Introduction to Antibiotics Flashcards
Antibiotics- definition
Substances produced by various species of microorganisms that surpress growth or destroy microorganisms. Including fungi, bacteria, and actinomyces
Bactericidal
Directly kill bacteria
Inhibitors of cell wall synthesis, cell membrane distributors, aminoglycosides, DNA gyrase inhibitors
Does not require functioning immune system
Bacteriostatic
Arrest growth or replication of bacteria. Host immune system then eliminates the pathogens.
Must have a functioning immune system
Bactericidal with a bacteriostatic antibiotic?
NEVER
General characteristics of ABX
All antibiotics can ellicit allergic response
Cross-sensitivity between agents in different classes
Target normal body flora in addition to pathogens
Classifications of ABX- Agents that inhibit cell wall synthesis
Penicillins Cephalosporins Cycloserine Vancomycin Bacitracin
Classifications of ABX- Agents that act directly on the cell membrane of the microorganism affecting permeability and leading to leakage of intracellular compounds
Detergents
- polymyxin
Classifications of ABX- Agents that interfere with protein synthesis by interaction with bacterial ribosomes
Chloramphenicol Tertracyclines Macrolides Clindamycin Streptogramins Ketolides
Classifications of ABX- Agents that interfere with protein synthesis by blocking initiation
Oxazolidinoses (linezolid)
Classifications of ABX- Agents that interfere with protein synthesis by inhibition of tRNA synthesis
Mupirocin
Classifications of ABX- Agents that interfere with protein synthesis by multiple mechanisms leading to disruption of RNA processing
Aminoglycosides
Classifications of ABX- Agents that inhibit DNA processing by
Inhibition of DNA topoisonerases
Quinolones
Inhibition of DNA-dependent RNA polymerase (Directly-rifampin and indirectly- nitrofurantoin)
Classifications of ABX- The antimetabolites- blocking bacterial folic acid pathway
Trimethoprim
Sulfonamides
Two ways antibiotics are used
As emperical therapy- before lab results and dx (broad spectrum)
As definitive therapy- after lab results and dx
Goal is to choose a therapy most selectively active for the organism, with the least potential for toxicity
Selecting an Antimicrobial agent
Decide if ABX if truly needed
Evaluation is necessary before administration of ABX since diagnosis may be masked w/out appropriate culture.
Host defenses
Low immune respsonses may result in therapeutic failure despite the use of appropriate and effective therapy.
Humoral immunity
Inadequacy in the immunoglobulins
Cellular immunity
Inadequacy in the phagocytic cells
Host factors- Age
Renal and hepatic metabolism can be affected by infants and elderly
Host factors- genetic factors
In patients w/ glucose-6-phosphate deficiency certain drugs can cause acute hemolysis
Host factors- disorders of the nervous system
Patients w/ seizure disorder usually occurs with high doses of PCN G
Patients w/ myasthenia gravis- susceptible to neuromusular blocking effects of certain antibiotics.
Host factors
Host defenses Age Genetic factors Pregnancy Drug allergy Disorders of the nervous system
Pharmacokinetic factors
Infection in the CSF-drug must cross the BBB
Penetration of the drug into the local area since many antibiotics are highly protein bound.
Knowledge of the pts kidney and liver status.
Resistance of microogranisms to antimicrobial agents
If the concentration of the drug required to inhibit or kill the microorganism is greater than the concentration that can be safely achieved then its resistant.
Resistance occurs becasue?
Drug fails to read target (Decreased intracellular concentration)
Drug is inactivated
Target is altered (change in binding site)
Adaptations that bypass need for binding sites
Antibiotic resistance-Drug fails to read target
Change in cell wall to increase efflux- TCN and quinolone resistance
Decreased cell membrane permeability-beta lactam and quinolone resistance
Decrease cytoplasmic membrane transport aminoglycosides
Antibiotic resistance- Drugs inactivated
Lactamases deactivate beta-lactams
Phosphotransferases and acetyltransferases deactivate amino glycosides
Antibiotic resistance- Target is altered
DNA gyrase prevents quinolone binding
Methylation of rRNA prevents macrolide binding
Antibiotic resistance- Adaptations that bypass need for binding site
Use alternative metabolic route in folate synthesis avoiding effects of trimethoprim
Resistance- antibiotic use
Exerts selective pressure on bacteria to acquire resistance to survive
Resistance- innate resistance
a long-standing characteristic of a particular species of bacteria
Resistance- Acquired resistance
Mutations-random events that confer a selective advantage to the bacterium
Transfer or plasmids-transduction, transformation, conjugation
Transduction
The intervention of a bacteriophage (a virus that infects bacteria)
Contains bacterial DNA which may contain a gene resistant to antibacterial agents
Resistance can be passed down to progeny
Transformation
Incorporates DNA from the environment into bacteria
Penicillin resistance in pneumococci and Neisseria
PBPs and DNA pieces probably from closely related species of streptococcus
Conjugation
Passage of genes from cell to cell by direct contact through a bridge
Conjugation occurs primarily among gram-negative bacilli.
