Pharm II_2024 Antibiotics Intervention: Azithromycin (1g once per week) x 3 weeks OR Doxycycline (200 mg daily) x 6 weeks Conclusion: *Azithromycin equivalent effect compared to doxycycline for MGD *No more GI adverse effects with azithromycin *Reduced dosing with azithromycin supports its use as alternative to doxycycline JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2023.0302Published online March 23, 2023. Diane T.Adamczyk, OD, FAAO Copyright © 2024 124 One gram of azithromycin once a week for three weeks vs. doxy for less amount but for a longer time - found that they have equivalent effects and GI effects but shown that azithromycin is good as an alternative to doxy 126 - systematic review that looks at all the articles in the literature - found that azithromycin was better in TBUT, staining, MG secretion, and other sign/symptoms - in the studies there was variability in how things were prescribed but concluded that macrolides and tetracyclines are effective but macrolides have better safety and efficacy than doxy - in every aspect looked at, all the findings favored the azithromycin 127 Pharm II_2024 Antibiotics Drugs Affec ting Protein Synthesis Chloramphenicol Diane T.Adamczyk, OD, FAAO Copyright © 2024 125 Causes Aplastic anemia 128 Pharm II_2024 Antibiotics Drugs Affec ting Protein Synthesis Chloramphenicol Chloramphenicol > Pharmacology > Bind to bacterial 50s ribosomal subunit >block protein synthesis > Bacteriostatic (some bactericidal activity) > Broad spectrum > G ra m p o sitive , g ra m ne g a tive > Resistant:P. aeruginosa > Chlamydia > Ba c illus a nthra c is (a nthra x) à was used in the US for this but d/c b/c of the aplastic anemia Diane T.Adamczyk, OD, FAAO Copyright © 2024 126 129 Pharm II_2024 Antibiotics Drugs Affec ting Protein Synthesis Chloramphenicol Chloramphenicol > Topic a l, ora l, IV or IM > IV used bacterial infection and anthrax > Oral and topical ocularung not available in US > ADRs > Aplastic anemia (topical or systemic) > Idiosyncratic (just happens) > No t d o se d e p e nd e nt > Systemic toxicity hasbeen reported in infantswith topical ocular use. Diane T.Adamczyk, OD, FAAO Copyright © 2024 127 130 Pharm II_2024 Antibiotics Chloramphenicol and Aplastic Anemia Mechanism of aplastic anemia and chloramphenicol: > Metabolism by intestinal bacteria +individual susceptibility > Intestinal bacteria can convert chloramphenicol into > dehydrochloramphenicol >which can induce DNA damage in intact bone marrow cells>derivativesof these cellsare 20 timesmore cytotoxic on DNA than chloramphenicol. > The host marrow may have greater capacity to then generate more toxic intermediates, or > The host stem cells DNA may be more sensitive to offending metabolite or > There may be decreased repaircapacity.. Conclusion and Considerations: Diane T.Adamczyk, OD, FAAO Copyright © 2024 > An association between ocular chloramphenicol and aplastic anemia cannot be excluded > For ocularadministration, lessabsorbed, lowerrisk > However, riskislessthan one per million treatment courses 128 What they think might be the mechanism - the metabolism but intestinal bacteria and susceptibility thinks causes the aplastic anemia - the conversion of chloramphenicol into dehdyrochloramphenicol (based on the gut bacteria or the pt’s body innately doing this) causes attacks on the bone marrow cells à the host marrow can create more toxic intermediates and more sensitive to offending metabolites are decreased repaired capacities - Conclusion was that association b/w ocular chloramphenicol and aplastic anemia canto be excluded 1 per million chances 131 Pharm II_2024 Antibiotics Estimates of aplastic anemia after topical use extremely low With increase