Antibiotics and Mechanisms of Action

• It is vital to heed instructions regarding when to initiate antibiotics, emphasizing that they should not be over-prescribed and viral infections should especially be addressed
• Specific mentions are also important, i.e., Clindamycin and C. diff

Antibiotic Stewardship

• Follow CDC guidelines on when to prescribe broad-spectrum antibiotics compared to using cultures and sensitivity (C&S) data
• Diagnostic tests like cultures and monitoring renal/liver function are key
• Monitoring also involves tracking vancomycin troughs
• Monitor through cultures, assessing renal/liver function, and monitoring troughs

Tetracyclines:

• Medications in this class available for systemic use in the US: demeclocycline, tetracycline, minocycline, and doxycycline
• Mode of action involves inhibiting bacterial protein synthesis through binding to the 30S bacterial ribosome, preventing aminoacyl tRNA access
• Tetracyclines have a basic 4-ring structure
• Broad-spectrum bacteriostatic drugs with use generally reserved as a second-line choice
• Effective against MSSA and MRSA, however, generally not preferred for typical Staph/Strep infections
• Tetracyclines exhibit a broad spectrum of activity, though more effective against gram-positive bacteria compared to gram-negative
• Doxycycline indications: atypical pneumonia acquired in the community, prevention of malaria, an alternative to penicillin for syphilis due to Treponema pallidum
• More tolerable than other tetracyclines with fewer gastrointestinal side effects, so minocycline is primarily used to treat acne
• Glycylcyclines such as Tigecycline are effective against Enterobacteriaceae, Acinetobacter, and B. fragilis
• Glycylclines have activity variations against different pathogens, and resistance has been observed
• Good activity against S. pneumoniae, H. influenzae, mycoplasma and chlamydophilia with respect to respiratory tract infections
• Doxycycline no longer advised for treating gonococcal infections due to increasing resistance, but it remains effective against chlamydia

Tetracycline Adverse Reactions and Precautions:

• Side effects: GI distress, heightened sensitivity to sunlight, hepatic and renal toxicity, leukocytosis, and discoloration of teeth in children
• Contraindicated in children and pregnancy due to binding to calcium in developing bones/teeth, causing discoloration and enamel dysplasia
• Can cause retardation of fetal bone growth/deformity or growth inhibition through deposition in osseous tissue
• Category D during pregnancy
• Distributes widely throughout the body into urine, prostate, and various tissues
• Absorption is affected by calcium, antacids, and minerals due to chelation, which interferes with absorption
• Primarily eliminated through urine, making dose adjustment necessary based on renal function among different tetracyclines
• Effective against streptococcal pneumoniae, Bacillus anthracis (Anthrax), Clostridium tetani, Brucella, Helicobacter pylori, Actinomyces, Rickettsia, Chlamydial diseases, syphilis, Lyme disease, and Mycoplasma

Sulfonamides:

• Common medications: trimethoprim-sulfamethoxazole (Bactrim/DS)
• Act by competitively inhibiting dihydropteroate synthase, impeding folic acid production
• Antimicrobial efficacy against Gram + and Gram - bacteria and parasites, but its utility is limited
• Many E.coli strains have become resistant
• Function as derivatives of para-aminobenzenesulfonamide, and must be directly linked to the benzene ring to function correctly
• Target sensitive microorganisms which have to create their own folic acid
• Bacteriostatic with high protein binding involving albumin

Sulfonamide Uses, Side Effects, and Precautions:

• No longer first-line therapy for UTIs given the increase in bacterial resistance; TMP-SMX is superior
• Other uses include nocardiosis, toxoplasmosis, and infections from E.coli, S. pyogenes, S.pneumoniae, H. influenza, and some protozoa
• Manifestation may occur a week after use unless there is already a known sensitivity
• Rapid GI absorption, with peak level concentrations achieved in 2-6 hours
• Adverse reactions are derm-related, e.g., rash, and fever
• Uncommon adverse effect of crystalluria may be avoided by consuming 1200ml of water daily
• Anticoagulants, sulfonylurea hypoglycemic agents, and hydantoin anticonvulsants all interact

