Antibiotics Lecture 2 Flashcards
Cephalosporins 1st generation
- Cephalexin- oral*
* Cefazolin- IV*
Cephalosporins 2nd generation
- Cefuroxime- oral*
* Cefoxitin- IV*
Cephalosporins 3rd generation
- Cefpodoxime- oral**
* Ceftriaxone- IV**
Cephalosporin 4th generation
• Cefepime- IV
Cephalosporin activity
Cephalosporins are less susceptible to β- lactamases giving them a broader spectrum of action compared to penicillins including Staphylococcus
In general, earlier generations have better Gram positive coverage than later generations*
In general, later generations have better Gram
negative coverage than earlier generations*
Common uses of Cephalosporins 1st generation
UTI, pharyngitis, mild skin or soft tissue infections, upper and lower respiratory tract infections
Common uses of Cephalosporin 2nd generation
Sinusitis, pharyngitis, otitis media, lower respiratory tract infections Cefuroxime- lyme disease
Cefoxitin and cefotetan also have anaerobic coverage (Bacteroides fragilis)
Common uses of Cephalosporin 3rd generation
Community acquired pneumonia, otitis media, upper respiratory tract infections, meningitis, febrile neutropenia,
Ceftazidime has coverage against Pseudomonas aeruginosa
Common uses of Cephalosporin 4th generation
Meningitis, febrile neutropenia, pneumonia, nosocomial infections, pyelonephritis
Adverse Reactions of Cephalosporin
- Cefixime- highest incidence of GI effects
- Cefprozil- lowest incidence of diarrhea
- Cefaclor-highest incidence of rash
- Cefotetan- has MTT side chain that can cause hypoprothombinemia and bleeding as well as a disulfiram like reaction ***
Special Considerations of Cephalosporin
Monitoring
• renal function
• Food
• Take with food- Cefaclor ER, cefuroxime suspension, cefditoren,
cefpodoxime tablets • Drug interactions
• Probenicid may increase concentrations of cephalosporins
• Use with caution in patients with a PCN allergy**
Cross sensitivity in penicillin allergic patients
Overall rate of allergic reactions to cephalosporins is 1%
Initial reported rate of cross sensitivity (10%) may have
been overestimated. It is believed that early cephalosporin antibiotics may have contained trace amounts of penicillin. Actual rate is ~ 3-7%
Patients are at higher risk of having a reaction with a first generation cephalosporin
Patients with a positive PCN skin test seem to be at higher risk. There is no skin test for cephalosporin allergy.
Monobactams MOA
Aztreonam
MOA: Bind to penicillin binding protein and inhibit cell wall synthesis which leads to cell death
Aztreonam
• Only monobactam available in the USA
• Has only Gram negative coverage including Pseudomonas; no Gram positive or anaerobic coverage
• Good for resistant infections b/c it is resistant to many
beta-lactamases produced by Gram negative bacteria
• No cross sensitivity with PCN or cephalosporin allergy
• IV or IM administration
• Doses must be adjusted for decreased renal function
• Low incidence of adverse effects -diarrhea
Carbapenems MOA
Imipenem/ cilastatin Meropenem Doripenem Ertapenem MOA: Bind to penicillin binding protein and inhibit cell wall synthesis which leads to cell death
Carbapenems
• Resistant to most beta-lactamases and are the drugs of choice for infections caused by ESBLs- extended spectrum beta- lactamases**
• Covers Streptococcus, Staphylococcus, Listeria, Gram negatives, and anaerobes; All cover Pseudomonas except ertapenem
• Doses must be adjusted for decreased renal function
• Cross sensitivity with PCN allergy- similar rate as cephalosporins***
• Adverse effects- nausea/vomiting, seizures (highest incidence with imipenem in patients with renal failure)
• Clinical uses include urinary tract and lower respiratory
infections; intra-abdominal and gynecological infections; skin, soft tissue, bone, and joint infections
• Imipenem is combined with cilastatin to prevent breakdown by renal dihydropeptidase.
Glycopeptide antibiotics
Vancomycin Telavancin
MOA: prevents cross-linking of the cell wall peptidoglycan during cell wall synthesis
works on the cell wall and leads to cell death
Vancomycin IV / PO
Gram positive coverage only
Used for MRSA infections- sepsis, endocarditis, meningitis, skin/ soft tissue infections
Oral dosage form is not absorbed- used for treatment of C. difficile only
Dosing for vancomycin is variable- based on actual body weight and renal function- most hospitals have dosing protocols run by pharmacists
Monitoring of serum levels is generally performed- trough should be above 10 mcg/ml to prevent resistance; goal- 10-20mcg/mL Adverse reactions- ototoxicity (sometimes permanent), nephrotoxicity (rare), injection site reaction
Risk of nephrotoxicity increased when other nephrotoxic drugs are administered with vancomycin (amino glycosides)
Vancomycin- Red Man syndrome
Infusion related reaction that is caused by the release of histamine
May cause erythematous or urticarial reactions, flushing, tachycardia, and hypotension.
