penicillins 65/66

Question 1

Penicillin G (Pfizerpen)

Answer 1

natural penicillin
parenteral admin (IV, IM)
only 33% absorbed after oral admin
60% plasma protein bound (ppb)
-active against many G+ and G-aerobic cocci (except strains producing penicillinase); most spirochetes; some G+ aerobic and anaerobic bacilli
-tend to be inactive against G- aerobic and anaerobic bacilli;
-Inactive against Mycoplasma, Rickettsia, fungi, viruses, and mycobacteria.

Question 2

Penicillin V Potassium (generic)

Answer 2

natural penicillin
oral admin (used for less serious infections, less active than PCN G against most orgs, only for minor infections)
modified side chain (R=phenoxymethyl) more stable in stomach acid
oral dose gives plasma levels 2-5x higher then PCN G
50-70% ppb

Question 3

Penicillin G Procaine (Wycillin)

Answer 3

natural penicillin

• used for S. pyogenes infections
• limited use for uncomplicated pneumococcal pneumonia or gonorrhea due to resistance
• injection can produce procaine reactions (bad taste, dizziness, palpitations, auditory and visual disturbances)

Question 4

Penicillin G Benzathine (Bicillin L‐A, Permapen)

Answer 4

natural penicillin

• strep pharyngitis (1 dose vs 10 days PCN V)
• prophylaxis for RF from GAS (shot every 3-4 wks)
• syphilis

can last 26 days!

Question 5

Penicillin G Benzathine + Penicillin G Procaine (Bicillin C‐R)

Answer 5

natural penicillin

Question 6

natural penicillins are dispensed as ??

Answer 6

UNITS

others dispensed by weight

Question 7

Methicillin

Answer 7

Penicillinase Resistant Penicillin ‐ Anti‐staphylococcal Penicillin

highly bound to plasma proteins (may result in clinical failure)
not used in US anymore
SE: intersitial nephritis
MRSA: usually also resist. to PCNs, ceph, amino glycosides, macrolides
40% ppb

Question 8

Nafcillin

Answer 8

Penicillinase Resistant Penicillin ‐ Anti‐staphylococcal Penicillin
highly bound to plasma proteins (90% ppb!-may result in clinical failure)
-penetrates CNS, may be used for Staph meningitis
IV admin, inactivated in the acidic gastric environment and shows irregular oral absorption with or without meal
-excreted by liver
most resistant to
Staphylococcal B lactamases
eliminated by biliary excretion, don’t need to adjust the dose for pts with renal failure

Question 9

Oxacillin (generic, Bactocil)

Answer 9

Penicillinase Resistant Penicillin ‐ Anti‐staphylococcal Penicillin
highly bound to plasma proteins (may result in clinical failure)
IV admin
excreted by liver
94% bbp!
eliminated by biliary excretion and by kidney, don’t need to adjust the dose for pts with renal failure?

Question 10

Penicillinase resistants

Answer 10

implies more resistance to b-lactamases

Question 11

Ampicillin (generic, Principen)

Answer 11

Extended Spectrum Penicillin (Aminopenicillin)
G+ AND G- coverage
can cause non-allergic skin rash
IV, oral absorption (40%, not as good as amoxicillin)
20% ppb
longer 1/2 life than PCN G
doses adjusted for renal failure

Question 12

Amoxicillin (generic, Amoxil, Trimox)

Answer 12

Extended Spectrum Penicillin (Aminopenicillin)
G+ AND G- coverage
oral, good absorption (95%) in presence or absence of food, therapeutic plasma levels are obtainable with a lower dose
can cause non-allergic skin rash
20% ppb
longer 1/2 life than PCN G
doses adjusted for renal failure

Question 13

Ticarcillin + Clavulanate potassium (Timentin); Ticarcillin (Ticar)

Answer 13

Antipseudomonal Penicillin (+B-lactamase inhibitors) combo bc of resistance
45% ppb
adjust for renal failure pts
-G- aerobic bacilli and mixed aerobic‐anaerobic infections (intra-abdominal, gene inf.)
(if Bacteroides, Ticar is alternative, metronidazole is preferred)
-pseudomonal infections (septicemia, UTIs) watch out for resistant strains which may arise
-may add an aminoglycoside (e.g. gentamicin)
SE: excess Na+, prolonged bleeding time