Trimethoprim-Sulfamethoxazole

• Trimethoprim (TMP) enhances sulfonamide effects by inhibiting bacterial dihydrofolate reductase (DHFR), resulting in synergistic antimicrobial activity
• Coadministration of a sulfonamide and TMP (TMP-SMX) blocks two sequential steps in tetrahydrofolate biosynthesis, rendering drug combination more effective than either agent alone
• Effective for susceptible bacteria in UTIs, while local resistance >20% should be avoided for empiric use
• Can be used to manage chronic bronchitis, acute OM in children, acute maxillary sinusitis in adults
• Amplifies sulfa effect with strong pseudomonas resistance
• Treatment options: BID x3 days for uncomplicated or 10-14 days in complicated or pyelonephritis.

Beta-Lactam Antibiotics

• Includes PCNs, cephalosporins, carbapenems, and monobactams, which share a common structure containing a β-lactam ring
• Inhibits transpeptidase, which is the last step in peptidoglycan synthesis
• Lethality is achieved via mechanisms which are both lytic, and nonlytic
• Natural PCNs combat aerobic, gram (+) organisms
• Resistance occurs due to changes in the PBP target, less medicine at the target, and enzymatic breakdown of the β-lactam structure
• Gram-positive bacteria are more prone to alterations in the PBP target
• Reduced penetration in gram-negative bacteria and active efflux pumps lead to increased resistance
• The synthesis of β-lactamases by bacteria inactivates β-lactam via enzyme alteration

Beta-Lactamase Inhibitors:

• By binding to β-lactamases and preventing them from hydrolyzing β-lactam agents present in the immediate environment, it can protect β-lactams
• Clavulanic acid has weak antimicrobial properties on its own, it is an irreversible inhibitor that binds β-lactamases found in both Gram- positive and gram-negative bacteria
• Sulbactam shares structural similarities with clavulanic acid, used intravenously or intramuscularly with ampicillin
• Tazobactam exhibits considerable efficacy against many β-lactamases that are plasmid-mediated, it is an ingredient in the compound piperacillin
• Avibactam and relebactam are non-β-lactam β-lactamase inhibitors that act against both narrow- and extended class β-lactamases, they’re structurally related
• Avibactam is combined with ceftazidime, while relebactam is co-formulated with imipenem/cilastatin

Penicillins:

• Agents with extended activity against Pseudomonas such as E.coli and Klebsiella -piperacillin and piperacillin/tazobactam; ticarcillin
• Commonly combined with beta-lactamase inhibitors
• Pipracillin/tazobactam contains the broadest spectrum of all PCNs, encompassing H.influenza, B. fragilis, and the majority of E.coli and Klebsiella
• MOA: PCN contains a thiazolidine ring, a β-lactam ring, and an attached side chain
• Includes use for Pneumococcal Infections, viridans group in endocarditis, anaerobes Infections, or infections with Actinomycosis or Listeria
• Classifications are based on the range of antimicrobial activity
• Penicillinase-resistant PCN are the preferred medications for S. Aureus and Staphylococcus epidermis, which are not methicillin resistant like Oxacillin, Cloxacillin, Dicloxacillin

Specific Penicillin Uses and Adverse Events:

• Aminopenicillins like Ampicillin and amoxicillin are broad spectrum, covering gram +/-
• Hypersensitivity reactions are the most common adverse effect as well as the most common cause of drug allergy
• Evaluate patient history for allergic reactions
• Conduct skin testing for allergy risk: Penicillin skin testing has a high negative predictive value
• Desensitization for true penicillin-allergic patients in a controlled setting with consideration for renal dysfunction adjustment
• Classified according to their spectra of antimicrobial activity.
• PCN G/PCN V- active against sensitive strains of gram + cocci, but ineffective against most strains of S. aureus.
• penicillinase. Aminopenicillins (Ampicillin, amoxicillin)- broad spectrum; cover gram +/-; can be compounded with clavulanate or sulbactam to prevent hydrolysis by A B-lactamases; Effect