This is not an allergic reaction
Management: stop the infusion, wait for it to subside then, slow the infusion rate down (infusion should be no faster than 1gm/ hr, but may need to be longer if Red Man syndrome occurs), may administer Benadryl prior to infusion
Telavancin
Similar to vancomycin, but is once daily dosing
Black box warning in pregnancy-may cause abnormal fetal development. Perform pregnancy test in women of child bearing age
Indicated for complicated skin and soft tissue infections. Investigational in nosocomial pneumonia
Dose must be adjusted for renal function
In clinical trials more patients experienced adverse reactions with telavancin compared to vancomycin
ADRs-Red Man syndrome;must infuse over at least 60 min., nephrotoxicity, GI upset, metallic taste.
Other cell wall or membrane active agents
daptomycin fosfomycin bacitracin cycloserine
Daptomycin (IV)
• Spectrum of activity is similar to vancomycin but it also covers vancomycin resistant enterococci (VRE) and vancomycin intermediate and resistant S. aureus (VRSA)
• Used for skin/soft tissue infections, bacteremia, endocarditis (not pneumonia!!)
• Doses must be adjusted for decreased renal function
• Adverse effects- injection site reaction, fever, chills,
diarrhea, nausea/vomiting
• Muscle cramps and weakness may occur- must monitor
CPK and discontinue drug if muscle pain and elevation of CPK > 5 times ULN occurs
Fosfomycin
oral formulation with Gram negative and Gram positive coverage. Used for UTIs in women, given as one time 3 gram dose.
Bacitracin
highly nephrotoxic when administered IV so it is only used topically. Used to treat surface lesions on skin or irrigation of wounds, joints
Cycloserine
covers Gram positive and Gram negative but is mainly used for treatment of resistant tuberculosis
Protein Synthesis Inhibitors- Tetracyclines (3)
Tetracyclines
• Tetracycline • Minocycline • Doxycycline
MOA of Tetracyclines
Tetracyclines bind to the 30 S ribosomal subunit, which prevents binding of tRNA to the mRNA- ribosome complex, thus interfering with protein synthesis
Tetracyclines common uses
Respiratory infections, community strains of MRSA (CA-MRSA), acne
Doxycycline- anthrax, chlamydia, lyme
Adverse Effects of Tetracyclines
• GIintolerance
• Photosensitivity
• Toothdiscolorationandabnormalbone
growth
• Do not use in second half of pregnancy or children <8 years old
Vestibular toxicity with minocycline
– dizziness, ataxia, nausea and vomiting- disappears within 24-48 hours after drug is discontinued
Special Considerations of Tetracyclines
Administration must be separated from food containing aluminum, magnesium, calcium, and iron by at least 1-2 hours
Food
• Minocycline: with or without
• Tetracycline: empty stomach
• Doxycycline: take with food due to GI intolerance (
absorption up to 20%) Monitoring
• Renal, hepatic, CBC, hematologic with long term use
tigecycline
• Glycylcycline antibiotic, Derivative of minocycline
• Covers Gram positive, Gram negative and anaerobes
• Indicated for complicated skin and skin structure infections and
complicated abdominal infections; has failed to demonstrate efficacy in hospital acquired pneumonia but is indicated for community acquired pneumonia.
• Has efficacy vs. MRSA, MRSE (staph epidermidis), VRE, and penicillin resistant Streptococcus pneumoniae.
• Has also shown efficacy against other multi-drug resistant organisms
• Phase 3 and 4 clinical trials have shown and increase in all cause mortality- mainly used for salvage therapy
4 types of Macrolides
- Erythromycin
- Clarithromcyin
- Azithromycin
- Fidaxomicin
MOA of Macrolides
Bind to the 50 S ribosomal subunit, inhibiting
bacterial protein synthesis
Common uses of Macrolides
Alternative for PCN allergic patients community acquired pneumonia pharyngitis skin/ soft tissue infections otitis media
Clinical uses of Azithromycin
• Primary outcome: determine whether azithromycin decreased
frequency of exacerbations in patients with COPD with increased
risk of exacerbations
• Intervention: azithromycin 250mg PO daily (n=570) x1 year vs.