Question 14

Piperacillin + Tazobactam (Zosyn); Piperacillin (Pipracil)

Ureidopenicillin

Answer 14

Antipseudomonal Penicillin (+B-lactamase inhibitors) combo bc of resistance
IV
*broader spec. and more active against G- bacilli/mixed anaerobic/aerobic infections (Pseudomonas, Kleb) than carbenicillin or ticarcillin

Question 15

Aztreonam

Answer 15

B-lactam drug (other)
monobactam (monocyclic B-lactam ring- unique!)
poor oral absorption, admin parentally
excreted by kidneys, adjust dose for renal impairment

Question 16

Imipenem + Cilastatin (Primaxin)

Answer 16

B-lactam drug (other)
carbapenem
broadest spectrum of activity
not absorbed orally

Question 17

Clavulanic acid

Answer 17

B-lactam drug (other)
B-lactamase inhibitor

not much abx activity (always used in combo), needed to prevent breakdown from bacterial B-lactamase
-most active against Amber class A B-lactamases, not good inhibitors of class C 
(B-lactam ring structure similar to amoxicillin; acts a suicide inhibitor of beta‐lactamase thus preventing the beta‐lactamse from breaking down amoxicillin).

Question 18

Tazobactam

Answer 18

B-lactam drug (other)
B-lactamase inhibitor

not much abx activity (always used in combo), needed to prevent breakdown from bacterial B-lactamase
-most active against Amber class A B-lactamases, not good inhibitors of class C

Question 19

Amoxicillin + Clavulanic acid (Augmentin)

Answer 19

Combination products containing Beta lactamase inhibitor
good oral absorption
high levels in urine, does not penetrate CNS
excreted in kidney, adjust for renal impairment

Question 20

Ticarcillin + Clavulanic acid (Timentin)

Answer 20

Combination products containing Beta lactamase inhibitor

Question 21

Piperacillin + Tazobactam (Zosyn)

Answer 21

Combination products containing Beta lactamase inhibitor

Question 22

core structure of PCNs

Answer 22

6-aminopenicillanic acid
B-lactam ring, Thiazolidine ring
(need intact rings for function!)
different pharmacokinetic, antibacterial props, different susceptibilities to breakdown based on R group

Question 23

mechanism of B-lactam abx

Answer 23

bactericidal against bacteria that are actively growing by inhibiting bacterial cell wall synthesis

inhibit transpeptidase (PBP)–>inhibit bac cell wall synthesis–>lysis and killing of bacteria (activate autolysins)

ultimate death: activation of cell‐wall autolytic enzymes called autolysins (murein hydrolases) and bacterial cell lysis.

Question 24

bacterial cell wall synthesis

Answer 24

net effect of this process is the production of glycan chains (alternating amino sugars; N-acetylglucoasamine and N‐acetylmuramic acid) that are cross‐linked by peptide chains
The final step in the production of the peptidoglycan cell wall is the complete cross‐ linking of the chains. This enzymatic process is accomplished by a transpeptidase enzyme located on the outside of the cell membrane.

Question 25

B-lactam abx inhibit the ?? how can they do this??

Answer 25

transpeptidase enzyme and the subsequent production of a highly cross‐linked peptidoglycan cell wall Penicillin covalently binds to the transpeptidase enzyme because there is a structural similarity between the penicillin molecule and the *D‐alanyl‐D‐alanine* end of the glycopeptide polymer (the normal substrate for the transpeptidase enzyme).

Question 26

penicillins exert their bactericidal effect only on ??

Answer 26

actively dividing cells that are producing cell wall. Penicillins will have little or no effect on dormant bacteria or on microorganisms that lack cell walls. (not active against mycoplasma)

Question 27

PCNs: good or bad selectivity??

Answer 27

good! humans do not have cell walls

Question 28

PCNs are often used in combination with an ?? for a synergistic killing effect. Avoid ??

