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• These antimicrobials target bacteria, fungi, and viruses.

Penicillin and Cephalosporins

• Penicillin's mechanism of action (MOA) involves interfering with the final stage of cell wall synthesis called transpeptidation, leading to a weak cell wall and cell death
• Penicillin is bactericidal and particularly effective against Gram-positive bacteria
• Gram-negative bacteria have an outer membrane that acts as a barrier to penicillin
• Cephalosporins share the same MOA as penicillin but tend to be more resistant to certain beta-lactamases

Gram-Negative Bacteria

• Gram-negative bacteria have an outer lipopolysaccharide membrane that acts as a barrier
• Gram-positive bacteria have a cell wall that is easily traversed

Four Main Classes of Penicillins

• Narrow-spectrum penicillins that are penicillinase sensitive include Penicillin G and V, which cover streptococcus species, syphilis, gas gangrene, and tetanus
• Narrow-spectrum penicillins that are penicillinase-resistant include methicillin, nafcillin, oxacillin, and dicloxacillin; treat infections caused by penicillinase-producing staphylococci, including MRSA, but have no activity against gram-negative infections
• Broad-spectrum penicillins include ampicillin and amoxicillin
• Extended-spectrum penicillins include piperacillin, which is active against Pseudomonas Aeruginosa; when combined with Zosyn, it extends the antimicrobial spectrum to cover penicillinase-producing organisms

Cephalosporin Generations

• First-generation cephalosporins like Cephalexin (Keflex) have a narrow Gram-positive spectrum of action and are susceptible to inactivation by some bacterial beta-lactamases.
• First-generation cephalosporins do not readily cross the blood-brain barrier (BBB) and have low concentrations in cerebrospinal fluid (CSF)
• Second-generation cephalosporins like cefuroxime sodium inhibit bacterial cell wall synthesis and have activity against both Gram-positive and Gram-negative bacteria.
• Second-generation cephalosporins are more resistant to inactivation by beta-lactamases than first-generation drugs but can still be hydrolyzed by some ESBLs produced by certain bacteria.
• Second-generation cephalosporins achieve good CSF concentrations, especially when the meninges are inflamed, and treat bacterial meningitis caused by Streptococcus pneumoniae and Haemophilus influenzae
• Third-generation cephalosporins like Ceftriaxone (Rocephin) inhibit bacterial cell wall synthesis and have a broad spectrum of activity against Gram-positive and Gram-negative bacteria.
• Ceftriaxone exhibits relative resistance to inactivation by many beta-lactamases and penetrates the blood-brain barrier well, achieving therapeutic concentrations in the CSF and the preferred agent for treating bacterial meningitis
• Fourth-generation cephalosporins like Cefepime inhibit cell wall synthesis, have activity against both Gram-positive and Gram-negative bacteria, and are highly resistant to inactivation by most beta-lactamases.
• Fourth-generation cephalosporins penetrate the blood-brain barrier well and achieve good CSF concentrations.
• Advanced-generation cephalosporins like Ceftaroline cover Gram-positive and Gram-negative bacteria, including MRSA, and are resistant to inactivation by many beta-lactamases.

Beta-Lactam Ring

• The beta-lactam ring is essential for the antibacterial activity of penicillins and cephalosporins
• These drugs work by interfering with bacterial cell wall synthesis because the beta-lactam ring mimics the structure of a natural substrate used by bacterial enzymes called penicillin-binding proteins (PBPs)
• Bacteria have developed beta-lactamases as a defense mechanism against beta-lactam antibiotics, which break open the beta-lactam ring, rendering the antibiotic inactive.
• Structural modifications and combining beta-lactam antibiotics with beta-lactamase inhibitors combat bacterial resistance