placebo (n=572)
• Results:
– median time to first exacerbation
• Azithro group 266 vs 174 (p<0.001)
– Frequency of exacerbation
• Azithro group 1.48 vs 1.83 (p=0.01)
– Quality of life (respiratory)
• Significantly better in azithro group
– Hearing decrements more common in azithromycin group
Adverse Reactions
erythromycin, azithromycin, clarithromycin
- Nausea/vomiting (25% with erythromycin)
- Abdominal pain
- Diarrhea
- Renal failure
- QT prolongation (risk erythromycin > clarithromycin > azithromycin)
- Azithromycin
- Cardiovascular risk*
- 2012 NEJM study being evaluated for potential risk
Adverse Reactions Fidaxomicin
• Gastrointestinal most common – Nausea 11%
– Gastrointestinal hemorrhage 4% – Vomiting
– Abdominal pain
• Hematologic (rare)
– Anemia, neutropenia
Drug interactions of Macrolides
- Erythromycin and clarithromycin are metabolized via cytochrome p450 and can increase concentrations of many medications
- E.g. theophylline, warfarin, cyclosporine
- Azithromycin may increase cyclosporine and digoxin levels
- Fidaxomicin: no known clinically significant drug interactions
Compliance of Macrolides
- Clarithromycin twice daily (ER is once daily)
- Erythromycin four times daily
- Azithromycin once daily x 5 days
- except for urethritis (single 1gm dose)
Food interactions of Macrolides
• Clarithromycin: with or without food
• Azithromycin ER suspension (Zmax®) and erythromycin: 1 hour before
or 2 hours after a meal
• Fidaxomicin: with or without food
Common uses of Clindamycin
Skin and soft tissue infections (CA-MRSA), anaerobic infections, aspiration pneumonia Alternative for dental prophylaxis in PCN allergic patients
Can be used for CA-MRSA, but resistance can develop rapidly
Adverse effects of Clindamycin
- GI: Diarrhea,nausea,dyspepsia
- Skin rashes
- Higher incidence of Clostridium difficile vs other antibiotics
- Hepatotoxicity
- Back pain: vaginal clindamycin
Food considerations of Clindamycin
• AdministrationwithfooddecreasesGIupset
• Administration with a full glass of water decreases
esophageal ulceration
Linezolid (Zyvox®) Common uses
Resistant infections such as MRSA or vancomycin resistant E. faecium Skin/soft tissue infections, bone/ joint infections, bacteremia, pneumonia
Special Considerations of Linezolid (Zyvox®)
• 99.5% of staphyloccocus aureus still susceptible
• Good pulmonary penetration
• Exhibits weak reversible inhibition of monoamine oxidase
• Use caution when giving to patients taking SSRI- close monitoring is required
• Avoid high tyramine containing foods
• Thrombocytopenia 30% (reversible) and peripheral or
optic neuropathy (not or only partially reversible)
• Thrombocytopenia more common in patients with renal failure
and prolonged treatment durations (> 2weeks)
• Oral formulation has 100% bioavailability
• May be preferable in PVL producing CA-MRSA strains
Aminoglycosides 6 types and MOA
• Gentamicin- IV
• Tobramycin- IV
• Amikacin-IV
• Streptomycin-IV- rarely used
• Neomycin- topical only except as prep for bowel surgery
(PO) and hepatic encephalopathy (PO)(second line)
• Kanamycin- topical only
• Mechanism of action- inhibits protein synthesis by binding to the 30S ribosomal subunit
Common uses of Aminoglycosides
Rarely used alone especially with Gram Positive organisms
UTI, pneumonia, meningitis(can be given IT), synergy with PCN or vancomycin for bacterial endocarditis
Adverse Reaction Aminoglycosides
- Ototoxicity- vestibular (vertigo and ataxia) and auditory (tinnitus and high frequency hearing loss)- usually not reversible
- Nephrotoxicity-riseinScr–althoughanincreasein trough concentration will be the first sign.
- Ototoxicityandnephrotoxicityusuallyonlyoccur when duration of therapy is > 5 days, in the elderly, or in patients with impaired renal function.
Dosing Methods of Aminoglycosides
• Dosinganddosingintervalsarevariable-dependson indication and renal function
– Doses are weight based
• Two dosing methods-
– conventional (usually q8 or q12h) or
– traditional and extended interval dosing (q24, q36h)
• Bothmethodsrequiremonitoringofrenalfunction and serum drug concentrations at least every few days.
