Drug/Application Clinical Mechanism Drug Interactions/ Comments
Uses Side Effects
Antibiotics
/ · Drugs used to treat infectious agents· Dosing: Antibiotics with low PAE – optimize the duration of time the serum is > MIC; Those with high PAE – peak conc. is important
Used in three ways:
· Empirical therapy
1. Determine if infected
2. Identify site of infection
3. Ascertain possible pathogens
4. Predict susceptibility
5. Obtain specimens for testing
· Definitive therapy
· Prophylactic therapy
Possible routes of administration: IM, SC, IV, topical / · Pharmacokinetics: successful therapy depends on the drug’s ability of killing the pathogen without causing harm
· Distribution: Difficult sites to access: brain, eye, prostate – contain permeability barriers
· Elimination: Most eliminated by kidney unless otherwise noted
· Post-antibiotic effect (PAE): suppression of bacterial growth after removal of antibiotic. PAE usually seen in gram (+) bugs, sporadically in (-) bugs.
· Antibiotics that inhibit cell wall synthesis (β-lactams and glycopeptides) have minimal or no PAE against gram (-) bugs
· Aminoglycosides- PAE-concentration-dependent killing
· b-lactams- no PAE-time above MIC determines efficacy / · Direct effects: the result of direct interaction b/w the drug and/or one its metabolites and a specific tissue or organ in the body.
· Hypersensitivity – Type I HS rxn, Coomb’s (+) hemolytic anemia, serum sickness, and Stevens-Johnson syndrome
· Changes in microbial flora - all antibiotics may lead to pseudomembranous colitis
· Drug interactions – esp. with Warfarin – enhances anti-coagulation
· Host factors – genetics, age
· Pregnancy / · Minimum inhibitory conc. (MIC) – the smallest conc. of the drug that inhibits the growth
· Minimum bactericidal conc. (MBC) – the conc. of the drug that will kill the bacterium
· Bactericidal: achievable blood concentration is > MBC
· Bacteriostatic: achievable concentration > MIC, but below MBC
Drug/Application Clinical Mechanism Drug Interactions/ Comments
Uses Side Effects
INHIBITORS OF CELL WALL SYNTHESIS
/ · / · / · / ·b-lactams
Bactericidal / Non-competitive inhibitors of transpeptidases (penicillin-binding proteins-PBPs)
Resistance mechanisms:
· Inactivation of antibiotics by β-lactamase – most common mechanism, those produced by S. aureus, hemophilus, and E. colo are relatively narrow in substrate specificity and woll hydrolyze penicillins but NOT cephalasporins
· Modification of target PBP’s – mech for MRSA and penicillin resistance in pneumococci
· Impaired penetration of drug to target PBP’s – presence of impermeable membram (gram neg)
· Presence of an efflux pump / · Possess a four member nitrogen-containing beta lactam ring
· Inhibit bacterial growth by interfering with a specific step in bacterial cell wall synthesis.
· Β-lactam antibiotics are structural analogs of the natural D-Ala-D-Ala substrate and are covalently bound by PBP’s at the active site.
· Binding leads to inactivation of the transpeptidase reaction – inhibiting peptidoglycan synthesis. / · High therapeutic index
· Type I – mediated by IgE – urticaria, rhinitis, angioedema, conjuctivits, or systemic anaphylaxis
· Type II – rare, interaction of IgG or IgM with antigen à complement activiation, eg. Hemolytic anemia
· Type III – most common – serum sickness, arthralgia, rash, fever, lymphadenopathy, or vasculitis
· Type IV – CMI: cutaneous eruptions or thrombocytopenia / · Cell wall is composed of a complex cross-linked polymer, peptidoglycan, consisting of polysaccharides and polypeptides
· PBP in bacteria catalyze the transpeptidase reaction that removes the terminal alanine to form cross link with a nearby peptide
Penicillin
/ · / · Beta-lactam ring fused to a 5-member, sulfur containing thiazolidine· Modification of side chain à differing properties
· Inhibitor of cell wall synthesis / · Penicillin allergy occurs in 0.5% of patients / ·
* Standard penicillins
/ · Targets gram (+) / · / · / · Probenecid-inhibits tubular secretion of penicillin- used therapeuticallyDrug/Application Clinical Mechanism Drug Interactions/ Comments
Uses Side Effects
*Penicillin G(benzylpenicillin - IV)
(crystaliine penicillin G – IM)
(Benzathine penicillin G – long lasting – 1 mo) / · Route – IV, IM
· Syphilis – treated with Benzathine penicillin G
· Rheumatic fever – treated with Benzathine penicillin G
· Neurosyphilis and meningitis due to S. Pneumoniae and Neisseria meningitides.
