Sulfonamides: Key Concepts

• When prescribing, avoid over-prescribing antibiotics as some conditions like URI are commonly viral
• Distinguish between when to prescribe broad-spectrum antibiotics versus when to prescribe based on culture and sensitivity results (C&S)
• Diagnostic tests associated with antibiotic stewardship and drug monitoring include cultures, Vancomycin trough levels, and assessing renal and liver function

Infectious Agents

Tetracyclines

• Common tetracyclines available for systemic use in the U.S. include Demeclocycline, tetracycline, minocycline, and doxycycline
• Mechanism of Action (MOA): inhibits bacterial protein synthesis by binding to the 30S bacterial ribosome, preventing aminoacyl tRNA access
• Broad-spectrum bacteriostatic drugs, generally considered second-line choices
• Active against MSSA and MRSA, contrary to general use for Staph/Strep infections
• Typically bacteriostatic with a broad spectrum of activity but are more effective agaisnt gram-positive microorganisms
• Doxycycline treats atypical community-acquired pneumonia, prevents malaria, and serves as an alternative for syphilis caused by Treponema pallidum
• Minocycline treats acne
• Glycylcyclines like Tigecycline (Tygacil) is effective against Enterobacteriaceae, Acinetobacter, and B. fragilis, for organisms resistant to tetracycline
• Tetracycline activity varies by pathogen, and resistance has been observed
• Effective against S. pneumoniae, H.influenzae, mycoplasma and chlamydophilia pneumonia
• Doxycycline is no longer recommended for gonococcal infections due to resistance, but can treat chlamydia as well as Epididymitis (Rocephin + doxycycline)
• Side effects include GI distress, photosensitivity, hepatic and renal toxicity, leukocytosis, and tooth discoloration in children and fetal bone problems
• Black Box Warning: readily bind to calcium in newly formed bone or teeth, causing discoloration and enamel dysplasia, and retardation of fetal bone growth
• Tetracyclines are avoided in pregnancy due to risks of deformity and growth inhibition -Potentiate warfarin and can cause rare hepatotoxicity
• Distribute widely, including urine, prostate, and tissues
• Calcium, antacids, and minerals form chelates and interfere with tetracycline absorption
• Tetracycline elimination pathways vary, requiring dose adjustments
• Effective against Streptococcal pneumoniae, Bacillus anthracis, Clostridium tetani, Brucella (brucellosis), Helicobacter pylori, and more

Sulfonamides

• Common medications include Trimethoprim-Sulfamethoxazole (Bactrim/DS)

• MOA: competitively inhibits dihydropteroate synthase, blocking folic acid synthesis

• Have antimicrobial activity against Gram + and Gram - bacteria, and parasites, but many strains of E.coli are resistant

• Sulfur must be directly linked to the benzene ring for sensitivity

• Highly protein-bound (albumin)

• No longer first choice for UTIs, but TMP-SMX preferred

• Treat Nocardiosis and Toxoplasmosis

• Treat E.coli, S. pyogenese, S.pneumonia, H. influenza, and some protozoa

• Absorbed rapidly from the GI tract, with 70-100% absorption and peak levels achieved in typically 2 - 6 hours

• Adverse Reactions: may take a week to manifest unless previously sensitized; primarily derm hypersensitivity reactions; rashes, fever, GI

• Black Box Warning: severe reactions include Steven-Johnson's syndrome, Vasculitis, Hemolytic anemia in patients with G6PD deficiency

• Interact with anticoagulants, sulfonylurea hypoglycemic agents, and hydantoin anticonvulsants

• Avoid use in pregnancy: increases risk for defects

• Bactrim still has a high usage due to its effectiveness despite resistance and allergies

• Trimethoprim (TMP) exerts a synergistic effect with sulfonamides; TMP inhibits bacterial dihydrofolate reductase (DHFR)

• Coadministration of a sulfonamide and TMP (TMP-SMX) introduces sequential blocks for production of tetrahydrofolic acid

• Figure 57-2 shows Steps in folate metabolism blocked by sulfonamides and trimethoprim

• Effective against UTIs, Chronic Bronchitis, Acute OM in children and AC Maxillary Sinusitis in adults