Benefits of extended interval dosing
– probable reduced nephrotoxicity
– decreased lab monitoring- do not need to measure
peaks
– no risk of having a sub-therapeutic peak level
– decreased pharmacy time for preparation
– decreased nursing time for administration – easier for home care doses
Extended interval dosing can be used for most Gram negative infections and some Gram positive.
4 types of Sulfonamides
- Sulfisoxazole
- Sulfamethoxazole/ trimethoprim
- Sulfadiazine
- Sulfasalazine
Sulfonamides MOA
Competitive antagonists of para-aminobenzoic acid (PABA)- which prevents formation of folic acid (folic acid is necessary for amino acid production)
Common uses of Sulfonamides
UTI, toxoplasmosis (in combination with pyrimethamine) Sulfamethoxazole- trimethoprim= 1st line for community acquired methicillin resistant staph aureus (CA- MRSA), PCP treatment and prophylaxis, upper respiratory infections
Sulfonamides- Adverse reactions
• Photosensitivity
• Nausea/vomiting/diarrhea
• Dermatologic
– Rash
– Steven -Johnsons syndrome or toxic epidermal necrolysis
(TEN)- fever and flu like symptoms, blistering and rash on skin and mucous membrane- very rare
• Blood dyscrasias aplastic anemia, granulocytopenia, thrombocytopenia, hemolytic anemia (in patients with G6PD deficiency)
• Nephrotoxicity can occur but is rare
• “Sulfa”allergies are common
Sulfa Allergies
- Cross sensitivity of sulfa allergy with sulfonamide antibiotic and non-antibiotics (e.g. glyburide, celecoxib) being criticized
- Structurethatcausesthehypersensitivity response in sulfonamide antibiotics (N1 heterocyclic ring) is absent in sulfonamide non- antibiotics
- Association between the two now thought to be due to a predisposition to allergic reactions rather than cross-reactivity
Special Considerations of Sulfonamides
• Administration
• Instruct patient to drink plenty of fluids while taking sulfonamides
• Numerous drug interactions
• Warfarin- can potentiate the effects (increased
INR)
• Methotrexate, phenytoin, digoxin
5 types of Fluoroquinolones
- Ciprofloxacin
- Ofloxacin
- Norfloxacin
- Levofloxacin
- Moxifloxacin
Fluoroquinolones MOA
Inhibit bacterial topoisomerase II (DNA gyrase) and IV thereby blocking DNA synthesis
Ciprofloxacin Ofloxacin Norfloxacin common uses
Norfloxacin- Uncomplicated UTIs
Cipro and ofloxacin- complicated and uncomplicated UTIs, gastroenteritis, prostatitis, STDs, skin infections, Cipro- anthrax PEP
Levofloxacin Moxifloxacin Gatifloxacin* (*opthalmic only) common uses
Similar indications as 2nd generation plus community acquired pneumonia and upper respiratory tract infections
Moxifloxacin is not used to treat UTIs
Adverse Reactions for Fluoroquinolones
- Nausea/ vomiting/ diarrhea/ constipation
- Tendonitis or tendon rupture- higher risk in elderly, renal insufficiency, and concurrent steroid use
- Photosensitivity
- Hepatotoxicity
- Hypoglycemia/ hyperglycemia
- QT prolongation
Special Considerations for Fluoroquinolones
- Administration
- Absorption is reduced when administered concomitantly with divalent or trivalent cations (magnesium, calcium, aluminum, iron, zinc) separate administration by at least 2 hours.
- Warfarin-mayincreaseINR-monitorclosely
- Avoidconcomitantusewithothermedications that may prolong QT interval (antiarrythmics, tricyclic antidepressants, etc).
