Cephalosporin Antimicrobials

Approach to Anti-microbials

• Choose a particular antimicrobial group like Cephalosporin.
• Determine the mechanism and site of action
• Identify where in the cell the antimicrobial acts.
• Explain how the antimicrobial works.
• Note if the antimicrobial is bacteriostatic or bactericidal.
• Identify elements of the antimicrobial's structure.
• List indications of susceptible bacteria per class, including gram-positive and gram-negative bacteria.
• Note if the antimicrobial is effective against MRSA or atypical bacteria, and where it is ineffective.
• Classify the antimicrobial and provide examples in each class/generation.
• Link clinical uses to bacterial species from microbiology reviews.
• Note absolute and relative/specific contraindications.
• Note safety during pregnancy (category) and breastfeeding.
• For class pharmacokinetics, attach routes of administration to examples.
• Note excretion pathway (renal vs hepatic) and dose adjustments in disease.
• Note notable drug interactions and exceptions.
• Identify significant adverse effects and cross-sensitivity with other classes.

Protein Synthesis Inhibitors

• Protein synthesis inhibitors include Tetracyclines, Macrolides, Aminoglycosides, Lincosamides, Oxazolidinones and others.

Tetracyclines

• Examples include Demeclocycline, Doxycycline, Minocycline, and Tigecycline.
• Bind to the 30S ribosomal subunit, causing a misread to the genetic code.
• Binding is reversible and occurs at a different site than aminoglycosides.
• Tetracyclines are bacteriostatic.
• 60-90% of tetracycline and >90% of doxycycline and minocycline are absorbed after oral use.
• Penetrate most body tissues and fluids, however, CSF levels are not therapeutic.
• Food decreases the absorption of tetracycline but not doxycycline or minocycline.
• Metallic cations affect absorption; antacids, vitamins, and mineral supplements also affect absorption.
• Tetracycline and minocycline are excreted in urine.
• Doxycycline is excreted via the intestinal tract.
• Treat Rickettsiae (spotted fever, typhus) and Spirochetes (syphilis and Lyme disease).
• Also effective against Helicobacter pylori, Vibrio sp (cholera), Brucella (brucellosis), Plasmodium vivax, falciparum (prophylaxis of malaria), Chlamydia (chlamydia), Bacillus anthracis (anthrax), Yersinia pestis (plague) and Mycoplasma sp. (Mycoplasma Pneumonia).
• Doxycycline is used for prevention of travelers’ diarrhea caused by E.coli and to treat acne.
• Demeclocycline is used as an adjunctive agent to treat the syndrome of inappropriate ADH secretion (SIADH).
• Adverse effects include gastric discomfort, esophageal erosions, and Fanconi syndrome from expired pills.
• Other adverse effects include calcified tissue discoloration of teeth and stunting of growth in children, fatal hepatotoxicity & renal damage, phototoxicity, and vestibular problems (Minocycline & Doxycycline).
• They may also cause superinfection with Candida (vagina) or Staph (intestine) and Clostridium difficile (pseudomembranous colitis).
• Pregnancy category D as use in 2nd/3rd trimester may cause permanent teeth discoloration; hepatotoxicity may occur in pregnant women.
• Enter breast milk and are normally discouraged in breastfeeding.
• Contraindications include allergy, renal insufficiency (except doxycycline), and children less than 8 years.