• Some use of GI infections (Shigella), Pneumocystis jiroveci in HIV, MRSA, Nocardia, and bacterial prostatitis

• Contraindicated in CCr is <50ml/min and amplifies affect of sulfa drug, with high resistance to pseudomonas

Beta-lactam antibiotics (\u03B2-Lactams)

• Includes PCN, cephalosporins, carbapenems, and monobactams with common structure (ẞ-lactam ring)

• MOA: inhibits peptidoglycan synthesis by acylating the transpeptidase via cleavage of the ẞ-lactam ring as well as lytic and nonlytic mechanisms

• Naturally active against aerobic, gram (+) organisms

• Greater activity against Gram(-) bacteria (Ex: Ampicillin, Amoxicillin, Augmentin)

• Mechanisms to Resistance: Alterations in PBP target, reduction of concentration at the target site, and enzymatic degradation of ẞ-lactam

• Resistance mechanisms include mutations, acquisition of low-affinity PBPs, and enzymatic inactivation

• Reduced penetration in gram-negative bacteria due to outer membrane barrier, active efflux pumps, and enzymatic inactivation via ẞ-lactamases produced by bacteria

• Targets for the actions of beta-lactam antibiotics are known as penicillin-binding proteins (PBPs) and induces loss of viability and lysis

• Bacteria often develop resistance to ẞ-lactam antibiotics by synthesizing ẞ-lactamase, and overcomes by using of ẞ-lactamase inhibitors

• ẞ-lactamase Inhibitors “protect” the ẞ-lactam from the ẞ-lactamase and prevent the enzymes from destruction

• Clavulanic acid has poor intrinsic antimicrobial activity but binds ẞ-lactamases produced by gram-positive and gram-negative microorganisms -Sulbactam is similar to clavulanic acid for Acinetobacter spp. and high dosages

• Tazobactam has good activity against many plasmid-mediated ẞ-lactamases and is available with piperacillin and ceftolozane

• Avibactam and relebactam are structurally similar non-ẞ-lactam ẞ-lactamase inhibitors for narrow- and extended-spectrum ẞ-lactamase

• Avibactam is co-formulated with ceftazidime, and relebactam with imipenem/cilastatin

• Vaborbactam is a boronic acid-based non-ẞ-lactam ẞ-lactamase inhibitor that provides broad inhibition and co-formulated with meropenem

Penicillin's

• Agents used for Pseudomonas, E.coli, Klebsiella and common with beta-lactamase inhibitors (tazobactam).

• Pipracillin/tazobactam has the broadest spectrum of all PCNs including MRSA, H.influenza, B. fragilis, and most E.coli and Klebsiella

• MOA: PCN consists of a thiazolidine ring connected to a ẞ-lactam ring attached to a side chain and classified by antimicrobial activity

• PCN G/PCN V- active against strains of gram + cocci but ineffective against most S. aureus

• Penicillinase-resistant PCN (nafcillin, dicloxacillin, oxacillin)- preferred agents for penicillinase-producing S. Aureus and Staphylococcus epidermis

• Isoxazolyl Penicillins: Oxacillin, Cloxacillin, Dicloxacillin for resistant strains

• Aminopenicillins (Ampicillin, amoxicillin)- cover gram +/-; can be compounded with clavulanate or sulbactam for A ẞ-lactamases; Effective for respiratory infections, urinary tract infections, enterococcal infections

• Used as antibacterial prophylaxis for asplenic patients and Penicillin for rheumatic fever prophylaxis

• Pnuemococcal infections require penicillin G for sensitive strains and Vancomycin and 3rd generation ceftriaxone for meningitis if resistance.

• B-Hemolytic Streptococcal Infections used Penicillin V preferred with Penicillin reduces risk of rheumatic fever, but less impact on glomerulonephritis.

• Other Streptococci and Enterococci Infections such Virdans group in endocarditis, Penicillin G is used for Gas gangrene and N. meningitidis

• Syphilis is treated best with with Penicillin G with desensitization for penicillin-allergic pregnant women and long term therapy for Actinomycosis.

