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Antimicrobials in Dentistry Classi cation of Antibacterial Agents Antimicrobial agents are classi ed based on chemical structure and mechanism of action: 1. Inhibitors of the cell walls synthesis (e.g: B-lactams & glycopeptides). 2. Disrupting the...

Antimicrobials in Dentistry Classi cation of Antibacterial Agents Antimicrobial agents are classi ed based on chemical structure and mechanism of action: 1. Inhibitors of the cell walls synthesis (e.g: B-lactams & glycopeptides). 2. Disrupting the cell membrane (e.g. polymyxins). 3. Inhibitors of protein synthesis 50S (e.g., chloramphenicol, macrolides, clindamycin, streptogramins) or 30S (tetracyclines, aminoglycosides) 4. Inhibit bacterial nucleic acid synthesis (DNA or RNA) (e.g. quinolones, rifampicin, metronidazole). 5. Antimetabolites (e.g: sulfonamides, trimethoprim) Classi cation of β-lactams B-lactam and the side rings: are the main core for the action of the B-lactams Modi cation to the R side chains on the ring lead to change in the: Pharmacokinetics of the drug Spectrum of activity Resistance to B-lactamase Examples: Penicillins, Cephalosporins, Carbapenems, Monobactam Mechanism of action B-lactams: B-lactam inhibit the peptidoglycan cross-link which is the last step in the peptidoglycan synthesis by acetylating the transpeptidase via the cleavage of the –CO —N– bond of the B-lactam ring. - Acts only on active growing cells (not dormant) - They are bactericidal and they are Time-dependent killers! Limitation: - Little direct tissue toxicity - Hypersensitivity - 0.7 - 10% of population - Serum sickness type (rare) - Anaphylactic shock (~ 0.01% of patients) - Skin rashes - Seizures (Especially the carbapenems) - Gastrointestinal - Diarrhea - Pseudomembranous colitis —> Caused by overgrowth of C. di cile - Hemolytic anemia (rare) - Positive direct Coomb’s Test 1 of 14 fi fi fi fi ffi Ampicillin and amoxicillin: - Amoxicillin is usually P.O, while ampicillin I.V. Drug Interactions - The use of ampicillin (or other broad-spectrum antibiotics) may decrease the e ectiveness of oral contraceptives by diminishing enterohepatic circulation - Chemically inactivation of aminoglycosides. Penicillins when combined with aminoglycosides crystallize and precipitate. - Therefore MUST NOT be administered simultaneously through the same I.V. line. The infusions should be separated by about 1 to 2 hours. - Carboxy- or Ureidopenicillins and aminoglycosides are synergistic in their anti-pseudomonas activity. - The bactericidal e ect of ampicillin may be reduced when other antibiotics (chloramphenicol, erythromycin, sulfa drugs and tetracycline) are used simultaneously 2 of 14 ff ff  Cephalosporin Cephalosporins consist of a B-lactam ring fused to a six member sulfur-containing dyhidrothiazine ring This modi cation in the side ring has lead to: More stability to bacterial B-lactamase→ broader spectrum of activity Penicillin-susceptible pathogens usually are cephalosporin-susceptible. Exceptions are Listeria and Pasteurella sp. Are resistant to cephalosporins. Not active against enterococci & MRSA (Methicillin-resistant Staphylococcus aureus). Excreted renally with few exceptions i.e. Cefoperazone (biliary excretion) Ceftriaxone with signi cant hepatic elimination Tetracyclines (inhibit 30S) Broad-spectrum bacteriostatic antibiotics with activity against G + and G – bacteria, some anaerobes (some Clostridia spp.), and atypical pathogens (Chlamydia, mycoplasma, and rickettsia). Mechanism of action: Bind reversibly to the bacterial 30S ribosome to inhibit binding of aminoacyl-tRNA to the mRNA- ribosome complex leading to inhibition of protein synthesis. Pharmacokinetics: Well absorbed orally with absorption being maximal for doxycycline and minocycline. Tetracycline chelate divalent metal ions which can interfere with their absorption and activity Limitations: - GI adverse e ects (Nausea, vomiting, diarrhea, candidiasis, enterocolitis). - Photosensitivity. - Avoided in pregnancy and children < 8 year old due to growth inhibition and discoloration of teeth. - Dose adjustment for minocycline in renal failure. 