Cephalosporins and Uses:

• First generation cephalosporins are effective for skin and soft-tissue infections, particularly against S.aureus and S. epidermis
• Third-generation cephalosporins are prescribed for severe infections like meningitis
• Can penetrate CSF, so can be used in meningitis
• Therapeutic Uses for Ceftriaxone/ Rocephin: Third-generation for serious infections like meningitis
• First-generation for skin and soft-tissue infections.
• Third-generation: broader indications, more active against gram negative bacterial; less active against gram + cocci;
• Fourth generation has a Beta lactamase and is resistant to it
• Fifth generation are anti- MRSA and have structural modifications

Antipseudomonal Cephalosporins:

• Include ceftazidime, ceftolozane/tazobactam, cefepime, and ceftazidime/avibactam, effective against P. aeruginosa
• Exhibit broader gram-negative efficacy
• Exhibit weaker gram-positive efficacy compared to third-generation medications
• Have structural modifications that allow for binding to altered PBPs
• Ceftaroline and ceftobiprole have shown effectiveness against MRSA strains.

Nucleoside Analogs:

• Acyclovir (Zovirax) serves as treatment for HSV-1 and HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes virus 6 (HSV-6)
• Famciclovir (Famvir) is used to treat HSV-1, HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and hepatitis B virus
• Ganciclovir & valganciclovir have activity against CMV and all herpes viruses
• MOA involves inhibiting viral DNA synthesis and replication

Black Box Warning

• Really excreted so should be reduced in renal insufficiency

Fluoroquinolones

• Targets bacterial DNA gyrase and topiosomerase IV essential for DNA replication
• Includes neuro (hallucinations, delirium, seizures, peripheral neuropathy, and possibly optic neuritis_

Glycopeptides

• These medications include Vancomycin, Teicoplanin, Telavancin, Dalbavancin, and Oritavancin
• Oral options is given for C. difficile colitis

Azole Antifungals:

• Fluconazole (Diflucan) is a brand spectrum azole treatment and treatment for cryptococcal meningitis
• Ketoconazole (Nizoral) topical use to treat dermatophytes and candidiasis

Nitroimidazoles:

• Metronidazole (Flagyl) and Tinidazole (Tindamax) are essential prodrug that creates leads to the formation of reactive compounds interacting with DNA, potentially disrupting its st
• Black box: Metronidazole has been shown to be CARCINOGENIC in mice and rats.
• Has disulfiram effects

Influenza Treatments

• Inhibit the virus by blocking a vital enzyme called neuraminidase which blocks spread of viral particles
• Amantadine and Rimantadine: inhibit early steps in viral replication, primarily targeting influenza A virus M2 protein- not indicated for Tx

Antiprotozoal Medications:

• Giardiasis Ο 5-7 Days of metronidazole (flagyl) usually suscessful ($4). ☐ 1 dose of tinidazole ($36-61). ☐ Paromomycin for pregnant women ($362).

Helminth Infections:

• May use Ivermectin that result mazza reaction
• Moxidectin Ο Differents binding activity than ivermectin for GABA-gated Cl - channels. Indications: treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older. Currently being investigated as an alternative treatment for scabies

Aminoglycosides

• May result in nephrotoxicity

HIV IN GENERAL NOTES:

• The best outcomes have been achieved using a 3-drug combo consisting of ARVS FROM AT LEAST 2 DIFFERENT DRUG CLASSES

HIV MEDICATIONS FOR PREP : PREEXPOSURE PROPHYLAXIS

• PEP is to prevent getting HIV from sex or injection drug use. PEP (post exposure prophylaxis) has side effects: nausea, diarrhea, headache, fever

PrEP IS HIGHLY EFFECTIVE FOR PREVENTING HIV

• PEP should be used only in emergency situations
• It is not meant to be taken regularly by people with frequent HIV exposure

CORTICO STEROIDS

• Corticosteroids do not appear to have any significant anti- inflammatory effect in COPD; there appears to be an active resistance mechanism. ICSs have no effect on the progression of COPD. ICS reduce the number of exacerbations in patients