Macrolides

• Examples are Azithromycin, Clarithromycin, Erythromycin, Fidaxomicin, and Telithromycin.
• Bind to the 50S ribosomal subunit causing a misread to the genetic code.
• Macrolides have primarily a bacteriostatic activity. Erythromycin is destroyed by gastric fluid so its enteric-coated tablets or esterified forms are used.
• Fidaxomicin is relatively poorly absorbed, and active only in the GI tract.
• Food decreases absorption of azithromycin and erythromycin; increases absorption of extended-release clarithromycin; no effect on immediate-release clarithromycin.
• Excreted mainly in bile (Metabolites of Erythromycin & Azithromycin appear in the bile while Clarithromycin appear in the urine)
• Inhibit cyp 450 (erythromycin, clarithromycin & telithromycin); Azithromycin least likely to interact.
• Effective against gram-positive and gram-negative bacteria and bacterial infections, including respiratory, gastrointestinal, genitourinary.
• Documented therapeutic use for group A streptococcal and pneumococcal infections when penicillin cannot be used.
• Treat syphilis and Lyme disease, Whooping Cough/Pertussis, Legionella pneumonia, Gastroenteritis, Diphtheria, Acne, Chlamydia and Mycoplasma Pneumonia
• Gastric discomfort may result with erythromycin more so than Clarithromycin & Azithromycin (better tolerated); taking with food may decrease GI disturbances.
• Ototoxicity may occur in some cases, with erythromycin resulting in dose-related tinnitus, dizziness and reversible hearing loss.
• Erythromycin may cause QT-interval prolongation, which predisposes to VT.
• Cholestatic Jaundice follows the estolate form of Erythromycin because of a hypersensitivity reaction.
• Erythromycin is not given IM because it causes severe pain; IV erythromycin may cause pain and phlebitis.
• Significant interactions include the possibility of Warfarin increasing elevation of INR; Lovastatin and sim vastatin may result in Rhabdomyolysis; Midazolam and Triazolam can cause somnolescence; and Theophylline can lead to N, V and seizures.
• Pregnancy category B (Erythromycin and Azithromycin). Breastfeeding is ok with erythromycin but Clarithromycin is category C.
• Do not use if persons are allergic to macrolides .
• Concomitant administration with astemizole, cisapride or terfenadine can cause QT elongation, VT, VF, TDP especially with erythromycin and clarithromycin via inhibition of metabolism.

Lincosamides-Clindamycin

• Clindamycin can be administered orally, topically, or parenterally.
• Binds to the 50S ribosomal subunit, inhibiting bacterial protein synthesis.
• Well absorbed orally, diffused in body fluids and bone except CSF, and concentrates in phagocytes.
• Drug is metabolized, and metabolites are excreted in urine and bile, and dissolves in water.
• Spectrum: anaerobes (Bacteroides fragilis) & G+ve; community-acquired methicillin-resistant S. Aureus
• Aerobic gram-negative bacilli and enterococci are resistant to Clindamycin
• Adverse effects may include - Clostridium difficile associated diarrhea - (pseudomembranous colitis, as with penicillins, cephalosporins, and fluoroquinolones), hypersensitivity reactions, and potentiates neuromuscular blocking agents
• Pregnancy category B
• Breastfeeding is not recommended
• Do not take if allergic to Clindamycin
• Use with caution if having Ulcerative Colitis

Chloramphenicol

• Administered via oral, topical, and parenteral routes.
• Binds to the 50S ribosomal subunit inhibiting peptidyl transferase activity/peptide bond formation,
• Primarily bacteriostatic,
• A nitrobenzene derivative well absorbed when taken orally, diffused in body fluids including CSF: and excreted in urine
• Hepatic metabolism
• Inhibits metabolism of phenytoin thus causing toxicity, however the effects of Phenytoin is reduced by phenobarbitone
• Penicillins antagonize it, and paracetamol increases the level leading to toxicity
• Effective against Gram-positive and gram-negative cocci and bacilli (including anaerobes) Rickettsia, Mycoplasma, Chlamydia
• Adverse Effects, Bone marrow depression: Can cause irreversible aplastic anemia (rare) or reversible bone marrow suppression (dose-dependent).
• Gastrointestinal issues: Nausea, vomiting, and diarrhea are common.
• Grey baby syndrome: Occurs in neonates due to immature liver metabolism, leading to toxicity
• Optic and peripheral neuritis: This can occur with prolonged use, causing visual and nerve disturbances
• Use in pregnancy if necessary as there is fetal risk involved (Pregnancy Category C)
• The label must state the type of use needed and the precautions to be taken.
• Category A: topical use. (eye drops/ointment).
• Enters breast milk: safety undetermined; caution advised during breastfeeding.
• Only use Chloramphenicol if no safer alternative drug is available due to severe side effects

