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Flashcards in Introduction to Antibiotics Deck (115):
1

Antibiotics- definition

Substances produced by various species of microorganisms that surpress growth or destroy microorganisms. Including fungi, bacteria, and actinomyces

2

Bactericidal

Directly kill bacteria
Inhibitors of cell wall synthesis, cell membrane distributors, aminoglycosides, DNA gyrase inhibitors
Does not require functioning immune system

3

Bacteriostatic

Arrest growth or replication of bacteria. Host immune system then eliminates the pathogens.
Must have a functioning immune system

4

Bactericidal with a bacteriostatic antibiotic?

NEVER

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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

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Classifications of ABX- Agents that inhibit cell wall synthesis

Penicillins
Cephalosporins
Cycloserine
Vancomycin
Bacitracin

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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

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Classifications of ABX- Agents that interfere with protein synthesis by interaction with bacterial ribosomes

Chloramphenicol
Tertracyclines
Macrolides
Clindamycin
Streptogramins
Ketolides

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Classifications of ABX- Agents that interfere with protein synthesis by blocking initiation

Oxazolidinoses (linezolid)

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Classifications of ABX- Agents that interfere with protein synthesis by inhibition of tRNA synthesis

Mupirocin

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Classifications of ABX- Agents that interfere with protein synthesis by multiple mechanisms leading to disruption of RNA processing

Aminoglycosides

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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)

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Classifications of ABX- The antimetabolites- blocking bacterial folic acid pathway

Trimethoprim
Sulfonamides

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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

15

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.

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Host defenses

Low immune respsonses may result in therapeutic failure despite the use of appropriate and effective therapy.

17

Humoral immunity

Inadequacy in the immunoglobulins

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Cellular immunity

Inadequacy in the phagocytic cells

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Host factors- Age

Renal and hepatic metabolism can be affected by infants and elderly

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Host factors- genetic factors

In patients w/ glucose-6-phosphate deficiency certain drugs can cause acute hemolysis

21

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.

22

Host factors

Host defenses
Age
Genetic factors
Pregnancy
Drug allergy
Disorders of the nervous system

23

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.

24

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.

25

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

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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

27

Antibiotic resistance- Drugs inactivated

Lactamases deactivate beta-lactams
Phosphotransferases and acetyltransferases deactivate amino glycosides

28

Antibiotic resistance- Target is altered

DNA gyrase prevents quinolone binding
Methylation of rRNA prevents macrolide binding

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Antibiotic resistance- Adaptations that bypass need for binding site

Use alternative metabolic route in folate synthesis avoiding effects of trimethoprim

30

Resistance- antibiotic use

Exerts selective pressure on bacteria to acquire resistance to survive

31

Resistance- innate resistance

a long-standing characteristic of a particular species of bacteria

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Resistance- Acquired resistance

Mutations-random events that confer a selective advantage to the bacterium
Transfer or plasmids-transduction, transformation, conjugation

33

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

34

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

35

Conjugation

Passage of genes from cell to cell by direct contact through a bridge
Conjugation occurs primarily among gram-negative bacilli.

36

Multiple drug-resistance bacteria

Methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacteria tuberculosis

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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

38

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.

39

Beta Lactam Compounds

Penicillins
Cephalosporins
Cabapenems
Monobactams
Beta lactamase inhibitors

40

Beta Lactam Compounds- Penicillins

Natural penicillin
Aminopenicillins
Penicillinase Resistanct Penicillins
Extended spectrum penicillins (Anti-psuedomonal)

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Beta Lactam Compounds- Cephalosporin

First generation- fifth generation

42

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

43

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

44

Beta-lactam ABX

Generally bactericidal
Most active against growing organisms
Many have gram-positive and gram-negative activity

45

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

46

What was the name of the original penicillin

Penicillin G

47

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)

48

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

49

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

50

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.

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Penicillin G or V- gram positive cocci

Streptococcus, enterococcus faecalis, listeria morlocytogenes

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Penicillin G or V- Anaerobes

Bacteroides species and fusebacterium species

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Penicillin G or V- gram negative

E. coli, H. influenzae, N. gonorrhoeae, Treponema be, and suspectible psuedomonas species.

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Amniopenicillins

Ampicillin and amoxicillin

55

Ampicillin and Amoxicillin

Activity of PCN G plus improved coverage of gram negative cocci adn Enterobacteriaceae
Not active against treponema or actinomyces

56

Ampicillin and Amoxicillin- therapeutic uses

URI (Otitis, sinusitis), uncomplicated UTI, meningitis, salmonella infections

57

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.

