Control-Find whatever antbiotic you’re interested in to learn unique facts about it (or scroll for memes)!

Natural Penicillins (Pen VK, Pen G, Pen G Procaine/Benzathine/Procaine & Benzathine)

Penicillin VK and Penicillin G

• • Pen G: Unstable in gastric juice (pH 2), thereby limiting absorption (IV only) 

• Pen VK: More stable, higher serum concentrations 

• Short T1/2, Renal elimination (tubular secretion)

• Removed by hemodialysis

• Bactericidal compounds. Maximal activity is based on TIME ABOVE MIC 

• Concentrations must be above MIC for 50% of the time for maximal effectiveness (30% for stasis).

• Spectrum

• Oral anaerobes (but not gut anaerobes like bacteroides/fusobacter)

• Gram positives

• Strep & Strep pneumoniae

• Viridans strep

• E. Faecalis, but not faecium 

• Neisseria. 

• Treponema pallidum (Syphilis)

• DO NOT cover MSSA/MRSA

• Indications

• Primarily syphilis 

• Others:

• Endocarditis

• Meningitis

• Strep pharyngitis

• Streptococcal toxic shock

Penicillin G Procaine (Long acting parenteral)

• IM
• Absorbed over about 2-4hrs
• Challenges associated with this drug:
  • Requires daily administration
  • Neisseria were resistant
• May cause dizziness

Penicillin G Benzathine (Long acting parenteral)

• IM
• Drug remained in serum for up to 4 weeks! 
• Challenge: severe joint pain

Penicillin G Benzathine/procaine (Long acting parenteral)

• IM
• LESS painful than benzathine

 

Antistaphylococcal Penicillins (Oxacillin, Nafcillin, Dicloxacillin) 

Oxacillin & Nafcillin

• Spectrum:
  • Gram positives 
    • Strep & S. pneumo
    • Viridans strep
    • MSSA but not MRSA
• IV ONLY – gastric acid causes breakdown
• Short T1/2
• Hepatic & Biliary excretion 
• Distribute into multiple tissues (skin/joint/lung/urine/CSF [with inflammation]), bile, peritoneal cavities
• May cause increased transaminases – more likely in these two drugs because their elimination is hepatic

 

Dicloxacillin

• ORAL! 
  • Increased F compared to oxacillin and nafcillin 
• Still have a short half-life 
• Used for mild SSIs
• Again, covers MSSA but not MRSA

Extended-spectrum Penicillins 

• Aminopenicillins (Ampicillin, Amoxicillin, Amp/Sulbactam, Amox/Clav)
•  Ureidopenicillins (piperacillin/tazobactam)

 

Ampicillin

• Has enhanced cell wall penetrating capability due to being a zwitterion at neutral pH. This allows them to easily penetrate through a gram negative cell’s porins. 
• Absorption is SATURABLE. Increasing dose does not produce greater effect. Higher doses lead to more diarrhea (this drug’s main problem).
• Penetrates lung, bone, CNS. 
• Used empirically in Listeria infections (esp. CNS)

Amoxicillin

• Oral ONLY 
• Reduced diarrhea vs. ampicillin
• Primary use is for upper respiratory tract infections 
  • Used empirically against S. pneumo (high dose)

 

Ampicillin/Sulbactam

• IV only (2 ampicillins: 1 sulbactam)
• Minimized impact of beta-lactamases, penicillinases, and cephalosporinases.
• Sulbactam is a “suicide inhibitor” 
  • Permanently inactivates beta-lactamases. Cannot be reused.
• Sulbactam has weak activity against Neisseria and Acinetobacter
• Both have short T1/2, renal elimination.
• Sulbactam penetrates CSF, lung, and bone similar to Ampicillin. 
• Empiric uses:
  • Surgical prophylaxis for intra-abdominal surgery
  • Head and neck infections involving the oral cavity
  • Sinus infections
  • MDR Acinetobacter infections
• Definitive uses:
  • Intra-abdominal, head and neck infections, and gynecologic infections

Amoxicillin/Clavulanate

• Only available in ORAL formulations

• Suicide inhibitor

• Inhibits beta-lactamases

• In contrast so sulbactam, no activity against Acinetobacter

• While amoxicillin is renally eliminated, clavulanate is eliminated by renal & hepatic mechanisms. 

• Primary complaint is diarrhea. 

• Primary use is in upper respiratory infections:

• Sinusitis

• CAP

• Otitis media

• Strep throat

 

Penicillin/tazobactam

• IV only 
• Short T1/2, renal elimination
• Extensive distribution into bile, CNS, lung, skin, urine, bone, peritoneum
• The only thing it does not cover is MRSA 
• More likely to cause cholestatic jaundice than other beta-lactams 
• Uses:
  • Healthcare infections where MDR is suspected
  • Intra-abdominal infections
  • Pneumonia
  • Complicated skin/skin structure infections 
  • Fever/neutropenia 

Cephalosporins

• 1st : Cefazolin, Cephalexin, Cefadroxil

 

Cefazolin & Cephalexin & Cefadroxil

• Cefazolin: IV ONLY! The only 1st gen with poor F 

• Cefazolin has unique use in surgical prophylaxis

• Short T1/2, renal elimination

• CSF penetration = POOR. Can’t be used for CSF infections. Active efflux from BBB.

• Good penetration into skin, bone/joint, urine, and lung (variable) 

• 1st gens do not cover strep pneumo. 