3 of 14 fi ff fi  Macrolides (inhibit 50S) Include erythromycin, clarithromycin & azithromycin. E ective against Gram (+) & (-), atypical [e.g.: Chlamydia, rickettsia, mycoplasma, mycobacteria, spirochetes] Antibacterial action may be bactericidal or bacteriostatic. Mechanism of action & resistance: Inhibition of protein synthesis via binding to the 50S ribosomal RNA of bacteria. Gram (-) bacilli eg. Pseudomonas and Acinetobacter species are resistant to macrolides (intrinsic resistance). Limitations: Development of resistance (all macrolides) and intolerance (mostly with erythromycin). GI adverse e ects: Nausea, vomiting, diarrhea, and anorexia (foqdan shaheya). Elevated liver function tests and hepatitis. Lincosamides - Clindamycin (inhibit 50S) MOA: Bind to 50S subunit & a ect bacterial protein synthesis Spectrum of activity: Bacteriostatic against G (+) aerobic and anaerobic bacteria. Resistance : - intrinsic resistance to gram(-) due to poor permeability through the cell membrane - cross-resistance with macrolides - PK: widely distributed into the tissues including bones, WBCs, and abscesses but poor penetration into the CSF. Side e ects & limitations: Nausea, diarrhea, rash, & contact dermatitis. Occasional: impaired liver function and neutropenia. Antibiotic-associated colitis caused by C. di cile. Require prompt treatment with metronidazole or vancomycin. 4 of 14 ff ff ff ff ffi  Aminoglycosides (inhibit 30S) Bactericidal antibiotics Agents include: Streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netlicin MOA: Inhibitors of protein synthesis that interfere with ribosomal function Concentration-dependent killing and a signi cant post-antibiotic e ects. More e ective when given as a single large dose than multiple smaller doses. PK: - Concentration is high in the renal cortex - Not highly penetrating to most tissue (should not be used as single agent for infections outside the urinary tract) - Excreted mainly by the kidney, excretion is directly proportional to creatinine clearance - Dosage adjustment in renal failure. Limitations: All aminoglycosides are: Nephrotoxic (reversible)- 5%-10% Ototoxicity (hearing problem): Auditory impairment (irreversible hearing loss) Vestibular toxicity (disturbances in balance) – mainly streptomycin More likely to occur in therapy > 5 days at higher doses, in the elderly, and in patients with renal insu ciency. Lecture notes: - They are not used that much as they have toxicity e ect, and dont cover a lot of bacteria. - It enhances the activity of Beta lactams if combined with it. - Has excellent a ect on gram enegative - Aminoglycosides rely on the oxygen produced by the bacteria that’s why they dont work on anaerobic bcteria. 5 of 14 ffi ff ff fi ff ff  Quinolone Antibiotics (Inhibit bacterial nucleic acid synthesis DNA, RNA) Mostly are synthetic uorinated analogs of nalidixic acid. Inhibit bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, thus inhibiting bacterial DNA synthesis. Usually bactericidal. Lecture notes: - the more we go in generations it is more active on gram positive, and become less e ective on gram negative. Adverse e ects Most common: nausea, vomiting, and diarrhea. Hyperglycemia, hyperuricemia, and hypercholesterolemia. QT prolongation & arrhythmia. May damage growing cartilage and cause arthropathy. Avoided during pregnancy. Metronidazole & Secnidazole ( agyl) MOA: form radical anions- interfere with bacterial DNA synthesis Antiprotozoal nitroimidazole drug with potent antibacterial activity against anaerobes (B. fragilis and C. di cile). Adequate oral absorption and penetration into CSF. Secnidazole has a long t 1⁄2 (~17 hr) than metronidazole (8 hr) Indications: Intra-abdominal infections (in combination). Antibiotic-associated enterocolitis (C. di cile). Trichomoniasis & bacterial vaginosis - secnidazole approved only for bacterial vaginosis (single dose) Gastric ulcer caused by H. pylori. Adverse e ects: include metallic taste, nausea, & diarrhea Lecture notes: - If there is a systemic involvement we use antibiotic, Fever, perocorotnitis - Clindamycin better for bone penetration 6 of 14 ffi ff ff fl fl ffi ff 7 of 14 Considerations for antimicrobial therapy Indicated clinical conditions for antimicrobial therapy 1. Pyrexia within last 24 hours – indicates a systemic response to the infection 2. Systemic symptoms like malaise, fatigue, weakness, dizziness, rapid respiration and local tender lymphadenopathy – indicate an impending sepsis 3. Trismus – indicates spread to perimandibular spaces and can extend to secondary spaces that can be potentially dangerous. Also trismus makes intraoral procedures di cult, which must wait until the trismus is relieved. 4. As a prophylaxis in patients with systemic conditions like rheumatic heart disease, endocarditis, heart / orthopaedic prosthesis. 