Multiple drug-resistance bacteria
Methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacteria tuberculosis
Inhibitors of cell wall synthesis
Mammalian cells lack cell walls
Cell wall inhibitors require actively proliferating microorganisms for maximal effect
B-lactam ABX, vancomycin, bacitracin are major members of this class
Consequences of Cell wall inhibition
Lytic death- cell wall breaks down cell and cell is destroyed
Non-lytic death- dissolve the cell inside out
Tolerance-inhibition of growth becoming bacteriostatic (Cell shuts down to survive) instead of -cidal.
Beta Lactam Compounds
Penicillins Cephalosporins Cabapenems Monobactams Beta lactamase inhibitors
Beta Lactam Compounds- Penicillins
Natural penicillin
Aminopenicillins
Penicillinase Resistanct Penicillins
Extended spectrum penicillins (Anti-psuedomonal)
Beta Lactam Compounds- Cephalosporin
First generation- fifth generation
Beta-lactam drugs
Defined by beta-lactam ring in chemical structure.
Inherently the beta-lactam ring is unstable to pH and beta-lactamases
Drugs undergo acylation; form covalent bond with trans-peptidase
Modifications of the beta-lactam ring define subclasses
Penicillins- thiazolidine ring
Cephalosporins- dihydrothiazine ring
Monobactam- no additional ring
Cabapenems- unsaturated ring with no sulfur external to ring
Beta-lactam ABX
Generally bactericidal
Most active against growing organisms
Many have gram-positive and gram-negative activity
Penicillins-Introduction
1928 discovery by Alexander Fleming
Widely used and relatively safe (Class B in pregnancy)
Beta-lactam ring (a thiazolidine ring) with side chains
What was the name of the original penicillin
Penicillin G
Penicillins Mechanism of Action
Interfere with the last step in bacterial cell wall growth
Works best on rapidly proliferating organisms
No effect on organisms without a cell wall (protozoa, mycoplasma, mycobacteria, fungi, and viruses)
Penicillin resistance
Inactivated by beta-lactamase
Modification of PBP target (mechanisms of MRSA and penicillin resistant to pneumococci)
Impaired penetration of drug to target PBP
Penicillin classification- Natural Penicillins
Penicilling G or V
Narrow spectrum, PCN G acid labile, penicillinase sensitive.
Highly active against sensitive stains of gram positive cocci (Not staphylococcus)
Anaerobes
Some gram negative
Penicillin G or V
Tx infections of upper and lower respiratory tract, throat, skin, and GU tract.
Prophylaxis in rheumatic fever, dental procedure for those at risk of endocarditis, gonorrhea or syphilis expose.
Penicillin G or V- gram positive cocci
Streptococcus, enterococcus faecalis, listeria morlocytogenes
Penicillin G or V- Anaerobes
Bacteroides species and fusebacterium species
Penicillin G or V- gram negative
E. coli, H. influenzae, N. gonorrhoeae, Treponema be, and suspectible psuedomonas species.
Amniopenicillins
Ampicillin and amoxicillin
Ampicillin and Amoxicillin
Activity of PCN G plus improved coverage of gram negative cocci adn Enterobacteriaceae
Not active against treponema or actinomyces
Ampicillin and Amoxicillin- therapeutic uses
URI (Otitis, sinusitis), uncomplicated UTI, meningitis, salmonella infections
Ampicillin and amoxicillin- resistance leading to combinatins with beta-lactamase inhibitors
Augmentin = Amoxicillin + Clavulanic acid
Ampicillin + sulbactam (unasyn)
Better coverage against H. Influenzae and Klebsiella sp.