• Uses:

• SSIs; MSSA; S. pyo/Agalactiae 

• UTIs; E. Coli 

• Definitive therapy for MSSA (cefazolin)  

• 2nd: Cefprozil, cefaclor, cefuroxime, Cefotetan, Cefoxitin

Cefprozil, Cefaclor, Cefuroxime, Cefotetan, Cefoxitin

• Bioavailability: Good for all except Cefotetan and Cefoxitin

• These are both IV ONLY 

• Cefotetan has the longest half-life 

• Both of these agents have anaerobic activity and are used as intra-abdominal agents 

• All are renally eliminated

• Cefprozil has the lowest renal elimination 

• Still struggle with CSF penetration

• 2nd gens can be broken down into respiratory and cephamycins

• Respiratory:

• Cefprozil

• Cefaclor

• Cefuroxime

• Cephamycins (just remember that they’re the IV forms)

• Cefoxitin

• Cefotetan

• They cover the same things except cephamycins cover anaerobes. 

• Respiratory cephalosporin uses:

• Upper/lower respiratory infection

• Otitis media

• UTI

• Cephamycin uses:

• Intra-abdominal infection

• Mycobacterial infection (cefoxitin) 

• Surgical prophylaxis 

• Cefotetan may cause a disulfiram-like reaction 

 

 

• 3rd: Cefixime, cefdinir, cefpodoxime, ceftriaxone, cefotaxime   

Cefixime, cefdinir, cefpodoxime, ceftriaxone, cefotaxime   

• Cefixime: Used for gonorrhea management 
• Ceftriaxone and Cefixime:  Longest 3rd gen half-lives
  • 🡪 Once daily dosing
• All have pretty low renal clearance so it is less likely to have to adjust for renal dysfunction (biliary cleared as well) 
• What we’ve been waiting for.. CSF penetration! 
• NO activity against ESBL and POOR activity against AmpC 
• Unlike 2nd gens, they lose activity against gut anaerobes like bacteroides 
• NOT ideal for MSSA – first and second gens are BETTER 
• Uses: 
  • CNS infections
  • Upper/lower resp tract infection
  • Otitis media
  • UTIs
  • Bone/joint
  • SSIs 
  • Intra-abdominal infections
• More frequent CNS side effects due to their CSF penetration abilities
  • Seizures
  • Confusion
  • Delirium 
• More frequent diarrhea because 3rd gens are the only cephalosporins with biliary elimination
• Ceftriaxone is contraindicated in neonates <28 days (hyperbilirubinemia) 
  • Ceftriaxone binds with calcium, forming Ringer’s lactate solution
  • Biliary sludging and nephrolithiasis may occur.
• Cefdinir should be taken separate from iron supplements 2 hours before or after dose. 

Antipseudomonal and Antistaphylococcal Cephalosporins

• Antipseudomonal: Ceftazidime, Cefepime, Ceftazidime/avibactam, Ceftazolane/tazobactam
• Anti-staphylococcal (anti-MRSA): Ceftaroline

Ceftazidime

• Activity against Achromobacter and stenotrophomonas, which is not seen with other members of the 3rd gen family 
• UNSTABLE against ESBL and AmpC 
• Ceftazidime should not be used for gram-positive infections.
• Covers every gram-negative except Acinetobacter. Because of its instability against AmpC/ESBLs, it is not ideal against species like Enterobacter/Citrobacter/Serratia. 
• Poor activity against B. fragilis
• Can penetrate CSF with inflammation

Cefepime

• POOR activity against Achromobacter and stenotrophomonas. 

• STABLE against AmpC

• Better gram-positive coverage (up to MSSA); PREFERRED for gram (+) over ceftazidime

• Some activity against Acinetobacter 

Ceftazidime/Avibactam

• Avibactam allows for inhibition of ESBL, AmpC, KPC and OxaA
  • Avibactam is a non-suicidal inhibitor and can be recycled.
• As with ceftazidime, still not ideal for gram positives. 
• Much better coverage against ESBL producing bacteria (Enterobacter, Citrobacter, Serratia, P. aeruginosa) than ceftazidime alone 
  • Although it does have activity against ESBL/AmpC, its activity is not better than carbapenems
• Predominant use in KPC-producing organisms 

 

Ceftolozane/tazobactam

• Similar to other anti-pseudomonal cephalosporins BUT it has greater activity against Pseudomonas aeruginosa. 
  • It is active against carbapenem-resistance pseudomonas.
• Use for P. aeruginosa infections (especially for carbapenem-resistant isolates)!

 

Ceftaroline 

• Ceftaroline is the active metabolite. Ceftaroline fosamil is the prodrug that gets converted to active ceftaroline by phosphatases. 
•  ACTIVE against MRSA (anti-staph/anti-MRSA agent)
• NO activity against ESBL and poor activity against AmpC
  • Loses activity pseudomonas/acinetobacter and reduced activity against Citro/Entero/Serratia
• Used in pneumonia, bacteremia, SSIs
• ADEs
  • CNS: seizures, confusion, delirium 
  • GI: N/V/D
  • Renal: interstitial nephritis 
  • Anaphylaxis: CROSS REACTIVITY with PCN allergy. DO NOT USE in patients with immediate onset reactions (anaphylaxis)
  • Hematologic: neutropenia, anemia, thrombocytopenia, False positive Coombs test

Carbapenems (Imipenem/Cilastatin, Meropenem, Doripenem, Ertapenem)

Anti-pseudomonal carbapenems: Imipenem/Cilastatin, Meropenem, Doripenem

• Cilastatin used with imipenem to inhibit DHP1, an enzyme that degrades imipenem
• Meropenem and Doripenem have a methyl group that blocks DHP1 hydrolysis and can be used without cilastatin.
• Meropenem and Doripenem have reduced epileptogenic potential (seizures) 
• CSF penetration! (greatest in meropenem)
• Of the beta-lactams, they require the shortest amount of time above the MIC to work effectively. 
• These drugs cover everything except MRSA, E. faecium, and Stenotrophomonas. That is why they’re nicknamed “Gorillacillin.”
• They are all stable against ESBLs and AmpC
  • Because of this, they have a tendency to select for resistant bacteria and are usually reserved as a last line of defense when other anti-pseudomonal drugs like Cefepime or Pip/tazo fail or there is clinical worsening while taking these medications. 
• Potency in order: Doripenem > meropenem > imipenem 
• All carbapenems (inc. ertapenem) interact with valproic acid and probenecid. 