Penicillin and Cephalosporin Reactions

• Penicillins can cause allergic reactions, like urticaria and anaphylactic shock, as well as diarrhea, nephritis, neurotoxicity, and hematologic effects.
• A history of Steven-Johnson syndrome or toxic epidermal necrosis from antibiotics means the drug should never be re-challenged
• Immediate reactions occur within minutes to an hour with hives and anaphylaxis symptoms
• Accelerated reactions take 1-72 hours, are less severe, and have symptoms like hives, fever, and joint pain
• Delayed hypersensitivity occurs days to weeks after drug exposure and presents with skin rash, blisters, or Steven Johnson/toxic epidermal necrosis.
• Clavulanic acid is a crucial penicillinase inhibitor combined with certain broad or extended-spectrum penicillins to combat antibiotic resistance.
• A combination of intravenous penicillin and an ahminoglycoside is a powerful antibiotic regimen when synergy, broad coverage, or overcoming resistance is crucial
• Watch for toxicity and resistance when using penicillin and aminoglycoside
• It is indicated for severe infections like endocarditis blood pathogens, neutropenic fever, and hospital acquiredinfection

Resistance to Antibiotics

• Resistance to penicillins and cephalosporins arises through beta-lactamase production, PBP modification, reduced permeability, increased efflux, and biofilm formation
• Antibiotic interactions: Patients who have had anaphylaxis, Stevens-Johnson syndrome or toxic epidermal necrolysis to PCN should not be prescribed cephalosporins, and some cephalosporins can enhance the effect of warfarin and increase the risk of bleeding

Carbapenems and Monobactams

• Carbapenems like Imipenem (primaxin) are given IV and can be used against Gram-negative and Gram-positive bacteria, penetrating well into tissues and CSF.
• For carbapenems, reduce the dose in patients with chronic kidney disease (CKD).
• High levels can cause seizures, so use with caution in patients with a PCN allergy
• Carbapenems are effective against bacteria resistant to penicillins, cephalosporins, and other antibiotic classes
• Carbapenems can treat Pseudomonas aeruginosa resistant to other antibiotics and hospital-acquired infections
• Monobactams, like aztreonam (azactam), have a beta-lactam ring not fused to another ring
• Monobactams targets Gram-negative aerobic bacteria, including Enterobacteriaceae and Pseudomonas, and can be used in those with allergies to PCN, cephalosporins, or carbapenems

Glycopeptides/Lipoglycopeptides

• Vancomycin treats MRSA infections and covers Gram-positive pathogens, including C.diff, MRSE, endocarditis, skin and soft tissue infections, and nosocomial pneumonia
• Vancomycin must be given orally to treat pseudomembranous colitis and C.diff because it stays primarily in the intestinal tract.
• Serious side effects of vancomycin include nephrotoxicity, red man syndrome, and ototoxicity.
• Combining vancomycin with other nephrotoxic drugs, such as aminoglycosides, NSAIDs, and diuretics, can cause kidney injury, enhance the effects of warfarin, and cause bleeding or ototoxic effects.
• Trough levels are the most crucial part of vancomycin monitoring 30 minutes before the next dose because of its narrow therapeutic window and toxicity risks
• Peak levels are the highest concentration of vancomycin in the blood, about 1-2 hours after it is finished

Telavancin and Aminoglycosides

• Telavancin inhibits bacterial cell wall synthesis similar to vancomycin, with a dual mechanism of action that disrupts bacterial cell membrane potential, leading to depolarization and cell death
• This may contribute to activity against some vancomycin-intermediate strains of *Staphylococcus aureus (VISA).
• Aminoglycosides inhibit bacterial protein synthesis and are used for serious Gram-negative infections -Aminoglycosides are normally part of a combination regimen to treat gram pathogens that are resistant

Aminoglycoside Concerns

• Nephrotoxicity and ototoxicity are the two main toxicities
• Signs of impending toxicity that need to be dealt with include decreased urine output, changes in electrolytes, fluid retention, weight gain, increased creatinine, tinnitus, hearing loss, and dizziness
• Prevent toxicity by getting a baseline kidney function, using the meds only when needed, monitoring dose, keeping the patient hydrated, and avoiding other nephrotoxic and ototoxic drugs

Aminoglycoside Toxicity

• Look at the severity of the infection, can you use an alternative, pre-existing kidney or hearing problems
• Pre-existing problems need to be considered for baseline assessment and drug monitoring.
• Other nephrotoxic drugs to consider: Vanc, loop diuretics, NSAIDS, ACE, and cyclosporins
• Ototoxic drugs to consider: VANC, loop diuretics, erythromycin, and aspirin