Oxazolidinones

• Linezolid and Tedizolid
• Bind to the 50S ribosomal subunit, inhibiting the formation of the 70S initiation complex thereby blocking the initiation of protein synthesis.
• Gram-positive bacteria effective against streptococci, enterococci, and staphylococci, (including MRSA and VRE.
• Limited activity against Mycobacteria and anaerobes like Fusobacterium and Clostridium species (Bacteroides activity not as effective)
• Linezolid is a reversible, nonselective monoamine oxidase inhibitor (MAOI). Risk of serotonin syndrome when combined with SSRIs, MAOIs, TCAs, triptans, pethidine, bupropion or buspirone.
• Hypertension reported with linezolid, especially in patients taking sympathomimetics, vasopressors, or doparninergic drugs, or those with uncontrolled hypertension, thyrotoxicosis and pheochromocytoma. Blood pressure must be monitored in these cases.
• Should be used in pregnancy only if potential benefits justify the risks (Pregnancy Category C); Use caution when breastfeeding; use only if it is safe.

Quinolones

• Examples: Ciprofloxacin, Gemifloxacin, Levofloxacin Moxifloxacin, and Norfloxacin
• Inhibit the activity of DNA gyrase and topoisomerase essential activity needed for bacterial DNA replication
• Have a concentration-dependent bactericidal activity.
• Oral absorption is decreased by Metallic cations (aluminium, CA Mg, Iron) that have affected the absorption of quinolones; antacids, vitamins and mineral supplements
• Most are metabolized in the liver and excreted in the urine, and moxifloxacin is eliminated in bile and feces.
• Treat Pneumonia, UTI, URI, Hospital Acquired Pneumonia, Typhoid, Chlamydia (ofloxacin), Osteomylitis, Legionella pneumonia and anthrax
• Examples of susceptible conditions may include - Haemophilus influenza, E. coli. Moraxella catarrhalis. Pseudomonas aeruginosa, Mycobacterium tuberculosis Campylobacter Sp, Salmonella, Shigella, and Vibrios Methicilin sensitive S. Aureus.
• Adverse effects : Nausea, vomiting, diarrhea. Headache, dizziness, seizures, confusion, myasthenia gravis exacerbation. Tendinitis, Achilles tendon rupture. arrhythmia, Photosensitivity for increased risk of sunburn. Hepatotoxicity . Risk of glucose imbalance and aortic aneurysm or dissection. Allergic Reactions
• Typically avoided, Unless absolutely needed (typically avoided unless safer alternatives are available, particularly for fetuses)

Sulphonamides: Folate antagonists

• Examples: Sulfamethoxazole and Trimethoprim (not a sulfonamide)
• Compete with PABA for bacterial enzyme dihydropteroate synthetase
• TMP competes with available DHF for dihydrofolate reductase.
• Bacteria is not able to properly create dna to form (bacteriostatic)
• TMP/SMX- works synergistically through sequential inhibition of folate synthesis.
• Well distributes in tissues and fluids and CSF
• Sulfonaamides/trimethoprim potentiates (enhance) the effects of hypoglycemia
• Metallic cations
• Can potentiate sulphonylureas causing hypoglycemia, phenytoin (with increased adverse effects), and warfarin (bleeding)
• Active against broad spectrum gram positive and many gram negative bacteria.
• E. coli - common cause of UTIs treated with sulfonamides or TMP/SMX
• Plasmodium and Toxasplasma - Combination therapies Sulfasalazine Used for IBD and broken down into sulfapyridine And 5-ASA, with local properties in order to have less side effects. • Sulfasalazine: Used for IBD, not IBS. It is broken down into sulfapyridine and 5-aminosalicylic acid (mesalazine), with local anti-inflammatory effects in the GIT.
• Effective in treating combination therapies in UTIs