· Meningococcal infection
· Streptococci (S. pnemo) / · Pharmacokinetics – penetrates CNS in high doses
· Elimination: Primarily renal (10% by glomerular filtration and 90% tubular secretion) / · HS reaction: rash, serum sickness, and rare anaphylaxis
· Hematologic – Coombs (+) hemolytic anemia, rare
· Neuromuscular irritability/seizures – associated with high dose penicillin therapy in patients with renal failure / · Probenecid - inhibits tubular secretion, can be used to increase blood concentration and prolong the half-life
· Resistance – in S. pneumoniae and meningococci in some parts of the world
*Penicillin V (phenoxymethylpenicillin) / · Route - Oral / · / · / · More stable in the presence of acid than Penicillin G
*Antistaphylococcal penicillins
(Methicillin – allegic intestinal nephritis)
(Nafcillin – IV, preferred to above, metabolized by liver)
(Oxacillin) / · Penicillin resistant staphylococci (S. aureus)
· Treat methicillin-sensitive staphylococcal infections (not active against MRSA) / · Stable to staphylococcal beta-lactamase
· / · Hematologic – esinophilia
· Neutropenia may occur with long course (>21d) of nafcillin
· Hepatic dysfunction with high dose oxacillin / ·
*Dicloxacillin / · Minor staphylococcal infections / · Antistaphylococcal penicillin Structural analog of oxacillin
· Well absorbed after oral administration / ·
*Aminopenicillins / · Enhanced activity against gram (-) bacilli
· Some streptococci
· Enterococci and L. monocytogenes – has more activity against than Pen G
· E. coli, proteus mirabilis, H. in fluenza, samonella, and shgella
· Broad spectrum / · Addition of an amino group to the penicillin side chain
· Inhibitor of cell wall synthesis
· Not b-lactamase resistant
· Distribution – Similar to other beta-lactams, can reach CSF in presence of inflamed meninges
· Elimination – primarily kidney, biliary excretion also occurs / · Macropapular rash in patients with mononucleosis, Chronic Lymphocytic Leukemia, or on allopurinol / · Spectrum:
· Gram (+)
· Gram (-) bacilli
· Formulated with beta-lactamase inhibitors to increase the spectrum of activity
*Amoxicillin
/ · Route – oral / · Aminopenicillin / · / ·*Ampicillin
/ · Route – IV· Meningitis / · Aminopenicillin
· Large dose – enters CSF / · / ·
Drug/Application Clinical Mechanism Drug Interactions/ Comments
Uses Side Effects
*Antipseudomonal penicillins / · Same spectrum as aminopenicillins plus additional activity against gram (-) bacilli including Pseudomonas aeruginosa (used in combo with aminoglycoside)· IV / · Exteded spectrum aminopenicillins
· Not stable against beta-lactamase
· Inhibitor of cell wall synthesis / · / · Subclasses
· Carboxypenicillins: ticarcillin
· Ureidopenicillins: piperacillin
b-lactamase inhibitors / · Available only in fixed-dose combination with beta-lactamase sensitive penicillins
· Inhibit beta-lactamases produce by staphylococci, gonococci, H. influenza, B. fragilis, and some enterobacteriaceae
· Used in the treatment of intra-abdominal infections, bite wound infection and infected cutaneous ulcers / · Beta-lactamase inhibitor
· Contain beta-lactam ring
· Covalently bind bacterial b-lactamase w/o intrinsic antibiotic activity
· Non-competitive inhibition / · / · Other combinations:
Ticarcillin/clavulanate
Piperacillin/tazobactam
*Clavulanate (Augmentin) / · Used in combination with AMOXICILLIN
· See above for uses / · Beta-lactam antibiotic with a beta-lactamase inhibitor / ·
*Sulbactam (Unasyn)
/ · Used in combination with AMPICILLIN· See above for uses / · Beta-lactam antibiotic with a beta-lactamase inhibitor / ·
Drug/Application Clinical Mechanism Drug Interactions/ Comments
Uses Side Effects
Cephalosporins
/ · Activity against gram (-) bacteria increases from 1st gen. to 3rd gen.· Antistaphylococcal activity decreases from 1st gen. To 3rd gen.