 

Ertapenem

• This drug DOES NOT COVER:
  • Pseudomonas
  • Acinetobacter
  • E. faecalis
  • E. faecium
    • Why??
      • Its structure has anionic character that results in decreased penetration through the porins of gram-negative bacteria.
• What’s its use then?
  • It stands out because of its half-life. It requires only once daily dosing. 
    • Eases transition to home care
• Like the other carbapenems, is it is stable against ESBL and AmpC and inactive against S. maltophilia.

 

Monobactams (Aztreonam)

ONLY active in gram-negative bacteria. Aztreonam 

• • Not active in Neisseria or Acinetobacter 
• While the same MOA as other beta-lactams (binding PBPs), it has a specific high affinity to PBP-3. PBP-3 is a septum peptidoglycan transpeptidase used in cell division.
  • Bactericidal; time dependent killing; T>MIC of at least 50% required
• Short half-life, renal elimination
• Administered IV, IM or Inhaled
• POOR eye penetration and POOR CSF penetration without inflammation
• Requires renal adjustment
• ACTIVE against Metallo-beta-lactamases (S. maltophilia) but INACTIVE against ESBLs and AmpC
  • Main mechanism of resistance to aztreoname is hydrolysis by beta-lactamases
• CAN BE USED in patients with penicillin allergy 
• Can also be used in combination with another beta-lactam when an aminoglycoside or fluoroquinolone is not appropriate. 

 

Aminoglycosides (Neomycin, Kantamycin, Gentamicin, Tobramycin, Plazomicin)

Neomycin, Kantamycin, Gentamicin, Tobramycin

• AG’s are NUCLEOPHILIC molecules that can easily be inactivated by transferring their own electrons – makes them an easy target for modification enzymes
• Unique membrane penetration
  • AG’s must pass through the outer membrane and the cytoplasmic membrane.
    • To get through the outer membrane, AG’s create porins that induce their uptake with Mg (II) bridges.
    • They then diffuse through the periplasmic space where they encounter the cytoplasmic membrane
      • They get through the cytoplasmic membrane via energy-dependent phase I (requires electron transport)
• Mechanism of action
  • Inhibits protein synthesis 
  • Elicits premature termination 
  • Incorporates incorrect amino acids 
• Activity of aminoglycosides are impacted by acidic pH, anaerobic conditions, hyperosmolarity, and divalent cations. 
• IV only, renal elimination
  • Elimination is Tri-phasic
    • Alpha, beta, and gamma phases. 
      • Alpha – distribution of drug from blood to tissue
      • Beta – elimination through kidney
      • Gamma – slow release of drug from binding sites (kidneys, ears)
• GOOD penetration into bone, synovial fluid, and urine
• POOR penetration into bronchial secretions, CNS (EVEN in inflamed conditions), eyes, bile, prostate and purulent fluid. 
• Concentration dependent killing
  • Cmax/AUC: 8-10
  • AUC:MIC: >100
• Always keep trough values <2mcg/mL to minimize toxicity
• AG therapy should be ONCE DAILY to minimize toxicity.
• AG’s are ACTIVE against mycobacteria, and many gram positives and negatives. However, they are almost never used as monotherapy and always as combination therapy, especially in deep-seated gram-positive bacteria (endocarditis or device-related infections). 
  • An exception is that an AG could be used as monotherapy with a UTI
• Resistance
  • Enzymatic modification is most common and is plasmid mediated.
  • Decreased uptake mechanisms are chromosomally mediated and usually cross-resistant to AG’s 
• Adverse effects
  • NEPHROTOXICITY
    • Non-oliguric renal failure (continues to produce urine)
    • A slow rise in serum creatinine is seen along with changes in urine input/output, and sometimes proteinuria. 
    • After several days of therapy, the AGs accumulate and cause epithelial cell necrosis 🡪 nephrotoxicity.
  • OTOTOXICITY
    • Irreversible vestibular and auditory effects 
      • Can occur during or after the end of therapy 
      • Can occur with standard dose or once daily dosing (equal risk); there is NO SAFE DOSE. 
      • There is no correlation between peak or trough concentrations, but increased risk with sustained high trough concentrations 
      • There is no relationship between serum AG and levels within the inner ear. 
      • Usually high frequency hearing loss goes first and may not be recognized clinically. Low frequency hearing loss shows loss in conversational hearing. 
      • GENTAMICIN most vestibulotoxic.  

Plazomicin

• Active against aminoglycoside-resistant isolates (aminoglycoside modifying enzymes)
• Active against ESBLs
• Active against carbapenem-resistant Enterobacteriaceae  
• Has a prolonged post-antibiotic effect 
• Has less gram-positive activity than the other aminoglycosides
• Plazomicin is ACTIVE against gentamicin-resistant Enterobacteriaceae, but activity is POOR against gentamicin-resistant Pseudomonas 
• Like aminoglycosides, not active against Stenotrophomonas 
• Like other AG’s, dose is adjusted for impaired renal function
• Therapeutic drug monitoring: Cmin <3mcg/mL in patients with UTI
• Nephrotoxic effects do occur, but tend to occur less. They occur more often with CrCl <60mL/min and high concentrations where trough values are >3mcg/mL
• Ototoxic effects not observed, but monitor closely. 