5. In patients with any kind of immunocompromise – AIDS, cancer, autoimmune diseases, corticosteroid therapy, patients with immune compromised diseases like cyclic neutropenia, pancytopenia, uncontrolled diabetes 6. After solid Organ transplant/grafts (cardiac/renal/bone marrow/liver/osseous implants) Non-indicated clinical conditions for antimicrobial therapy 1. Pain – (Analgesics/ Anti-in ammatory drugs are indicated) 2. Oedema (Edema) – (Anti-in ammatory drugs indicated) 3. Redness/heat (Anti-in ammatory drugs indicated) 4. Purulence – (Resolved by drainage of pus / debridement) 5. Abscess – localized (e.g., alveolar abscesses, periodontal abscesses) – (Resolves by incision and drainage) 6. Draining sinus tract. (Removal of foci of infection resolves drainage and sinus tract may heal on its own or may have to be surgically excised.) 8 of 14 fl fl fl ffi  Anti virals: Mechanism of action of anti-HSV Most of these drugs inhibit DNA polymerase by: A. Competing with nucleotides on the DNA polymerase substrate site —> Nucleoside analogues Examples: Acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, valganciclovir, cidofovir, tri uridine These drugs need to be Activated by phosphorylation, analogues of deoxyribonucleosidetriphosphates (dGTP) Require viral enzymes to phosphorylate and activate the drug: thus, inhibition of viral DNA synthesis rather than the host cell (selectivity) B. Inhibition of DNA polymerase: Non-nucleoside DNA polymerase inhibitors—> Foscarnet Mechanism of action Active drug/(Pro-drug): Acyclovir/(Valacyclovir) Penciclovir/(Famciclovir) Ganciclovir/(Valganciclovir) Mechanism of action of nucleoside analogues: ▪ They all require 3-steps of phosphorylation before being active: ▪ One phosphorylation step by viral kinase (e.g: thymidine kinase or UL-97 kinase), ▪ then 2 phosphorylation steps by host cell kinases to nucleotide (guanosine) analogues ▪ These analogues inhibit the viral DNA-polymerase ▪ Only actively replicating viruses are inhibited ▪ Resistance to thymidine kinase or DNA polymerase to one of the drugs can confer cross- resistance to other drugs Acyclovir and valacyclovir: Requires 3 phosphorylation steps for activation, rst of which is by the viral thymidine kinase and then the di- & tri-phosphate by the host kinases Thus, acyclovir is selectively activated, and the active metabolite accumulates only in the infected cells Acyclovir is Active against: HSV2 (0.03–2.2 μg/mL), a tenth as potent against VZV (0.8–4.0 μg/mL) and EBV, least active against CMV (generally > 20 μg/mL) and HH-V6 Valacyclovir is a prodrug rapidly converted to acyclovir after oral administration via rst- pass enzymatic hydrolysis in the liver and intestine. As e ective as oral acyclovir in HSV and more e ective in herpes zoster Adverse e ects: depend on the route Local irritation - topical Nausea, vomiting, diarrhea, headache - oral Transient renal dysfunction or neurologic toxicity - high oral dose or IV 9 of 14 fl ff ff fi ff fi  Neutropenia in neonates Famciclovir and penciclovir: Famciclovir is inactive prodrug of the active drug penciclovir. Penciclovir is similar to acyclovir in its spectrum of activity and potency against HSV and VZV. It is also inhibitory for HBV. Valganciclovir and Ganciclovir: It is monophosphorylated intracellularly by viral TK during HSV infection and by a viral phosphotransferase encoded by the UL97 gene during CMV infection. Especially active against CMV About 100X more active than acyclovir against CMV and achieves 10X higher intracellular concentration- allowing for reducing dose frequency Valganciclovir is a prodrug of ganciclovir 10 of 14  Overview of antifungal targets A. Cell wall: The echinocandins (e.g., caspofungin) inhibit the formation of glucans in the fungal cell wall. B. Cell membrane: Amphotericin B and other polyenes (e.g., nystatin) bind to ergosterol in fungal cell membranes and increase membrane permeability and cell death. The imidazoles and triazoles (itraconazole,etc.) inhibit 14αsterol demethylase, prevent ergosterol synthesis, and lead to the accumulation of toxic 14αmethylsterols. The allylamines (e.g., nafti ne and terbina ne) inhibit squalene epoxidase and prevent ergosterol synthesis. C. DNA synthesis: Metabolites of 5 uorocytosine can disrupt fungal RNA and DNA synthesis. D. Mitotic cell division: Griseofulvin inhibits microtubule assembly, thereby blocking fungal mitosis. E. Other targets: Oxaboroles inhibit fungal aminoacyly tRNA synthase, thereby inhibiting fungal protein synthesis. Amphotericin B: The broadest spectrum of activity as antifungal drug Spectrum: Amphotericin B is either fungicidal or fungistatic, depending on the organism and the concentration of the drug. Bind, sequester, and extract ergosterol in the cell membrane leading to cell death PK: administered by slow IV infusion AmpB is insoluble in water and must be formulated with arti cial lipids to form liposomes The liposomal preparations are associated with reduced renal and infusion toxicity but are more costly Adverse e ects: - AmpB has low therapeutic index Immediate