in resistance to fluoroquinolones, suggest use of topical chloramphenicol in select cases Vision threatening keratitis that failed first line antibiotic drops; No hx/family hx of blood dyscrasias; Only adults; With informed consent https://doi.org/10.1016/j.ophtha.2020.05.015 Diane T.Adamczyk, OD, FAAO Copyright © 2024 129 The aplastic anemia instances was very low so suggested to use it in certain circumstances since there is growing resistance to antibiotic in general so if there is no personal or family history of blood dyscrasias and the antibiotics that the pt is already using and they have a vision threatening keratitis then maybe should consider using chloramphenicol so if this saves someone's sight then consider using it 132 Pharm II_2024 Antibiotics Antibacterials Affecting Intermediary Metabolism (Folic Ac id) Diane T.Adamczyk, OD, FAAO Copyright © 2024 130 133 Pharm II_2024 Antibiotics Drug s A ffe c ting Interme d ia ry Metabolism (Folic Acid) -Sulfonamides -Pyrime tha mine -Trimethoprim Diane T.Adamczyk, OD, FAAO Copyright © 2024 131 Sulfonamides think allergies! And a lot of resistance to sulfonamides 134 Pharm II_2024 Antibiotics Principles of Pharmacology. Golan et al. 2012 Diane T.Adamczyk, OD, FAAO Copyright © 2024 132 End result is DNA/RNA/proteins à bacteria and humans need this We start with pteridine and PABA and then there is an enzymatic rxn that happens and you get a byproduct and then the next step includes the glutamate and then you get tetrahydrofolate and what happens is that the antibiotics come in at diff points in the cycle sulfa drugs come in pretty early trimethoprim and methotrexate and pyrimethamine come in and block the DHFR and stop it from continuing 135 Pharm II_2024 Antibiotics Drugs Affecting Intermedia ry Metabolism (Folic Ac id) Diane T.Adamczyk, OD, FAAO Copyright © 2024 > Inhibition of nuc leic a c id synthesis > Sulfonamides > Trimethoprim 133 136 Pharm II_2024 Antibiotics Antibacterials Affecting Intermediary Metabolism Sulfonamides Diane T.Adamczyk, OD, FAAO Copyright © 2024 134 137 Pharm II_2024 Antibiotics Antibacterial Affecting Intermediary Metabolism Sulfonamides Sulfonamides B r o a d spectrum Gram positive and gram negative Also: Chlamydia Toxoplasma Resistance to Staphylococcus, Pseudomonas a. Diane T.Adamczyk, OD, FAAO Copyright © 2024 135 Main use of sulfonamides is toxoplasmosis 138 Pharm II_2024 Antibiotics Antibacterials Affecting Intermediary Metabolism Sulfonamides > Pharmacology > Inhibit synthesis of folic a c id (c hemic a l required for synthesis of nuc leic a c id and protein) > Huma ns: a bsorb preformed folic a c id > M inima l effec t on host c ells > Ina c tiva ted by: PABA > Local anesthetics: procaine, tetracaine, benoxinate are estersof PABA and therefore can inactivate sulfonamides > Inhibited/effectiveness may be reduced by blood, pus(purulent exudatescontain PABA) > Bacteriostatic Pharmacology. Harvey, et al. 2012 Diane T.Adamczyk, OD, FAAO Copyright © 2024 136 - bacteria make its own folic acid but humans don’t - minimum effect on host cells and these drugs are inactivated by PABA - local anesthetics are esters of PABA so when using anesthetics they mimic PABA and when combined with topical sulfa drug then it inactivates the sulfa drugs - if someone has an purulent exudate with bacterial conjunctivitis then the pus will have PABA which will inactivate the sulfa drug 139 Pharm II_2024 Antibiotics Pa ra -a minobenzoic Acid > O rga nic c ompound > Is a n intermediate for synthesis of folic acid (folate) by bacteria > Sulfona mide drugs a re struc tura lly simila r to PABA > Interfere in PABA converting to folate in bacteria > Result in bacterial folate deficiency and decrease