Sulphonamides : Topical, TMP/SMX and TMP

• Topical sulfonamides: used for burns (silver sulfadiazine, mafenide acetate) and vaginitis (sulfanilamide). • TMP/SMX: Active against Pneumocystis jirovecii used for prevention in immunocompromised patients. • Inactive against: Anaerobes, Treponema pallidum, Mycobacterium, Mycoplasma, Pseudomonas aeruginosa and Enterococcus •TMP alone - used for chronic prostatitis
• Susceptible for Organism and indications
• Adverse effects - hypersensitivity reactions to many • Crystalluria - precipitation of sulfonamides - patient hyrdation • Hematolgic disorders agranulocytosis
• Can precipitate when sulfonamide is combined with albumin •Photo sensitivity / sensitivity to light leading to skin reactions. •GI distrubances, nausuea, voumiting and diarrhea

Folate Inhibitors

Long term use results in -anemia of megablastic type- interference of synthesis

• Pregnancy C
• Contraindicated near term, risk of kernicterus
• not recommended during breastfeeding
• Allergic
• Inhibit liver/folate
• To pervent- cryaturial, encourage patient hydation and urine output of 1,200-1,500

Metronidazole

• Bactericidal, enters bacterial cells and disrupts DNA syn
• Effective against obligate anaerobic bacteria
• Effective against protozoa - G lambilla + E - hystolica
• Metabolized in liver- and excreted in urine
• Inhibits the metabolism of warfarin
• Absorbed in the cells
• DOC - bacerial vaginosis
• GI disturbance
• CNS - peripheal nuero
• Metallic tests and dark urine
• Contraindications of metrodizaoles
• Age less than 1 month Allegt to metro- or sevvere renal inscufficieny

Nitrofurantoin

• Batericidal and used in order to treat bacterial dna. Used for prophylaxisis
• effective and most effective against e-coli, saprhpyticus and enter facultis, variable suscepitle for proteus
• Resistant proteus/pseduomas
• Used for prophylaisus and treatment of uncompicated UlIS
• GI- issues, cns effects, peripheal nueropathy
• Contraindicated in pregnant or breastfeeding

Antibacterial Drugs: Beta-Lactams

• Select a particular antimicrobial group. Examples are are cephalosporin. Indicate the site of Action and the pharmaceutical chemisty.
• Can use a list of gram + and -. Place where there are resistant strands and include a list abbreviations.
• Linkindications

Cell Wall Synthesis

• Beta Lactams :Pencilills, cephalosproins,caropemems, polymyxins, bancomycin and bacitracin

Subgroups

• main- pencillins and Cephalosporin
• Presence of B Lactams ring-

Aminoglycosides

• Amikacin, Centamicin, tobramycin, streptomycin, neomycin, Kanamycin
• Bind ro 30-s ribsomal subinit causing a misread to genetic code, concentration to gentic code
• Structure contaions
• Oral/Aminoglycosides poorly absorbed from GI and mostly andministered perenterally: neomycinis the exception
• penicillin with help/tranports sysyem and aminoglycosies
• Excreted by gloemular

Sulfonamides

• Topical Use of Burms -Inacitve. against anaerodes -TMP Alone :Used for chronic pros and As and pros for UTIS

Caepholosporin

Cross reaction w/ Penicillins is between Lin Reversible vitamin K effect when inhibited, and liver Not recommended during breastfeeding

Monobactums

Has side effects/injectionsites and can cuade epidermal

• Has not cross-react with beta lactamas therapy-
• Can treat Gram - negative, gram negative, p. Aeriginosa and is not active Vs Anaerobes and Vs gram/ Postive.

Carbapenems

• can have imipenem with seizure side-effects.
• Enterococcus, p. Airgeinosa and Anareobes
• Most effective for resistance of H. influenzae and bateria for Acquired

Vamcomycin

• INHIibItis cellwall snth
• Oral or Perentral • Side effect with infusion is to avoid is a Red -Person Syndroms is is a histanive mediated reaction- avoid w/ 60 min side- effect.
• Has kidney Nephro toxicity if gives w/ Aminoglycoside.
• Alleregy: ContraIndicated
• Oral- Treat Glostiudian