Pharm Exam 2: Infectious disease

Emergence of resistance Clostridioides (formerly Clostridium) difficile Drug toxicity

The cell wall Bacterial protein synthesis Bacterial DNA replication

Bacterial cell wall is comprised of peptidoglycan strands . The final step in the synthesis of a bacterial cell wall is a cross-linking of peptidoglycan strands (transpeptidation). Penicillin-binding protein (PBP) is the enzyme that catalyzes this step in the final stage of cell wall synthesis. Beta-lactam antibiotics compete for this enzyme since they are similar in chemical structure to the pieces that form the peptidoglycan chain. Beta-lactam antibiotics inhibit the growth of sensitive bacteria by inactivating enzymes located in the bacterial cell membrane, which are involved in the 3rd stage of cell wall synthesis.

Grouped together based upon a shared structural feature, the beta-lactam ring. Beta-lactam antibiotics include: Penicillins Cephalosporins Cephamycins Carbapenems Monobactams Beta-lactamase inhibitors Mechanism of resistance: production of enzymes that decrease penetration, alteration in PCN binding protein

Inhibit bacterial cell growth by interfering with cell wall synthesis. PCNs bind to and inactivate the penicillin-binding proteins (PBPs) Sensitivity Natural penicillins: Streptococcus Enterococcus strains Some staphylococcus (non-penicillinase producing) Aminopenicillins have greater activity against gram-negative bacteria due to enhanced ability to penetrate the outer membrane organisms. Combination with beta-lactamase inhibitors to broaden their spectrum Amoxicillin/clavulanate, ampicillin/sulbactam (+haemophilus influenzae) Pipericillin/tazobactam(+pseudomonas aeruginosa)

Well absorbed from GI tract, but several are unstable in acid: dicloxacillin, and amoxicillin better absorbed than ampicillin (give IV) Highly protein bound with good distribution to most tissues Small amount is metabolized, most excreted as unchanged drug in the urine Dosing is based upon weight in the pediatric population Short half life - multiple IV doses

Relative low incidence Hypersensitivity reactions IgE mediated hypersensitivity Maculopapular rash/urticaria Patients may be given desensitization therapy (time consuming) GI: most common with oral administration Loss of normal flora balance Fungal overgrowth C. difficile colitis In rare cases, leukopenia, thrombocytopenia, and hemolytic anemia can occur with penicillin

Commonly prescribed for infections such as those of the upper and lower respiratory tract, urinary tract seen in primary care. Used to treat CNS and infections and sexually transmitted diseases. Amoxicillin is first line drug for acute otitis media and sinusitis PCN for streptococcal pharyngitis Amoxicillin/clavulanate (Augmentin) first line drug for infection following bites including human. • choice for endocarditis (gram +)

Monitoring Return to office for evaluation of symptom relief Acute care setting May follow up if no symptom resolution Patient Education Resistance ADR’s Completing course

Prevents the breakdown of the beta-lactam by organisms that produce the enzyme, thereby enhancing the antibacterial activity. Examples Amoxicillin-clavulanic acid Ampicillin-sulbactam Piperacillin-tazobactam Ticarcillin-clavulanic acid Because these drugs are eliminated by glomerular filtration, renal dysfunction necessitates dosage changes. tx: intrabd, bites, foot infection (DM), lung abscessed

Structurally and chemically similar to PCN’s. Interfere with bacterial cell wall synthesis by binding to and inactivating the PBPs. First-generation (i.e. cefazolin and cephalexin) • Used for skin and soft tissue infections • Primarily active against gram-positive bacteria, S. aureus and S. epidermidis Second-generation (i.e. cefaclor) - Active against same as 1st generation, plus Klebsiella, Proteus, E. coli Third-generation (ceftriaxone) • Used for broader indications • More active against gram-negative bacteria Fourth-generation (i.e. cefipime, ceftazidime) • Resistant to beta-lactamase • Antipseudomonal Fifth-generation (i.e. ceftaroline) - Active against MRSA

Oral formulations absorbed from GI tract, enhanced by food Widely distributed to most tissues Some highly bound to proteins Some are metabolized to less active compounds Most excreted via kidneys, in various degrees as unchanged drug

Used for therapeutic failure in acute otitis media Cellulitis, erysipelas 1st generation: Strep pharyngitis Cephalexin, cefpodoxime, cefixime can be prescribed for UTI Ceftriaxone and cefixime used for Gonococcal infection Cefpodoxime, cefuroxime, or parenteral ceftriaxone for community-acquired pneumonia in combination with azithromycin for atypical coverage Not for use in CNS bc don’t penetrate CNS Tx: UTI, surgical prophylaxis, skin infections, Respiratory inf

Hypersensitivity reactions * maculopapular rash, itching 3-10% cross reactivity between PCNs and cephalosporins Transient GI effects

Interferes with bacterial enzymes required for the synthesis of bacterial DNA. Inhibit two bacterial enzymes which have essential and distinct roles in DNA replication Provides extensive gram-negative activity Avoid in general pediatric population Tendon rupture (low risk) Exceptions exist Avoid in Pregnancy/breast feeding Increasing resistance due to overprescribing Can no longer be used for GC Resistant TB

Well absorbed, take on empty stomach for best absorption Half life of 4 – 12 hours Removed by dialysis Excellent bioavailability

Complicated UTI, pyelonephritis infections, chronic bacterial prostatitis No longer effective in gonorrhea Pneumonia/chronic bronchitis exacerbation PCN resistant S. pneumoniae, skin infections, bone/joint infections, complicated intra-abdominal, infectious diarrhea, travelers diarrhea Meningitis prophyxlaxis (ciprofloxacin)

Relatively low ADR profile Black Box warning for tendonitis/tendon rupture • Elderly at higher risk • Can have delayed onset, 120 days to months after administration Pseudomembranous colitis and transient GI effects QTc prolongation (rare) Do not prescribe to children < 18 yrs

Monitoring • Watch for prolonged use • QT prolongation • ECG in patients taking QT prolonging drugs (i.e. amiodarone) Patient Education: • Food delays absorption (concentration dependent killing) • Many drug interactions • Take with full glass of water • May cause dizziness, palpitations, nervousness • If tendon tenderness occurs stop medication and notify provider

Inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. Atypical organisms commonly resistant to beta-lactam antibiotics are often susceptible Cross resistance seen to all in class Well absorbed from the GI tract

Weak bases, activity increases in alkaline media, rapidly absorbed from duodenum Exhibit enterohepatic recycling • May contribute to GI side effects • Tissue levels are higher than serum levels Potent inhibitors of CYP 450 3A4 ½ life for azithromycin: 50-72 hours

First line option for outpatient community acquired pneumonia +/- ceftriaxone for drug-resistant streptococci Chlamydia Pertussis H. Pylori infections (clarithromycin) Legionella PNA and COPD: Combo med use with macrolide AND beta-lactamase inhibitior

Relatively safe and effects are dose related Erythromycin : nausea, vomiting, abdominal pain, cramping, and diarrhea Hepatotoxicity (rare) Ototoxicity

Monitoring • Monitored for altered response to concurrent medications metabolized by - CYP450 3A4 or 2C9 • Hepatic/renal impairment • Hearing loss (rare) Patient Education • ADR’s • Drug interactions