· No loss of antistreptococcal activity
· Activity against enterobacteriaceae superior to that of aminopencillins
· Resistant to most b-lactamases / · Beta-lactam ring fused to a six-member sulfur-containing dihydrothiazine ring
· Individual cephalosporins are created by side-chain substitutions
· Inhibitor of cell wall synthesis / · Approximately 10% cross-allergenicity between cephalosporin and penicillin
· Avoided in patients who show IgE-mediated penicillin allergy / · Classified into different generations based on their spectrum
First Generation Cephalosporin
/ Activity against· Streptococci
· Staphylococci
· E. coli
· P. mirabilis
· Klebsiella pneumoniae
· Useful against skin and soft tissue infections due to streptococcus pyogens or S. aureus
· Prophylaxis against infection following surgical procedures / · / · Used as alternatives to penicillins in penicillin=allergic individuals
*Cefazolin / · IV only
· Skin/soft tissue infections / · 1st generation / · / ·
*Cephalexin (Keflex) / · Oral / · 1st generation / · / ·
Drug/Application Clinical Mechanism Drug Interactions/ Comments
Uses Side Effects
*Second Generation Cephalosporin / · Genrally used against mixed aerobic/anaerobic infections· Against B. fragilis (ONLY 2nd gen)
· Activity against H. influenzae (β-lactamase producers or not)
· Community-acquired respiratory tract infections due to S. pneumoniae or H. influenzae
· Against enterobacteriaceae
· Children infections: streptococci, S. aureus, and H. influenzae / · / · / · Not used for meningitis
· Cefuroxime
· Cefprozil
*Third Generation Cephalosporin
- look for the “t” for third / · Increased activity against aerobic gram (-) bacilli
· Esp. against Enterobacteriaceae and H. influenza
· Reduced activity against S. aureus
· Treat nosocomial pneumonia: gram - bacilli
· IV / · Stable to beta-lactamases that are produced by H. influenza and N. gonorrhoeae, and many of those produced by enterobacteriaceae / · / · NOT effective against type I chromosome mediated inducible cephalosporinase produced by Enterobacter sp., citrobacter freundii, serratia marcescens, and P. aeruginosa
· Oral form is available but has reduced activity, only used for enterobacteriaceae
*Cefotaxime / · Activity against meningeal pathogens (S. pneumoniae, N. meningitidis, and H. influenzae) / · 3rd generation
· Enters CNS / · / ·
*Ceftriaxome / · Activity against meningeal pathogens (S. pneumoniae, N. meningitidis, and H. influenzae) / · 3rd generation
· Enters CNS / · / ·
*Ceftazidime / · Active against P. aeruginosa / · 3rd generation / · / ·
Drug/Application Clinical Mechanism Drug Interactions/ Comments
Uses Side Effects
*Fourth Generation Cephalosporin / · Excellent activity against enterobacteriaceae and P. aeruginosa· Good activity against S. aureus / · / · / · Cefepime – IV
· NO activity against:
MRSA
Enterococci
Listeria
B. fragilis
Carbapenems
/ · Broadest spectrum of all antibiotic / · Beta-lactam ring fused with a 5-member carbon containing penem ring· Inhibitor of cell wall synthesis / · / · Meropenum – similar activity as imipenem but does not produce toxic metabolite and is slightly more active against aerobic gram (-) bacilli and less active against gram (+) cocci
*Imipenem
‘Rambocillin- blows everything away, including your kidney’ / · Very broad spectrum
· IV only
Used against
· Streptococci
· Enterobacteriaceae
· P. aeruginosa
· Hemophilus species
· Anaerobic bacteria, inc. B. fragilis / · Has better penetration and access (through pore channels) to the periplasmic space in gram (-) bacteria
· Resistant to b-lactamases
· Pharmacokinetics: low oral bioavailability, well distributed to most tissue, and excreted by the kidneys / · Seizures
· Elimination: broken down by the kidney by human beta-lactamase (dehydropeptidase-1) to a nephrotoxic metabolite / · ALWAYS co-administered with Cilastatin, a dehydropeptidase-1 inhibitor
· NOT active against enterococcus faecium, legionella, mycoplasma, or chlamydia sp.