Glycopeptides (Vancomycin)

Vancomycin

• Available as IV or Oral

• Exclusively a gram-positive agent:

• Staph (MSSA/MRSA), S. epidermidis 

• Strep

• Enterococcus (Faecalis ONLY) 

• Corynebacterium

• Listeria

• Bacillus

• C. diff (Oral formulation ONLY) 

• The oral form is not absorbed and concentrates in the GI to kill C. diff.

• If using more than 2g/day for >10 days, requires therapeutic drug monitoring

• Gram positive oral anaerobes (peptostreptococcus)

• MOA:

• Inhibits peptidoglycan synthesis by recognizing D-alanine-D-alanine bonds, and binding to them. Cell wall cannot form.

• CSF penetration depends on if meninges are inflamed or not. 

• Decent lung penetration – enough to kill most bacteria. 

• DOSING:

• Empiric: 15mg/kg IV q8-12h, use actual body weight

• Critically ill: loading dose of 25-30mg/kg to achieve SS faster  

• Vancomycin requires therapeutic drug monitoring

• Trough goal should be about 15-20mcg/mL

• Check the trough prior to the 4th dose 

• Red-Man Syndrome

• A histamine-like reaction that will present with flushing, tachycardia, warmness, a rash on the face/upper body area, but NOT associated with an allergy.

• It occurs due to rapid infusion of vancomycin.

• Aim to infuse at <10mg/min

• Consider co-administrating with antihistamines 

• Pregnancy category B. 

• No (few) drug interactions

• Vancomycin is concentration dependent

• Estimate AUC: Total vancomycin dose in 24h / clearance

• Goal AUC/MIC to maximize killing: 400mg/L

• More frequently used equivalent is a trough goal of 15-20mcg/mL

• Resistance

• Van A gene will change D-alanine-D-alanine to D-alanine-D-lactate, so vancomycin won’t recognize the bond. 

• Results in VRE

• Staph aureus can pick up the van A gene via plasmids 

• Results in VRSA 

 

Lipoglycopeptides (Telavancin, Dalbavancin, Oritavancin)

Telavancin

• Dual MOA – it acts at the cell wall and cell membrane 
  • 1) Same as vancomycin – interacts with D-ala-D-ala bond at the cell wall (peptidoglycan)
  • 2) Hydrophobic tail penetrates cell membrane, causing it to depolarize and increases its permeability 
• FDA approved for HAP and VAP 
• MORE potent than vancomycin for MRSA and MSSA 
• ACTIVE against VRE Enterococcus that have VanB (NOT vanA)
• Co-formulated with Hydroxyl-propyl-Beta-cyclodextrin to enhance solubility 
• Renal elimination 
  • Renal adjustment required. Do not use if CrCl <10mL/min
  • Cure rates decreased for ABSSSIs with CrCl <50mL/min
  • Watch for renal adverse events/SCr increases
• ADEs
  • Taste disturbance (metallic/soapy taste) most common
  • CONTRAINDICATED in pregnancy 
  • CONTRAINDICATED  with heparin
  • Caution using other QT-prolonging agents 
  • Can prolong aPTT for up to 18 hours (interferes with phospholipid agents used in measuring thromboplastin time/prothrombin time, as well as interfering with coagulation-based factor X assays) 

Long-acting Lipoglycopeptide: Dalbavancin

• Use: ABSSIs
• Gram-positive activity 
  • VanB and VanC VRE (not Van A)
  • MRSA/MSSA 
  • Great for gram-positive anaerobes  
  • 2 week half-life! – once weekly dosing (or twice) 
    • Serum concentrations can stay above MIC for over a month 
  • Reconstitute with ONLY WATER or 5% dextrose
  • Administer over 30 minutes
  • Rapid infusion -> red man syndrome 
  • N/D/Ha
  • No drug-drug interactions 

Long-acting Lipoglycopeptide: Oritavancin

• • MOST potent of vancomycin, dalbavancin, linezolid, etc. 

• ACTIVE against VanA

• ACTIVE against VISA/VRSA

• Half-life 8-10 days 

• Renal elimination, but does not require renal adjustment because it is cleared very slowly.

• ONLY administer with 1000mL of D5W 

• Monitor patients with CHF because of such a large volume of fluid

• ONLY administer over 3 hours

• Artificially prolongs aptt up to 120 hours

• Artificially prolongs INR and PT (prothrombin time) for 12 hours

• Monitoring warfarin effectiveness unreliable 

• Most common ADE:

• N/V/D/Ha

• Limb or subcutaneous abscesses 

• MONITOR patients for osteomyelitis (more cases reported in oritavancin than vancomycin) 

• Uses of Dalbavancin/Oritavancin

• Avoiding hospitalization because of their long half lives that can remain in plasma for over a month

• Minimizing extended hospitalization stays

• Preventing need for multiple IV therapies 

• Could help with compliance with those unable to maintain IV access (e.g. homeless) 

 

Daptomycin (a lipopeptide)