Penicillinase-Resistance Penicillins (antistaphylococcal penicillins)
Nafcillin, oxacillin, dicloxacillin
Methicillin and cloxacillin no longer available in US
Penicillinase resistance, narrow spectrum
Staph resistant to this class is called MRSA
Penicillinase-Resistance Penicillins (antistaphylococcal penicillins)- tx
Used in treatment of staphylococcal infection with high beta-lactamase production (cellulitis and endocarditis)
Not active against gram-negative or anaerobic organisms
Antipseudomonal penicillins
Piperacillin, ticarcillin, carbenicillin (PO)
Maintains activity of PCN G but gain great gram negative coverage including psuedomonas
Coverage against H. influenzae and kelbsiella sp
No coverage against treponema palladium or actinomyces
Gram negative infections in combo with aminoglycosides (bacteremias, pneumonias, resistant UTIs, infections in burn patients)
Antipseudomonal penicillins- resistance issues and are paired with beta-lactamase inhibitors
Piperacillin + tazobactam = zosyn
Ticarcillin + clavulanic acid= timentin
Beta-lactamase inhibitors
Clavulanic acid, sulbactam, tazobactam
Structurally similar but lack antibacterial activity
Act as suicide inhibitors -> potent, irreversible inhibitors of many lactamases.
Extends the spectrum of the ABX its paired with
Addition of Beta-lacamase inhibitors- Aminopenicillins
Amoxicillin + clavulanic acid (augementen)
Ampicillin + sulbactam (unasyn)
Addition of Beta-lacamase inhibitors- Antipseudomonal penicillins
Piperacillin + tazobactam (Zosyn)
Addition of Beta-lacamase inhibitors
Increased coverage against H. flu, staph, moraxella catarrhailis
Variable coverage against gram (-) bacteria- pseudomonas, enterobacter, E. coli, klebsiella, serratia due to resistance to these beta-lactamase inhibitors.
Penicillin administration- oral only
Penicillin V, amoxicillon w/ or w/out clavulanic acid
Penicillin administration- Oral and IV
Nafcillin, ampicillin
Penicillin administration- IV only
Antipseudomonal penicillins = piperacillin w/ or w/out tazobactam
Penicillin administration- depot forms
procain and bensathine PCN G
Penicillin pharmacokinetics-absorption
Many cannot be administered orally (due to destruction in acid)
Food may decrease the absorption of available oral penicillins
IV route bypasses absorption considerations and is preferred for serious infections.
Penicillin pharmacokinetics- Distribution
Widely distributed with tissue level=to serum
Poorly penetrate the eyes, CNS, and prostate
ONLY PENETRATE THE CNS WHEN MENINGES ARE INFLAMED.
Penicillin pharmacokinetics- metabolism
Most penicillins are not metabolized by dependent on the kidney for elimination
Penicillin pharmacokinetics- elimination
Kidney excretion is the main route of elimination (except antipseudomonal PCN and nafcillin via billiary excretion)
Penicillins are filtered (10%) and actively secreted (90%) into the urine
Active secretion can be blocked by probenecid
Doses need to be adjusted in renal insufficiency
Penicillins Adverse Effects
Hypersensitivity
Allergic responses develop in respinse to beta-lactam ring and derivatives (Cross rxn)
Anaphylactic shock is rare
Serum sickness- urticaria, rash, fever, angioedema
Interstitial nephritis and hemolytic anemia
Desensitization protocols are available.
Penicillins adverse effects
GI upset with oral agents
Diarrhea
Secondary infections- vaginal candidiasis
Hepatitis w/ oxacillin
Neutropenia w/ nafcillin
Abnormal platelet aggregation with ticarcillin and carbenicillin
PCN drug interactions
Don’t give concurrently with TCN or other bacteriostatic agents
Anti-pseudomonal PCN affect warfarin metabolism
Cephalosporins Intro
Discovered 1948 by Guisepee Brotzu
Similar to penicillins chemically, MOA, and toxicity
Bactericidal
Inhibit bacterial-cell wall synthesis similar to PCNS
Structurally contain a dihydrothiazine ring connected to the B-lactam ring making them more resistant to hydrolysis by B-lactamase (Broader spectrum of activity)
Classified by 5 generations
Category B in pregnancy
Cephalosporin Resistance
Mutations or carried on plasmids
Mutations in PBP
Production of Beta-lactamases
Alteration in cell-membrane porins in gram negative bacteria
1st Generation Cephalosporins Spectrum
Good aerobic gram-positive, above the diaphragm anaerobes and community acquired gram negative coverage.