systemic reaction due to cytokine release (eg: TNF-α& IL-1 ) Fever and chills (1-3 hrs after starting IV), headache, vomiting, Hypotension Renal impairment: (renal tubular acidosis, K+ and Mg wasting_ - reversible Requiring potassium supplementation. Caution must be exercised in patients taking digoxin and other drugs that can cause potassium uctuations Anemia Thrombophlebitis: adding heparin to the infusion may alleviate this problem Nystatin: Polyene antifungal and has similar structure, chemistry, MoA and resistance pro le to AmpB Used for the treatment of cutaneous and oral Candida infections Negligible absorption through the GI tract Not used parenterally due to systemic toxicity (acute infusion-related adverse e ects and nephrotoxicity) Administered as: An oral agent (“swish and swallow”) or (“swish and spit”) for the treatment of oropharyngeal candidiasis (thrush) Used topically for cutaneous candidiasis 11 of 14 ff fi fl fi fl fi ff fi  Vaginal application for vaginal candidiasis (azoles are more e ective) Azole antifungals: Two di erent classes: - Imidazoles:, miconazole, ketoconazole, clotrimazole, - Triazoles: uconazole Have comparable clinical bene t to AmB with less AE. Candida glabrata exhibits reduced susceptibility to the azoles, whereas Candida krusei and the agents of mucormycosis are more resistant They have similar mechanisms of action and spectrum of activity, but their PK and therapeutic uses vary signi cantly MoA: Azoles are predominantly fungistatic. They inhibit 14-α demethylase (a fungal cytochrome P450 enzyme) thereby blocking the demethylation of lanosterol to ergosterol → fungal membrane structure and function disruption and inhibition of fungal cell wall Drug interactions: All azoles inhibit the hepatic CYP450 3A4 isoenzyme to varying degrees. Ketoconazole > itraconazole > voriconazole > uconazole Contraindications Azoles are considered teratogenic, and they should be avoided in pregnancy unless the potential bene t outweighs the risk to the fetus. QT prolongation Drugs targeting cell wall: Echinocandins: Caspofungin, micafungin, and anidulafungin Echinocandins interfere with the synthesis of the fungal cell wall by inhibiting the synthesis of β(1,3)-D-glucan, leading to lysis and cell death. Available as IV administration Have potent activity against Aspergillus and fungicidal against most Candida species including those resistant to azoles The most common adverse e ects are fever, rash, nausea, and phlebitis at the infusion site. They should be administered via a slow IV infusion, as they can cause a histamine-like reaction ( ushing) when infused rapidly Caspofungin: for patients with invasive candidiasis Micafungin: used for mucocutaneous candidiasis 12 of 14 fl fl fi fi ff fi ff fl ff  Oropharyngeal candidiasis in nonpregnant adults: Initial therapy For most patients with mild disease, topical therapy is preferred; ▪ Clotrimazole troches or miconazole mucoadhesive buccal tablets appear to be more e ective than nystatin. ▪ Oral uconazole (200 mg loading dose, followed by 100 to 200 mg daily for 7 to 14 days) can be used for initial therapy if a patient cannot use troches or suspension because of the possibility of aspiration or being unable to follow directions or is at risk for disseminated disease due to severe mucosal breakdown. For patients with severe disease: ▪ Fluconazole is generally the preferred treatment due its ease of administration, low side e ect pro le, low risk of drug interactions, and cost ▪ Other oral azoles (eg, itraconazole oral solution, posaconazole suspension, voriconazole) are also e ective for initial therapy Oropharyngeal candidiasis in adults Pregnancy: Oral azoles are teratogenic and should not be used during the rst trimester Clotrimazole troches, miconazole buccal tablets, and nystatin swish and swallow topical therapies can be used. For patients who have severe thrush in the rst trimester, intravenous amphotericin B can be used, but this is rarely needed. There are no data regarding the use of echinocandins in pregnancy. Treatment of oral candidiasis in children Neonates: Nystatin topical (100,000 units/mL) at a dose of 0.5 mL to each side of the mouth four times a day between feeds for 5 to 10 days Oral miconazole gel has a better cure rate (>90%), but systemic absorption may occur, and gastrointestinal side e ects are reported in 6% of premature neonates Neonates with inadequate response to topical nystatin can be treated with oral uconazole (3 mg/kg, once a day for seven days). 13 of 14 fi ff fl ff fi fi fl ff ff  Know the side e ects of amphotericin B Know the drug interaction of anoles Know the rst line and second line of canidasis 14 of 14 fi ff