Daptomycin

• Bactericidal 
• FDA approved for:
  • Complicated SSSIs
  • Staph. Aureus bloodstream infection 
  • Right-sided endocarditis caused by MSSA/MRSA
• Does NOT cover pneumonia
• Does NOT cover left-sided endocarditis 
• POOR CSF penetration
• Unique MOA:
  • Lipid tail inserts itself into the membrane (calcium mediated)
  • Causes membrane to depolarize
  • Ions (K+) efflux out of the cell, inhibiting protein and other macromolecule synthesis
  • 🡪 Cell dies, but the cell does not rupture
    • Less of an immune response is elicited as a result 
• Spectrum is only gram-positive:
  • MSSA/MRSA
  • Enterococci (VRE)
  • Strep
  • Gram-positive anaerobes 
• Renal elimination – consider monitoring SCr 
• Dosage is based on CrCl and the type of infection
  • Duration of treatment for cSSSI: 7-14 days
  • Duration of treatment for S. aureus bacteremia: 2-6 weeks 
  • Higher doses needed for enterococci and persistent bacteremia 
• ONLY administer in 0.9% NaCl (NS) – not compatible with dextrose diluents 
• Must infuse at 30 minutes or inject (IV Push) in 2 minutes
• Adverse effects and warnings: 
  • Most common ADEs are N/D/C/Ha
  • Warnings: 
    • Rhabdomyolysis or myopathy 
      • Monitor CPK levels at baseline and weekly thereafter
      • Monitor or hold for patients taking HMGCoA reductase inhibitors
      • Discontinue daptomycin if myopathy is present and CPK is > 5X normal (1000 U/L)
      • Discontinue daptomycin if patient is asymptomatic and CPK is 10X normal (2000 U/L) 
    • Eosinophilic pneumonia
      • Occurs 2-4 weeks after starting daptomycin 
      • Improves with discontinuation and steroid therapy 
      • Suspect eosinophilic pneumonia in patients with fever, hypoxia, or pulmonary infiltrates
• No drug interactions
• Daptomycin can cause false prolongation of INR and PT with some thromboplastin reagents. 
• Resistance in Enterococci and S. aureus:
  • Mediated by dltA gene
    • Causes changes in cell membrane permeability; cell membrane has less affinity for daptomycin 
  • Mutations in genes associated with phospholipid synthesis 

Oxazolidinones (Linezolid, Tidezolid)

Linezolid

• BacterioSTATIC
• Linezolid binds inhibits protein synthesis by binding to the 50s ribosome peptidyl transferase center (PTC; the 23s rRNA) and stopping the growth of bacteria. Blocks the formation of 30S and 50S ribosome complex. 
• The acetamide group of linezolid causes a reduction in its activity 
• Spectrum is gram-positive
  • MSSA/MRSA
  • Enterococcus (VRE)
  • Strep
  • Gram-positive anaerobes 
  • Mycobacterium and Nocardia
• FDA approved for: 
  • VRE
  • Nosocomial and CA pneumonia
  • Uncomplicated and complicated SSSIs
• IV and PO both have 100% F 
• NO renal or hepatic adjustment needed 
• GOOD CSF penetration 
• Adverse events:
  • Myelosuppression
    • Thrombocytopenia > anemia > neutropenia 
    • Usually happens after > 2 weeks of use 
    • Perform a weekly CBC 
  • Optic neuritis with use >28 days
  • Peripheral neuropathy with use > 28 days 
• Interactions:
  • None, but can act as an MAOI inhibitor 
    • May interact with serotoninergic agents, MAOIs, and tyramine-containing foods
    • May cause serotonin syndrome within 6 hours of use
      • Mental status changes, hyperreflexia, shivering, fever, diarrhea, tremors
• Resistance:
  • Mutations of the 23s rRNA (the portion of the 50S that binds the 30S subunit) 
  • cfr gene can cause resistance in Enterococci and Staph. aureus  

Tedizolid

• A PRODRUG 
• A phosphate modification increases solubility, bioavailability, and limits the reaction with MAOIs
  • When this phosphate is cleaved and replaced by an OH group, it remains active against cfr genes!
• Tedizolid has two extra rings that allow tighter binding (greater potency) to the PTC (the 23s rRNA) of the 50s subunit. 
• Same MOA as linezolid – prevents translation of proteins. 
• Used for ABSSSIs; treatment duration 6 days 
• More potent than linezolid in every way and retains activity against linezolid-resistant MRSA
• Like linezolid, bacteriostatic and 100% F, and NO adjustments for renal or hepatic impairment 
• Possibly  WEAKER interaction with MAOIs than linezolid 
  • Evidence is lacking since they excluded patients taking MAOIs in their trials
• Most common ADE is Nausea
• Tidezolid RETAINS ACTIVITY against VRE and linezolid-resistant MRSA that have the cfr gene

Tetracyclines and Glycylcyclines 

• Tetracyclines (Tetracycline, doxycycline, minocycline, Eravacycline, Omadacycline)
• Glycylcyclines (Tigecycline)

All tetracyclines

• BacterioSTATIC
• NONE have activity against Pseudomonas 
• Entry into cell and MOA:
  • Gram-positives: Enter via pH-dependent active transport 
  • Gram-negative: Enter via porin channels 
  • Inhibits protein synthesis and elongation by acting on the 30s subunit
• Active against various atypicals like parasites/spirochetes
• ADEs:
  • GI side effects: N/V/D/Heartburn/Epigastric pain
  • Photosensitivity & Hyperpigmentation
    • Blue-black discoloration occurs in scars/inflammation
    • Muddy-brown pigment occurs on sun-exposed areas
      • Use sunscreen and protective clothing 
  • Teeth can become yellow/gray/brown; permanent 
  • Bone growth can be inhibited in infants/children under 8 y/o
    • Reversible 
    • Avoid use 
  • Nephrotoxicity
  • Neurotoxicity 
    • Neurototic effects seen more in minocycline (dizziness, vertigo, tinnitus) and these effects are seen more often in women
    • Pseudotumor cerebri can also occur (high pressure that develops in brain and mimics a tumor) 
  • AVOID IN PREGNANCY  – can cross placenta and have toxic effects on fetus (retard skeletal development) – this effect goes hand-in-hand with its other bone growth inhibition effect. 
• Reduced risk of C. diff infection
• Interactions:
  • CATIONS (di/trivalent) reduce absorption
    • Take 1-2 hours before or 2 hours after 
    • Buzz word: multivitamin
  • Oral anticoagulants:
    • Increase bleeding risk by decreasing vitamin K production
  • Oral contraceptives
    • Reduce birth control drug levels
      • Use mechanical means of contraception in addition to BC