Tetracyclines

• Tetracyclines (doxycycline/minocycline) inhibit protein synthesis in bacteria and treat chlamydia, Gram-positive and -negative bacteria, atypical species, mycobacteria, spirochetes, acne, and rosacea
• Tetracycline is well-absorbed orally, binds to teeth/bones and tumors high in calcium, and is eliminated in urine.
• Minocycline can be administered PO and IV and reaches therapeutic levels in CSF, saliva, and tears, making it useful of treat meningococcal carrier states and get metabolized in the liver
• Doxycycline can be administered PO and IV, gets to therapeutic levels in CSF, and is preferred in patients with renal disease because it is eliminated in feces
• All tetracyclines cross the placental barrier and concentrate in fetal bone and teeth.
• Calcium, aluminum, magnesium, iron, and zinc decreases tetracycline absorptions

Tetracycline Concerns

• Common adverse tetracycline effects: GI discomfort, esophagitis, always take on empty stomach
• Deposition in bones and teeth leads to discoloration, hypoplasia of teeth, and temporary growth restriction in children
• Liver toxicity can occur with high doses, especially in pregnant women or with pre-existing liver/kidney disease
• Tetracyclines eliminated through the kidneys so kidney disease can cause increased side effects or failure
• Tetracyclines increase sun sensitivity, leading to severe sunburn, dizziness, vertigo, tinnitus, and begin intracranial hypertension

Macrolides

• Macrolides (erythromycin, clarithromycin, azithromycin) inhibit bacterial protein synthesis and are bacteriostatic, inhibiting bacterial growth rather than directly killing bacteria, but can be bactericidal at high doses and against certain bacteria
• Macrolides have a broad spectrum of activity, target Gram-positive bacteria, MSSA, and atypical bacteria, and treat respiratory tract infections, H.flu, chlamydia, h.pylori and Moraxella
• Erythromycin's most common side effect include GI upset, high doses cause smooth muscle contraction that causes gastric contents to move into the duodenum, transient deafness, cholestatic jaundice, and liver toxicity
• Azithromycin causes irreversible hearing loss and prolonged QT intervals.
• Macrolides interfere with liver metabolism and result in toxic levels of other drugs (warfarin)

Erythromycin and Clarithromycin

• Erythromycin and clarithromycin interfere with the liver metabolism of many drugs, inhibitors of CYP450 (Alfuzosin, Atorvastatin, Carbamazepine, Sildenafil, Warfarin)
• Change in guy flora can lead to digoxin toxicity
• Fidaxomicin (Dificid)'s MOA disrupts bacterial transcription and terminates protein synthesis, resulting in cell death
• Narrow spectrum coverage- Gram + aerobes and anaerobes (staph, strep, c.diff)
• Unique target site different than macrolide (no cross-resistance)
• First line agent in severe c-diff when other options don't work, very expensive

Clindamycin

• Lincosamides-clindamycin treats Gram-positive bugs, MRSA, Streptococcus, and Gram-positive and -negative anaerobes
• Resistance increases with use for gram-negative aerobes
• Used for MRSA, streptococcus and + and - anaerobes and skin and soft tissues
• The most serious side effects with clindamycin: accumulation in those with severe liver/renal disease, may lead to diarrhea (which may be an overgrowth of C. diff) treat this with Vanc or metronidazole
• Interacts with CYP3A4, so it can inhibit or induce, also can enhance warfarin and cause bleeding

Linezolid

• Oxazolidinones include linezolid (Zyvox), which treat Gram-positive pathogens, including resistant pathogens.
• Targets MRSA and VRE, and focuses on Gram-positive bacteria
• Weekly CBC's needed to assess thrombocytopenia and potential bone marrow suppression with Linezolid
• Causes a serotonin syndrome with large quantities of tyramine-containing foods, SSRIs, or MAOIs (reversed when the antimicrobial is stopped)
• Can cause irreversible peripheral neuropathy (when used for more than 28 days) and optic neuritis (greater than 28 days)

Quinupristin/Dalfopristin

• Streptogramins include Quinupristin/Dalfopristin (Synercid), which have a Gram-positive cocci, MRSA, VRE spectrum of activity
• Many adverse effects limits it to severe infections caused by vancomycin-resistant enterococcus faecium.
• It is an alternative for patients who are allergic to penicillin and cephalosporins.