58

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

59

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

60

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)

61

Antipseudomonal penicillins- resistance issues and are paired with beta-lactamase inhibitors

Piperacillin + tazobactam = zosyn
Ticarcillin + clavulanic acid= timentin

62

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

63

Addition of Beta-lacamase inhibitors- Aminopenicillins

Amoxicillin + clavulanic acid (augementen)
Ampicillin + sulbactam (unasyn)

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Addition of Beta-lacamase inhibitors- Antipseudomonal penicillins

Piperacillin + tazobactam (Zosyn)

65

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.

66

Penicillin administration- oral only

Penicillin V, amoxicillon w/ or w/out clavulanic acid

67

Penicillin administration- Oral and IV

Nafcillin, ampicillin

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Penicillin administration- IV only

Antipseudomonal penicillins = piperacillin w/ or w/out tazobactam

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Penicillin administration- depot forms

procain and bensathine PCN G

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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.

71

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.

72

Penicillin pharmacokinetics- metabolism

Most penicillins are not metabolized by dependent on the kidney for elimination

73

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

74

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.

75

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

76

PCN drug interactions

Don't give concurrently with TCN or other bacteriostatic agents
Anti-pseudomonal PCN affect warfarin metabolism

77

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

78

Cephalosporin Resistance

Mutations or carried on plasmids
Mutations in PBP
Production of Beta-lactamases
Alteration in cell-membrane porins in gram negative bacteria

79

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)

80

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

81

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)

82

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

83

Summary of 2nd generation cephalosporins

Gram (+): 2nd generation < 1st generation (somewhat)
Gram (-): 2nd generation > 1st generation (Significantly)

84

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.

85

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

86

Summary of 3rd generations cephalosporins

Gram (+): 1st generations > 2nd generation or 3rd generation
Gram (-): 3rd generation= 2nd generation > 1st generation

87

4th Generation Cephalosporins- Spectrum

Cefepime (maxipime) IM/IV
Good activity against both gram(+) and gram (-) bacteria; ALSO ANAEROBIC COVERAGE

88

4th Generation Cephalosporins- coverage

P. aeruginosa, H. influenzae, N. meningitidis, N. gonorrhoeae
Enterobacteriasceae that are resistant to other cephalosporins

89

4th Generation Cephalosporins- clinical use

Intra-abdominal infections, respiratory tract infections, skin infections

90

Summary of 4th generation cephalosporins

Improved gram (+) compared to 2nd and 3rd generations (Closer to 1st generation)
Retain gram (-) = or > 2nd and 3rd generations

91

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

92

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

93

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.

94

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

95

Cephalosporin drug interactions

Increased serum levels if co-administered with probencecid
Increased effects of warfarin- cefotetan, cefazollin, cefoxitin, ceftriaxone

96

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)

97

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

98

Carbapenems- meropenem (Merrem)

Greater activity against gram-negative
Intra-abdominal infections
Meningitis > 3 mo. of age

99

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

100

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

101

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

102

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

103

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

104

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.

105

Cycloserine

Inhibition that ultimately disrupts assembly of cell wall synthesis.
HIghly susceptible to resistance

106

Cycloserine- indications

restricted for use as a secondary anti-tubercular drug

107

Cycloserine- ADRs- very toxic

CNS toxicity-reversible w/pyridoxine
Renal impairment will accelerate toxicity

108

Vancomycin Mechanism and Spectrum

Acts on diff binding site than beta-lactamase but has the same effect on cell wall synthesis.
Bactericidal

109

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

110

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.

111

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.

112

Vancomycin clinical use

Main indication for parenteral vancomycin is for methicillin resistant staph aureus or staph epu
Used for penicillin resistant pnemococcus pneumonia

113

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

114

Bacitracin-MOA

Polypeptide compound
Interferes w/ recycling steps of the phospholipid carrier of petidoglycan synthesis
Not a very specific target (membrane lipid)

115

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