 

Tetracycline

• IV formulation no longer available due to hepatotoxicity
• AVOID IN RENAL IMPAIRMENT
• Can cause hepatitis 
• All tetracyclines have a long half-life except Tetracycline 
• HIGHEST renal elimination
• TAKE ON AN EMPTY STOMACH, food reduces absorption 50% 

 

Doxycycline

• • IV and PO
  • 100% F
  • SAFE in renal impairment due to high fecal excretion
  • Does NOT cause hepatitis
  • ADEs:

• Pill esophagitis 

• • • Take with 8oz water and stay upright for 30 minutes 
• Carbamazepine, phenytoin, and barbiturates  DECREASE half-life of doxycycline, thus decreasing its therapeutic effect. 

 

 

Minocycline

• IV and PO
• 100% F (slide says 90% to be specific, but IV and PO conversions are 1:1) 
• Does not need renal or hepatic adjustment 
• LOWEST fecal elimination
• ADEs
  • Long-term use of minocycline can cause blue-black gum discoloration due to bone pigmentation under the gums 

Tigecycline (Glycylcycline)

• Steric hindrance allows tigecycline to overcome efflux pumps and ribosomal protection
• Most common ADEs: Nausea/Vomiting 
• NO dosage adjustment in renal impairment 
• Adjust for severe hepatic impairment: 25mg IV q12h vs typical 50mg IV q12h
• DO NOT USE for bloodstream infections/bacteremia
  • Drug’s Vd is high and binds tissues very well – leaving serum concentrations very low
• Uses:
  • CAP
  • Complicated intra-abdominal infections
  • Complicated skin and skin structure infections 
• WARNING:
  • Mortality was HIGHER with tigecycline use. Only use when no other alternatives are available
• Resistance to Tigecycline:
  • Tet genes – plasmid mediated
  • Efflux pumps (gram positive and negative)
  • Ribosomal protection proteins 

 

Omadacycline

• IV or PO
• LOWEST renal elimination
• LOWEST protein binding 
• Uses:
  • CAP
  • ABSSSIs
• ADEs:
  • Transaminitis, hypertension, insomnia, gastrointestinal upset

 

Eravacycline

• Use: Complicated intra-abdominal infections 
• If using a strong CYP3A inducer concomitantly, Eravacyline’s clearance is increased.
  • UP DOSAGE to 1.5mg/kg q12h
• DO NOT USE Eravacycline for complicated UTIs
  • In clinical trials it did not show statistical non-inferiority vs Ertapenem 

Sulfonamides (Bactrim)

TMP/SMX (Bactrim)

• • Sulfonamides are analogs of PABA 
    • Competitively inhibits dihydropteroate synthase, reducing dihydropteroic acid concentrations
  • Trimethoprim inhibits dihydrofolate reductase, reducing tetrahydrofolate concentrations
  • Almost 100% F
  • Available as oral/oral suspension/IV 
  • Dosage depends on the infection
    • Dosage is based on trimethoprim component
    • Use adjusted bodyweight for obese patients 
  • ADJUST for renal dysfunction
  • TMP/SMX is FIRST LINE for:
    •  Nocardia
    • Stenotrophomonas maltophilia
    • B. cepacian 
    • Pneumocystis jiroveci
  • Covers MSSA/MRSA
    • Beta-lactams more effective for MSSA
  • Does NOT cover Pseudomonas or enterococcus 
  • NO anaerobic or atypical coverage 
  • Resistance:
    • Permeability barriers/efflux
    • Altered binding to dihydrofolate reductase (trimethoprim)
    • Altered binding to dihydropteroate synthase (sulfonamides)
    • Resistance can be transferred to other organisms 

• • Pregnancy category D

• • ADEs

• • • Most common side effects are GI related: N/V/D/Anorexia 

• • • Hyperkalemia can be caused by TMP (it has a potassium-sparing effect)

• • • Increased SCr from TMP, but filtration is not affected

• • • Interstitial nephritis or crystalluria from sulfonamide 

• • • Interactions

• • • TMP:

• • • Dofetilide

• • • Phenytoin

• • • Warfarin

• • • Digoxin

• • • SMP:

• • • Nephrotoxic agents

• • • Methenamine – Avoid 

• • • Elvitegravir

• • • Sulfadiazine (a different drug than TMP/SMX) is used for toxoplasmosis 

 

Fluoroquinolones (Ciprofloxacin, Levofloxacin, Moxifloxacin, Gemifloxacin, Delafloxacin) 

Ciprofloxacin

• Of the fluoroquinolones, it has lower F than most (except Delafloxacin) 
• Of the fluoroquinolones, its half life is the lowest (along with Delafloxacin) – needs BID dosing vs. once daily for others. 
• Renally eliminated
• Think gram-negatives (Pseudomonas included)
• Cipro specific drug interactions (due to its CYP1A2 inhibition potential):
  • Theophylline – increases levels. AVOID concomitant therapy
  • Cyclosporine – increases levels 
  • Methotrexate – inhibits renal tubular transport 

 

Levofloxacin

• Of the FQ’s, has the HIGHEST renal elimination. Best for urinary penetration.
• BEST for lung penetration. Think strep pneumo and respiratory infections. 
• Covers PSEUDOMONAS 
• Covers MSSA (not MRSA) 

Moxifloxacin

• Of the FQs, LOWEST renal elimination. Not useful for UTIs
• Of the FQs, HIGHEST half-life
• 2nd best for lung penetration. Think strep pneumo and respiratory infections.
• Covers ANAEROBES 
• Covers MRSA 
• Does NOT cover pseudomonas

 

Gemifloxacin

• Low renal penetration. Not useful for UTIs. 