Cephalosporins

• MOA: Inhibit bacterial synthesis, similar to penicillin, with different PBP binding profiles and lack of binding to essential PBPs in Enterococcus so the drug is innefective

• Used in sinusitis, otitis media, gonorrhea, bronchitis, and skin infections

• Therapeutic uses: skin and soft-tissue infections (Cefazolin for surgical prophylaxis) and meningitis

• Ceftriaxone is excellent and used for gonorrhea, empiric treatment of meningitis

• 1st Generation: For gram+ bacteria, E. coli, Klesiella, and Proteus. Cephalexin and cefadroxil.

• 2nd Generation has both gram+ and gram- bacteria. Cefuroxime and cefaclor.

• 3rd Generation has Gram- bacteria, B-Lactamase, and has weak Gram+ action. Ceftibuten and Cefixime

• 4th generation has primarily Gram+ actions, and Ceftolazone/tazobactam

• 5th Generation are Anti-MRSA and have structural modifications for altered PBPs.

Nucleoside analogues

• MOA: antiviral drugs must either block entry into the cells or be active inside host cells to be effective, by Inhibition of DNA synthesis and replication
• Acyclovir (Zovirax): treats HSV-1, HSV-2, varicella-zoster, Epstein-Barr, cytomegalovirus, and herpes virus 6
• Valacyclovir (Valtrex) is converted to acyclovir after oral administration; more effective against VZV
• Famciclovir (Famvir): treats HSV-1, HSV-2, VZV, EBV, and hepatitis B virus
• Penciclovir: Topical tx for HSV or VZV infections
• Ganciclovir & valganciclovir: are active against CMV and all herpes viruses. Indicated for CMV retinitis

Fluoroquinolones

• Common generation Meds:
  • 2nd generation: Ciprofloxacin and Ofloxacin
  • 3rd Generation: Levofloxacin
  • 4th Generation: Moxifloxacin, Gemifloxacin, Delafloxacin
• MOA: Target bacterial DNA gyrase and topiosomerase IV, which are enzymes essential for DNA replication
• Not used for cellulitis, but it is used in UTIs, prostatitis, sexually transmitted diseases , GI and abdominal infections, respiratory tract infections, bone and joint infections, other infections.
• -Administered for 4-6 whs for prostitis, or STDs with ofloxacin and Levofloxacin and for Travlers diarhea 1-3 days

Glycopeptides

• Common Meds:(Vancomycin, Teicoplanin, Telavancin, Dalbavancin, Oritavancin)
• MOA: bactericidal, Inhibition of bacterial cell wall synthesis in gram-positive bacteria
• Vancomycin indications include infections with Clostridium difficile colitis, Skin/soft tissue and Bone/joint infections CNS endocarditis and Vascular catheter infections
• Allergy history must be assessed because it is a very high law suit and malpractice issue ★Black box: PT Education:

Azole antifungals

• •Azole antifungals categorized into imidazoles and triazoles Available Azole Agents: -Ketoconazole: Replaced by itraconazole, mainly used topically.
• Itraconazole: Triazole with a broad spectrum, especially active agains
• Fluconazole: Effective against Candida and
• Voriconazole: Superior efficacy against invasive apergillosis Treatment - - Approved for Prophylaxis
• broad spectrum for Candida, asperigilillus cryptococcus, and mucormycosis.
• treats thrush, yeast infections, and fungal infections.
• Topical treatments - micronazole, clonrimazole
• systemetic therapy with keto carries risk of hepatoxicity, so not used
• Systemetic side effects includ minor GI issues, rarely serious liver issues.

AntiProtozoals

• Treat ameobiasis with cornerstone with metronidazole, or timidazole to get anti-infection. if Colitis or liver abscess
• Giardias: treat 5-7 days metronidazole
• -Trichomoniasis
• treat balbesosis

Helinth Infections

• Treat nematode and cestode with albendazole and mebendazole
• Side effects mostly mild gi effects monitor liver action

Ivermectin causes increased membrance permeablity to nerve and muscle cells and paralysis Death Treats :

• Onchocerciasis, l filariasiastrongyloidiasisenterobiasis, cabieshead licTopical moxidectin and praziquantel drug of choice for treatment with schistomes and liverslucks

Test your knowledge of sulfonamide antibiotics. Explore their mechanisms of action, clinical uses, and potential adverse effects. Learn about drug interactions and contraindications associated with sulfonamide therapy.