Monobactams
/ · / · Monocyclic beta-lactam – single ring structure attached to a sulfonic acid group / · / ·*Aztreonam
‘A bullet through an AZ tree is a negative thing’ / · Targets aerobic gram (-) bacilli inc. P. aeruginosa
· No activity against gram (+) bacteria or anaerobes
· IV only / · Only binds transpeptidases of gram (-) / · Essentially nonallergic / ·
Drug/Application Clinical Mechanism Drug Interactions/ Comments
Uses Side Effects
Glycopeptides
/ · / · / · / ·*Vancomycin
- Bactericidal
‘Vanquishes gram (+)’ / · Targets gram (+) bacteria -esp. those resistant to b-lactams
· MRSA
· β-lactam resistant strains of coagulase (-) staphylococci, enterococci, and pneumococci
· Serious infections with S. aureua, enterococci in pts. intolerant of β-lactam antibiotics
· Given orally for C. dificile
· Used as an IV
· Endocarditis prophylaxis for selected GU or GI procedures in β-lactam intolerant pts. / · Inhibits cell wall synthesis
· Covalently binds terminal two D-alanine residue at the free carboxyl end of pentapeptide
· Sterically hinders the elongation of peptidoglycan backbone
· Unable to penetrate the cell membrane of gram (-) bacteria
· Low oral availability
· Excreted unchanged by the kidneys, half-life = 6 hrs
· Diffuses across serous membranes into pleural, pericardial, synovial, and ascitic fluid
· Enters CNS only at high doses
· Unaffected by beta-lactamase production or PBR alteration / · No cross-reactivity between beta-lactams and vancomycin
· Patients with anuria, half-life = 7 days
· Nephrotoxicity
· Ototoxicity
· ‘Redneck’ or ‘red-man’ syndrome- histamine release w/ rapid infusion-slow infusion better / · 15% of enterococci resistant to vancomycin
· Vancomycin-resistant enterococci (VRE) is often resistant to all other antibiotics à incurable
· VanA – Genes are carried on Transposable elements thant encode enzymes responsible for resistance
· D-Ala-D-Ala terminal is converted to D-Ala-D-lactate on resistant enterococci
· S. aureus strains gaining enterococcal transposon
Drug/Application Clinical Mechanism Drug Interactions/ Comments
Uses Side Effects
INHIBITOR OF PROTEIN SYNTHESIS / · / · Ribosomes are the site of protein synthesis in both prokaryotic and eukaryotic· The differences in ribosomes between bacteria and humans provide a useful target for antibiotics
· Selective toxicity for bacteria / · / · Ribosomes:
· Bacteria – total 70S
Small: 30S = 16S + 21 proteins
Large: 50S = 23S 5S rRNA’s + 21 proteins
· Humans – total 80S
Small: 40S
Large: 60S
*Aminoglycosides
‘A mean guy hits his opponent in the ear and kidney. He drops, paralyzed.’ / · Bactericidal for aerobic gram (-) bacteria, staphylococci (in combo), and mycobacteria (in combo)· Used only in serious infections due to enterobacteriaceae and P. aeruginosa and in a hospital setting
· IV only
· Once daily dosing/ single large dose – conc. dependent killing therefore the peak conc./MIC ration is the best predictor of bacterial killing
· Significant post antibiotic effect (PAE)
· Synergistic w/ penicillins / · Irreversible inhibitors of protein synthesis
· Crosses outer membrane through porin channels (passive diffusion)
· Then actively transported across the cell membrane by an oxygen dependent mechanism
· Binds IRREVERSIBLY to the 30S ribosomal subunit
· Blocks initiation of protein synthesis
· Blocks further translation and elicits premature termination
· Incorporation of incorrect amino acid
· Absorbed poorly for GI
· Highly polar compounds – don’t enter cell readily
· Low intracellular conc. except in proximal renal tubule
· Do NOT enter CSF
· Excreted by kidneys – glomerular filtration
· Half-life = 2-3 hr
· Consist of two or more amino sugars linked by glycosidic linkage to a hexose nucleus / · Nephrotoxicity – concentrates in renal tubules - Reversible
- Increased when combined with another nephrotoxic drug
· Ototoxicity (auditory and vestibular) - permanent
· Risk of toxicities are dose and duration dependent
· Control with MONITORING
· Neuromuscular paralysis
· Half-life in renal impairment = 24 – 48 hr / · Resistance:
· Bacteria produce transferases enzymes that inactivate the aminoglycoside
· Mutation of porin or of the 30S subunit
· Aminoglycoside-modifying enzymes (AMEs) differ among aminoglycosides – so bacteria may be resistant to one but not to another
· Anerobic bacteria are innately resistant to aminoglycosides - lack the oxygen dependent transport
· Other aminoglycoside: - Amikacin – contains structural change that prevents its inactivation by many bacterial enzymes
- Neomycin
*Streptomycin
/ · Activity against mycobacterium tuberculosis / · Aminoglycoside / · / ·Drug/Application Clinical Mechanism Drug Interactions/ Comments