Delafloxacin

• Of the FQs, LOWEST oral bioavailability 
• Like Levo and Moxi, FDA approved for CAP
• FDA approved for acute bacterial skin and skin structure infections
• Covers ANAEROBES 
• Covers PSEUDOMONAS 
• Covers MRSA 
• The only FQ that covers E. Faecalis (not faecium)
• Does NOT produce QT prolongation effects 
• Package label states that FQs should be used when there is no alternatives for all FQs EXCEPT Delafloxacin 

 

Macrolides (Erythromycin, Clarithromycin, Azithromycin) 

Erythromycin 

• WORST gram-negative activity (A>C>E)
• Oral base formulation needs enteric coating. Esters are more resistant/better absorbed.
• The BEST absorbed erythromycin ester oral formulation is erythromycin estolate.  
• Don’t take any erythromycin EXCEPT E. estolate with food (does not affect estolate version) 
• Absorbed in duodenum 
• Minimal distribution into CSF. Highly protein bound.
• NO adjustment required in renal impairment (bile and fecal elimination) 
• Crosses placenta/into breast milk 
• Erythromycin is the ONLY approved macrolide for Diptheria infections 
• Unique off label use – Gastroparesis (prokinetic agent) 
• Of the macrolides, has the GREATEST chance of causing hepatotoxicity (starts 10-20 days after treatment [long term use]) 
• Strongly inhibits CYP3A4
  
  
  

 

 

Clarithromycin

• Has a methoxy instead  of a hydroxy at C6 
• Clarithromycin as a parent drug is active, and it also has an active metabolite. 
• BEST gram-positive activity (C>E>A) 
• Resistance found in mycobacterium & H. pylori
• The only macrolide (at least from lecture) NOT available IV 
• First pass reduces F to 50-55% (HIGHEST F) 
• May be given WITH or WITHOUT food
  • Give ER versions with food, though. 
• Metabolized by the LIVER. Metabolism is SATURABLE.
  • Higher doses equate to longer half-lives 
• 20-40% excreted in urine. ADJUST dose if CrCl < 30mL/min
• NO dosage adjustment w/ hepatic impairment
• GI, cardiac, and hepatotoxic effects LESS than erythromycin
• Use with H. Pylori infection
• Use with Mycobacterial infections (M. leprae and M. Avium Intracellulare) 
• Use with Resp. tract infections 
• Like erythromycin, strong inhibitor of CYP3A4  

Azithromycin

• Instead of 14 membered rings, has 15 carbon ring. 
• Has a nitrogen in place of carbonyl group at 9a (in place of ketone found in erythromycin) 
• WORST gram-positive activity (C>E>A)
• BEST gram-negative activity (A>C>E)
• Absorbed rapidly but incompletely (F=30-40%) 
• Has high drug concentrations within cells
• Excreted via biliary route 
• Very little (12%) excreted in the urine
• Has the LONGEST half life (40-68h) due to its tissue binding ability
• GI, cardiac, and hepatotoxic effects LESS than erythromycin
• Of the Macrolides, Azithromycin is preferred in resp. tract infections
  • Chlamydia, pertussis, mycobacterial infections
• Z-pak dosing: 500mg PO day 1, then 250mg PO day 2-5
• A single 1g dose can be given for uncomplicated gonococcal urethritis due to C. trachomatis. 
• LOWEST likelihood of the macrolides to cause drug interactions 

 

Fosfomycin

Fosfomycin

• F is low – use limited to UTIs (bladder infections; cystitis) 
• Enters the cell via two active transport mechanisms:
  • Glycerophosphate transport (GLpT)
  • Hexose phosphate uptake system (UhpT)
• Blocks cell wall synthesis; bactericidal
• Binds the MurA enzyme by acting as a phosphoenolpyruvate analog and blocks the initial step in peptidoglycan synthesis. 
• Oral ONLY 
• Short half-life, renal elimination 
• Active vs MSSA/MRSA/Enterococcus/UTI-related gram negatives, among others
• NOT ACTIVE against S. Saprophyticus**, Stenotrophomonas, Burkholderia, anaerobes 
• Resistance
  • MurA alterations
  • Overexpression of enolpyruvyl transferase – overpowers Fosfomycin activity. 
  • Transport alterations (remember it has to get transported by GLpT & UhpT )
  • Fos A, Fos B, Fos C (Fosfomycin modifying enzymes) 
• GI: Diarrhea/nausea most common 
• Interactions:
  • Drugs that stimulate motility decrease absorption of Fosfomycin
  • Fosfomycin might minimize aminoglycoside accumulation.. less nephrotoxicity?
• Uses:
  • Uncomplicated acute cystitis 
  • Complicated cystitis
  • Prophylaxis
• Given as one dose
• It is expensive 