Synercid Side Effects and Pregancy

• Synercid causes venous irritation, hyperbilirubinemia, and arthralgias and myalgias at high doses, inhibits CYP 450
• Pregancy category B- only use if necessary

Folic Acid Inhibitors

• Sulfonamides inhibit an enzyme called dihydropteroate synthetase, disrupting bacterial DNA replication and cell growth
• Trimethoprim inhibits dihydrofolate reductase converting dihydrofolate to tetrahydrofolate (THF).
• Sulfonamides interfere with folic acid synthesis

Trimethoprim

• Trimethoprim interferes with folic acid utilization by targeting a bacterial enzyme that is significantly different from the human equivalent
• Sulfonamides are for Gram-negative and -positive bacteria, enterobacteriaceae, h.flu, streptococcus, nocardia
• Sulfadiazine combined with pyrimthamine treats toxoplasmosis
• Trimethoprim Uses are 20-50 fold more potent than sulfonamides, and treat UTIS
• Used UTIs, Respiratory tract, Pneumocystis jirovecii Pneumonia, GI, and skin.
• Both drugs inhibit different steps in the bacterial folic acid
• By blocking two steps, the combination has a synergistic effect, meaning that it is more impactful that drug alone
• Combination targets two steps in the same pathway, it is more difficult for bacteria to develop resistance compared to when either drug is used alone.

Sulfonamide Risk Factors

• Sulfonamides and Stevens-Johnson syndrome patients have highest risk of anemia and kernicterus
• SJS begins with flu-like symptoms, followed by spread of blisters that can involve the mouth, eyes, and genitals.
• Affects those that suffer from G6PD deficiency
• Can trigger an immune response that attacks red blood cells, causing them to rupture (hemolysis)

Drug Monitoring

• Sulfonamide induced crystalluria: Use adequate hydration and alkalization of the urine, which prevents it
• Side effects: TMP/SMX is associated with more sever skin reactions (SJS/TEN) compared to tetracyclines and macrolides
• Teeth issue: tetracyclines uniquely affect teeth development in young children and in utero.
• QTc prolongation: Macrolides (especially erythromycin and clarithromycin) can prolong the QTc interval, a risk not typically associated with TMP/SMX or tetracyclines.
• Drug Interactions: Macrolides (erythromycin and clarithromycin) are notable for their interactions through CYP450 inhibition, while TMP/SMX and tetracyclines have different interaction profiles.
• Dont prescribe sulfonamides to patients with heart conditions unless cutting dose by 50%

Fluoroquinolones

• Inhibit DNA gyrase and topoisomerase IV, Broad spectrum antibiotic
• Use Caution! Black Box Warning!
• Cause tendinitis and tendon rupture, risk increased in those taking corticosteroids.
• Avoid Concurrent Use with erythromycin and other drugs associated with prolonged QT interval, can increase risk for arrhythmias

Tetracycline and pregnancy

• Not to be used in pregnanacy and or children younger than 8 Causes liver toxicity especially in pregnant women and those with pre-existing liver/kidney disease Benign intracranial HTN, Benign Intracranial Hypertension, dizziness, vertigo, and tinnitus

More antibiotic concerns

• Can also not be used in pregnant or breastfeeding women
• All tetracyclines cross the placental barrier and concentrate in fetal bone and teeth.
• Separate interactions by 2-4 hrs
• Can cause liver toxicity especially in pregnant women and those with pre-existing liver/kidney disease Benign intracranial HTN, Benign Intracranial Hypertension, dizziness, vertigo, and tinnitus
• Not to be used in pregnanacy and or children younger than 8 Causes liver toxicity especially in pregnant women and those with pre-existing liver/kidney disease