in bacterial growth Diane T.Adamczyk, OD, FAAO Copyright © 2024 137 These have similar structures which is why you get this interaction with PABA and the sulfa drugs 140 Pharm II_2024 Antibiotics Antibac terials Affec ting Intermediary Metabolism Sulfonamides > Pharmacology > Inhibit synthesisof folic acid (chemical required forsynthesis of nucleic acid and protein) > Humans:absorb preformed folic acid > Minimal effect on host cells > Bacteriostatic Diane T.Adamczyk, OD, FAAO Copyright © 2024 138 To get folic acid you start with pteridine and PABA combining and add the glutamate to get the folic acid What happens is that b/c of the similarities in structures with the PABA the sulfa drugs come in and stop the process from occurring b/c the sulfa drug replaces the PABA and so the folic acid cannot be made So sulfa drugs inhibit the synthesis of folic acid and since humans don’t make it there is barely any effect on the human host 141 Pharm II_2024 Antibiotics PA B A Organic compound- Is an intermediate for synthesis of folic a c id (folate) by bacteria Sulfona mide drugs a re struc tura lly simila r to PABA Interfere in PABA converting to folate in bacteria Decrease in ba c teria l growth Diane T.Adamczyk, OD, FAAO Copyright © 2024 139 142 Pharm II_2024 Antibiotics Antibacterials Affecting Intermediary Metabolism Sulfonamides Sulfonamide Use: Topical: Blepharitis Conjunctivitis Oral: Toxoplasmosis Diane T.Adamczyk, OD, FAAO Copyright © 2024 140 Sulfas not used much b/c of resistance 143 Pharm II_2024 Antibiotics Drugs Affecting Intermediary Metabolism Sulfona mides > Oral: > Sulfamethoxazole > Sulfadiazine > Topical: > Sulfacetamide > Combination with steroids Diane T.Adamczyk, OD, FAAO Copyright © 2024 141 Sulfonamides with steroids will make pt happy but mainly b/c of the steroid 144 Pharm II_2024 Antibiotics Drug s A ffe c ting Interme d ia ry M e ta b olism Sulfonamides: Sulfadiazine and Sulfamethoxazole > Sulfadiazine and Sulfamethoxazole: > Inhibits the pathway that leads to synthesize parasitic DNA > Toxoplasmosis > Sulfa d ia zine /p yrime tha mine o r > Sulfamethoxazole/trimethoprim (Bactrim) Diane T.Adamczyk, OD, FAAO Copyright © 2024 142 If lesion is near the optic nerve or macula then use it since it is vision threatening so come in and use the cocktail of drugs to get this under control oral sulfa drugs inhibit the synthesis of parasitic DNA 145 Pharm II_2024 Antibiotics Antibacterial Affecting Inte rme d ia ry M eta b olism Sulfonamides Sulfonamides > Broad spectrum > Gram positive and gram negative > Also: > Chlamydia > Toxoplasma > Sulfadiazine/pyrimethamine or > Sulfamethoxazole/trimethoprim (Bactrim) > Resistance to Staphylococcus, Pseudomonas a. Diane T.Adamczyk, OD, FAAO Copyright © 2024 143 With toxoplasmosis you get satellite lesions so concerned for the macula - come with pyrimethamine and trimethoprim each with sulfa drug 146 Pharm II_2024 Antibiotics Drug s A ffe c ting Interme d ia ry M e ta b olism Sulfo na mid e s: Sulfa c e ta mid e > Sulfacetamide Ophthalmic (Bleph 10) > Solution and Ointment > Broad spectrum > Staph and Pseudomonas resistance > Resistance Diane T.Adamczyk, OD, FAAO Copyright © 2024 144 Resistant to staph and pseudomonas 147 Pharm II_2024 Antibiotics Drug s A ffe c ting Interme d ia ry M e ta b olism Sulfo na mid e s: Sulfa c e ta mid e > Sulfacetamide Ophthalmic (Bleph 10) > Contraindications > PABA containing compounds (ester type local anesthetics) > Reduce effectiveness > Purulent exudates(interfere with action) > Hypersensitivity reactions Diane T.Adamczyk, OD, FAAO Copyright © 2024 145 If using any of the local anesthetic then will negative the sulfa drug and the purulent exudate will negate it too 148