Nitrofurantoin

Nitrofurantoin

• Macrobid (macrocrystalline) is more tolerable than microcrystalline (less D/N)
• Has short half-life and is eliminated in urine and bile
• Alkaline urine may reduce its effectiveness 
• It relies on concentrating in the urine to work, so impaired renal function may have limited effectiveness 
• It does not penetrate well into kidneys, CSF, eyes etc. Only useful for bladder infections (cystitis) 
• Take with food!! 
• Technically contraindicated in CrCl <60ml/min but still used at 40+ mL/min
• CONTRAINDICATED in pregnancy >38 weeks and neonates <1 month 
• ADEs
  • GI: N/V (dose related)
  • Pulmonary toxicity/fibrosis with long-term use 
  • Urine discoloration (brown) 
  • False positive glycosuria test 
  • Magnesium antacids (reduces nitro absorption)
  • Probenecid (increases Nitro serum concentration) 
• Only for cystitis, typical treatment duration 5 days. Primarily GI sx.
• Consider Fosfomycin for long-term use (prophylaxis) 

 

Polymyxins (Colistin, Polymyxin B)

Colistin

• IV or inhalation only (inhalation optimizes lung exposure)
• Poor penetration to lung, tissue, pericardial fluid, CSF 
• Colistin is given as an INACTIVE PRODRUG (Colistimethate sodium, CMS)
  • CMS gets cleared by renal elimination OR converted to Colistin (active)
• Colistin is eliminated by non-renal clearance – the high concentrations found in urine are CMS being converted to colistin. 
• Because of being found in urine, it is BETTER than polymyxin B for UTIs
• Colistin requires a loading dose to be used 
  • When calculating dose, CrCl is calculated with Jellife equation 
  • Actual or ideal BW is used, whichever is lower

 

Polymyxin B

• IV only 
• NON-renal elimination
• Unlike colistin, administered in ACTIVE form
• Gets REABSORBED in kidney, resulting in low urinary concentrations; not useful for UTIs
• Dosing must be adjusted for renal function 
• Of the two, considered more reliable due to being administered in active form

 

Lincosamides (Clindamycin) 

Clindamycin

• BacterioSTATIC (like macrolides)
• Inhibits the 50S subunit (like macrolides) 
  • Inhibits peptide bond formation (inhibits translocation, like macrolides) 
• Spectrum is gram-positive and anaerobes 
  • Strep, MSSA/MRSA 
  • Anaerobes: bacteroides, prevotella, fusobacterium, Clostridium
    • C. perfringens only, NOT C. Difficile
  • Pneomucystis jirovecii (fungus) 
  • Protozoa (Toxoplasma gondii and plasmodium falciparum) 
• Resistance to clindamycin (same as macrolides) – erm gene.. methylates adenine of 23s RNA of the 50s subunit. This can be constitutive or inducible. 
  • Thus, cross resistance to macrolides and clindamycin and streptogramin B
  • Phenotypically, bacteria with this gene would be called “MLSB” 
  • Resistance is plasmid mediated. 
• The D test (for Staph – only staph have the erm gene. Strep have the mef gene) 
  • This test is useful when your staph isolate is erythromycin resistant and clindamycin susceptible. 
    • If this occurs, you need to perform a D-test. 
      • D-test result positive: Staph can become resistant to clindamycin during therapy. Do not use.
      • D-test negative: Can use clindamycin for therapy. 
• Oral form nearly COMPLETLEY absorbed (available PO/IV/IM, and topical)
• Penetrates most fluid/tissues EXCEPT CSF 
• Clindamycin is metabolized by the liver and thus may ACCUMULATE in severe hepatic failure
• After IV therapy stopped, antimicrobial activity can persist in feces for >5 days 
• NO ADJUSTMENT in renal failure or hepatic disease – monitor
• Uses:
  • SSTIs (INCLUDING CA-MRSA) 
  • Respiratory tract infections (due to its anaerobic activity)
    • Abscesses, anaerobic pleural space infections
  • Other anaerobic infections 
    • (infections of the female genital tract)
    • Prophylaxis of endocarditis in patients with valvular disease undergoing certain dental procedures (pts. With penicillin allergies) 
  • WITH primaquine, alternative agent for pneumocystis jirovecii pneumonia 
  • WITH Pyrimethamine, AIDS-related toxoplasmic encephalitis 
  • Surgical prophylaxis
  • Topical form for acne vulgaris, bacterial vaginosis 
• ADEs 
  • GI: N/V/D; mostly with PO 
  • Big risk for C. Diff infection 
  • May block neuromuscular transmission
  • Weigh benefit vs risk in pregnancy
  • AVOID while breast feeding 

Nitroimidazoles (Metronidazole)

Metronidazole

• INERT (prodrug) until activated in the cell 
• MOA:
  • 1) Drug ENTERS the cell via passive diffusion
  • 2) An ELECTRON TRANSFER to metronidazole’s nitro group occurs.
    • Results in a reactive free radical
    • The free radical INTERACTS WITH DNA 
  • 3) DNA synthesis is INHIBITED and damaged. Oxidation, breaks. Etc.
  • 4) DNA DEGRADES, host cell DIES. Then there is a RELEASE of INACTIVE END PRODUCTS of the drug. 
• ANAEROBES ONLY does not work in aerobes
  • Mainly Bacteroides (low resistance) 
  • Can also be used for parasitic infections and H pylori 
• Oral caps/tabs, IV, topicals (creams/gels/lotions/vaginal gels) 
• NO dosage adjustment in renal impairment 
• 50% dose reduction in severe hepatic impairment 
• 100% F; IV to PO conversion 1:1 
• Protein binding <20%, low protein binding and very lipophilic.
• Large Vd makes it effective for getting into tissues 
  • PREFERRED AGENT FOR CNS ANAEROBIC INFECTIONS 
• ADEs
  • CNS (ataxia, encephalopathy, seizure, aseptic meningitis) 
  • Peripheral neuropathy (w/ prolonged use, reversible. Most common)
  • Disulfiram-like reaction (Antabuse reaction) 
• SAFE pregnancy; defer breastfeeding if taking large doses of metronidazole
• Bacteroides resistance: nim genes