- Cipro is least likely to cause QT prolongation, moxifloxacin is the most likely
Metronidazole
intra-abdominal infections, gynecologic infections, pseudomembranous colitis caused by Clostridium difficile, eradication of H. pylori (in combination with other agents)
Special Considerations for Metronidazole
• GI: nausea/vomiting, xerostomia (dry mouth), dysgeusia (usually manifest as a metallic taste), anorexia and abdominal pain
• CNS: peripheral neuropathy, seizures, encephalopathy- requires discontinuation of metronidazole
• Administration
– Extended-release tablets: Administer on an empty stomach,
at least 1 hour before or 2 hours after meals. Drug interactions
Ethanol??- avoid alcohol during administration and 3 days after administration due to potential risk of disulfiram-like reaction
May increase INR for patients on warfarin
May also increase concentrations of phenytoin
Nitrofurantoin common uses
Urinary tract infection
Special Considerations of Nitrofurantoin
• Do not use in CrCl less than 60mL/min
• Administration
• Food or milk may enhance GI tolerance
• Adverse effects
• GI- nausea and vomiting
• Serious AE with long term therapy- hepatotoxicity and
pulmonary toxicity- avoid in elderly
• Drug interactions
– Probenicid increases serum concentrations
• Efficacy
• 96% of E. coli show susceptibility in vitro to nitrofurantion vs. 87% with Bactrim
Commonly used antibiotics that DO NOT require renal dosage adjustments
- Ceftriazone
- Metronidazole
- Clindamycin
- Nafcillin/oxacillin/dicloxacillin • Azithromycin
- doxycycline
General principles of TB treatment
• A minimum of two drugs and usually three or four must be used simultaneously to prevent resistant strains
• Treatment duration is, at minimum, six months and up to two to three years for multidrug-resistant (MDR)TB
• Isoniazid and Rifampin are preferred first line agents
• Example of regimen:
– Isoniazid x 6 months
– Rifampin x 6 months
– Ethambutol continue for the first 2 months then d/c – Pyrazinamide continue for the first 2 months then d/c
Isoniazid- IV and PO
MOA
- MOA-inhibit the biosynthesis of my colic acid-a necessary component of the bacterial cell wall
- Administer with pyridoxine 10-50mg per day to minimize adverse CNS effects and peripheral neuropathy in patients with other risk factors for neuropathy (diabetes, elderly)
- Spectrum of activity-mycobacterium
Adverse reactions of Isoniazid- IV and PO
• CNS- peripheral neuropathy; if pyridoxine not given.
• Hepatitis- occurs in 2.1% of patients; d/c drug if
patient reports fatigue, loss of appetite and nausea /vomiting. Some clinicians also suggest d/c ing drug if LFTs rise to 3X the upper limit of normal, but this is not always necessary. Baseline and periodic LFTs should be performed
• Other:epigastric distress, xerostomia, hyperglycemia, metabolic acidosis, urinary retetion, gynecomastia in males, systemic lupus like symptoms.
Drug interactions of Isoniazid- IV and PO
- Separate administration from antacids by 1 hour
- INH may increase concentrations of benzodiazepines, carbamazepine, and phenytoin
- INH inhibits monoamine oxidase so use avoid co-administration with other MAO inhibitors
Rifampin- IV and PO
- Inhibits RNA synthesis by binding to the beta subunit of RNA polymerase.
- Active against Gram positive and Gram negative cocci, mycobacteria, and chlamydia.
- Uses: TB treatment and prophylaxis, leprosy, MRSA, MSSA, used to eliminate meningococcal carriage, prophylaxis of Haemophilus influenzae type B
Adverse reactions Rifampin- IV and PO
- Changes color of urine, sweat, tears, and contact lenses to an reddish-orange color
- GI distress, nausea, vomiting, diarrhea
- Flu like symptoms- fever, chills, myalgia can occur in up to 50% of patients receiving rifampin
- Renal- interstitial nephritis, glomerulonephritis, and nephrotic syndrome
Drug Interactions Rifampin- IV and PO
- Significant inducer of many CYP 450 enzymes so there are many significant drug interactions
- Has been shown to decrease the effectiveness of oral contraceptives!!
Ethambutol- PO
- Exact mechanism is unknown but it appears to inhibit RNA synthesis
- Spectrum of activity- mycobacterium
Adverse reactions/ Drug interactions of Ethambutol
• Optic neuritis- usually dose related and vision generally returns to normal after d/c of drug. Occurs after at least 2 months of therapy with doses of 25mg/kg/day or greater
• Pulmonaryinfiltrates
• Hepatotoxicity
• GI-N/V/D
• Drug interactions= Not many….
– Separate administration from aluminum hydroxide by 4 hours
Pyranzinamide
- Active vs only mycobacterium tuberculosis
- Mechanism of action- unknown
- Pyrazinamide is converted to it’s active form pyrazinoic acid by enzymes released by the mycobacteria
Adverse reactions/ Drug interactions of Pyranzinamide
- Hepatotoxicity - usually seen after prolonged treatment with doses of 40-50 mg/kg/ day
- Arthralgia can occur in up to 40% of patients probably secondary to hyperuricemia (pyrazinamide inhibits the excretion of uric acid). Usually does not cause problems but if acute gout develops- d/c drug.
- Hypersensitivity reactions may occur- rash, eosinophilia
Second Line Agents
- Ethionamide
- Capreomycin
- Cycloserine
- Aminosalicylic acid
- Kanamycin
- Amikacin
- Fluoroquinolones
- Linezolid
- rifabutin