Stable against staph produced penicillinase
IV= Cefazolin (Ancef)
PO= Cephalexin (keflex)
1st Generation Cephalosporins - Use
Used for septic arthritis in adults, skin infections, acute otitis media, prophylaxis for clean surgeries, and gram (+) infections in pts that cannot take penicillin
2nd Generation Cephalosporins- Spectrum
Two classes w/in second generation Added gram (-) coverage (ie moraxella, neisseria, salmonella, shigella, haemophilus influenzae) IV and PO= cefuroxime (zinacef, ceftin) Added anaerobic coverage (especially B. Fragilis) IV= cefotetan (cefotan)
2nd Generation Cephalosporins- Use
Added gram (-) IV and PO= cefuroxime (zinacef, ceftin) Useful for sinusitis, otitis, CAP Added anaerobic coverage IV- cefotetan (cefotan) Useful for tx of abd and gynecological infections
Summary of 2nd generation cephalosporins
Gram (+): 2nd generation < 1st generation (somewhat)
Gram (-): 2nd generation > 1st generation (Significantly)
3rd Generation Cephalosporins- Spectrum
Expanded gram-negative coverage and penetration of BBB
Cefpodoximine (Vantin), cefdinir (omnicef), cefixime (suprax)=oral
Cefotaxime (claforan)
Ceftriaxone (rocephin) = IV and IM
Ceftazidime (fortaz) distinguishes itself w/ increased anti-pseudomonal coverage.
3rd Generation Cephalosporins- clinical use
Used to tx a wide variety of serious infections caused by organism that may be resistant to other antimicrobial agents
Drugs of first choice in tx of meningitis, pneumonia in children and adults, sepsis, peritonitis
Tx of UTI, skin infections, and oesteomyelitis, Neisseria gonorrhea infections
Summary of 3rd generations cephalosporins
Gram (+): 1st generations > 2nd generation or 3rd generation
Gram (-): 3rd generation= 2nd generation > 1st generation
4th Generation Cephalosporins- Spectrum
Cefepime (maxipime) IM/IV
Good activity against both gram(+) and gram (-) bacteria; ALSO ANAEROBIC COVERAGE
4th Generation Cephalosporins- coverage
P. aeruginosa, H. influenzae, N. meningitidis, N. gonorrhoeae
Enterobacteriasceae that are resistant to other cephalosporins
4th Generation Cephalosporins- clinical use
Intra-abdominal infections, respiratory tract infections, skin infections
Summary of 4th generation cephalosporins
Improved gram (+) compared to 2nd and 3rd generations (Closer to 1st generation) Retain gram (-) = or > 2nd and 3rd generations
5th Generation Cephalosporin
Ceftobiprole medocaril
Approved March 2008
Tx of complicated skin and skin structure infections (MRSA)
Inhibits PBPs involved in cell wall synthesis
Well tolerated-nausea and taste disturbances
IV form only
Cephalosporins Pharmacokinetics
Orally administered absorbed rapidly
Presence of food may increase, decrease, or not affect absorption
Extensive distribution (most don’t cross CSF except cefuroxime, cefotaxime, ceftriaxone, cefepime)
Most eliminated via kidneys
Cephalosporins toxicities/ side effects
Hypersensitivity same spectrum as PCN
Structure is structurally different allowing use in PCN allergy pts
5-10% cross sensitivity
Pts w/ anaphylaxis or angioedema with PCN should not recive
Suprainfection- resistant organism and fungi may proliferate.
Cephalosporins toxicities/ side effects (2)
GI upset- N/V/D
1-3% allergic rxn - rash, fever, eosinophilia, urticaria
Cholelithiasis
Blood dyscrasias- eosinophilia, thrombocytopenia, leukopenia
Methylthiotetrazole side chains
Cephalosporin drug interactions
Increased serum levels if co-administered with probencecid
Increased effects of warfarin- cefotetan, cefazollin, cefoxitin, ceftriaxone
Carbapenems (the most broad spectrum)
Resistant to many beta-lactamases, most broad spectrum of beta-lactam class of ABX (gram + and gram - coverage)
Ertapenem (Ivanz), and imipenem-cilastin (primaxin)
Meropenem (merrem)
Carbapenems- Ertapenem (Ivanz), and imipenem-cilastin (primaxin)
Coverage included resistant gram (-) bacilli (P. aeruginosa), gram (+) bacteria (MRSA, enterococcus), and anaerobes (bacteroides)
Tx of UTI, pneumonia, intra-abdominal infections, skin and soft tissue infections
Carbapenems- meropenem (Merrem)
Greater activity against gram-negative
Intra-abdominal infections
Meningitis > 3 mo. of age
Carbapenems- Pharmacokinetics
Given parenterally-> unstable in stomach acid
Cilastin inhibits dehydropeptidase I which inhibits imipenem by breaking beta-lactam ring
Well distributed in the body
Renal excretion
Carbapenems- toxicities
Well tolerated- N/V, phlebitis at infusion site, leukopenia, elevated LFTs
Seizures in pts w/ renal failure
High degree of cross-sensitivity with PCN
Carbapenems- Drug interactions
Ertapenem cant be infused w/ dextrose or other medications
Meropenem reduces valproic acid levels
Meropenem and ertapenem category B- safe
Imipenem/cilatin category C- not removed from option when considering risk vs. benefit
Monobactams
Aztreonam (Azactam) the only monbactam available in the US
Spectrum of activity is purely gram-negative rods (inihibits mucopeptide synthesis in cell wall by binding to PBP, resistant to most beta lactamases)
No cross reactivity with PCN or cephalosporin allergic pts
Monobactams- pharmacokinetics
Tx of gram (-) infections- pneumonia, soft-tissue infections, UTI, intra-abdominal and pelvis infections
Acid Labile
Widely distributed including inflames meningeal tissue
Excreted in urine unchanged
Monobactams- Toxicity
No major toxicity- rash, N/V, elevated LFT, transient eosinophilia
No reported drug interations
Special populations- category B in pregnancy and safe in kids over 9 mo.
Cycloserine
Inhibition that ultimately disrupts assembly of cell wall synthesis.
HIghly susceptible to resistance
Cycloserine- indications
restricted for use as a secondary anti-tubercular drug
Cycloserine- ADRs- very toxic
CNS toxicity-reversible w/pyridoxine
Renal impairment will accelerate toxicity
Vancomycin Mechanism and Spectrum
Acts on diff binding site than beta-lactamase but has the same effect on cell wall synthesis.
Bactericidal
Vancomycin Mechanism and Spectrum- mechanism of resistance
Acquired (plasmid born)- VanA phenotypes. A component of the peptidoglycan has modified so that vancomycin can not bind.
Innate resistance- most gram negatives-outer membrane resistance penetration
Vancomycin
Active against gram positive organisms only.
Including beta-lactamase producing varieties
Reserved for pts allergic to B-lactams with serious gram (+) infections, infections resulting from MRSA, and used in antibiotic associated enterocolitis.
Vancomycin Pharmacokinetics
Not absorbed when given orally and used orally in tx of C. Diff.
Given IV to maintain levels in a range that enhances outcome and avoids toxicity.
Widely distributed including CNS when meninges are inflamed.
Not metabolized by 90% renally excreted.
Vancomycin clinical use
Main indication for parenteral vancomycin is for methicillin resistant staph aureus or staph epu
Used for penicillin resistant pnemococcus pneumonia
Vancomycin-adverse effects
Local and infusion related reactions- red man syndrome (very flushed, hot, and itchy); phlebitis
Ototoxicity- irreversible hearing damage
Nephrotoxicity- reversible damage to the kidneys
Bacitracin-MOA
Polypeptide compound
Interferes w/ recycling steps of the phospholipid carrier of petidoglycan synthesis
Not a very specific target (membrane lipid)
Bacitracin- clinical use
Very nephrotoxic, so limited to topical use
Most gram (+) cocci and bacilli are sensitive
Often combined with neomycin or polymyxin or both