Answer 28

``` aminoglycoside antibiotic (e.g. gentamicin) Avoid in vitro mixing of penicillin family members with an aminoglycoside antibiotic in the same solution. (-/+-->deactivation) ```

Question 29

mechanisms of bacterial resistance (*one of the most important mechs for resistant to PCNs*)

Answer 29

enzymatic destruction of PCN by bac enzymes: B-lactamases break down B-lactam ring to yield inactive penicillin acid (> 300 B-lactamases have been ID'd) -substrate for this enzyme (PCN) can induce production of this enzyme in bacteria (promotes resistance!!) -G+ bac produce large amounts of B‐lactamases that get secreted outside of the bac (S. aureus) -G- bac produce B-lactamases that are found between the outer and inner membranes. Since these ‐lactamases are located at the PCN site of action the bacteria have maximal protection against the drug.

Question 30

another mechanism for abx-resistance

Answer 30

Structural differences in the PBPs (other than transpeptidase) (e.g. high molecular weight PBPs with low affinity for antibiotic). example: highly PCN‐resistant Strep pneumo has 4 out of 5 PBPs with decreased affinity for PCN; Methicillin resistance in Staph is caused by the acquisition of a high molecular weight PBP via a transposon.

Question 31

how to overcome resistance for orgs that have dec. affinity for PCN

Answer 31

give high dose PCN to compensate/overcome

Question 32

yet another mechanism for abx-resistance

Answer 32

Inability of the PCN to penetrate to its site of action in *G- orgs*: there is an OM that can function as a barrier to PCN. Small hydrophilic antibiotics can pass through the outer membrane through proteins called *porins*, which act as aqueous channels. Broader spec. abx and many cephs diffuse through these porins, but Penicillin G has difficulty passing through these porin channels. also, efflux pumps can also pump drug out of the bacteria before the drug can act. (resistance mechanism in some G-bacteria) examples: *Pseudomonas* can lack high permeability porins P. aeruginosa, E. coli and N. gonorrhoeae – Active efflux (G+ orgs: the peptidoglycan cell wall is near the surface of the bacteria. The PCNs easily penetrate to the outer layer of the cytoplasmic mem. and their site of action)

Question 33

pharmacokinetics of PCNs

Answer 33

variable oral absorption, depends on acid stability and ability of food to dec. absorption give 1-2 hrs before or after meal **except Amoxicillin** absorption in presence or absence of food also, for parental admin, IV is better than IM-may cause irritation

Question 34

PCNs can bind to ?

Answer 34

plasma proteins and greater than 95% binding results in less free drug available to fight infection

Question 35

PCN concentrations in most tissues are equal to serum, but have hard time penetrating some tissues like ?? however, during bacterial meningitis, ??

Answer 35

prostate, eye, brain the BBB is disrupted (the meninges are inflamed) and PCN can pass into the brain (used for tx, about 5% plasma conc.)

Question 36

PCNs rapidly excreted by ??

Answer 36

the kidneys short half-life (30 min) 10% glomerular filtration 90% by tubular secretion (organic acid secretory mech) adjust dose for many PCNs in renal failure and premies/infants who have dec. renal function

Question 37

Example Dosing with Renal Impairment

Answer 37

(Creatinine Clearance 10 mL/min): Give 1/4th to 1/3rd of the normal dose.

Question 38

?? can block tubular secretion, can be used to inc. plasma levels of PCN (can block transport out of CNS, again therapeutic strategy)

Answer 38

Probenicid (for gout)

Question 39

some PCNs excreted mostly into ??

Answer 39

the bile don't need to be adjusted with renal failure, but LIVER failure *Nafcillin* *Oxacillin* (test question)

Question 40

the most adverse rxn to PCNs are

Answer 40

* hypersensitivity and allergic reactions* - intact PCN and breakdown products can bind to host proteins and act as Ags for the production of anti-PCN-Abs - may have anti-PCN Abs even if never received PCN (environmentally, i.e. milk) - adults more susc. than children * the major Ag determinant is degradation product *Benzyl penicilloyl*

Question 41

?? administrations more commonly assoc. with hypersn rxns

Answer 41

Parenteral and esp. topical administration (don't use topically bc of this) more so than oral if allergic to one PCN fam men, more likely to be allergic to others (1 exception, later) -cross-allergic and cross-sensitizing, sensitization appears to occur in direct proportion to the treatment duration and total dose of PCN received in the past

Question 42

most common allergic reaction are ??

Answer 42

*type 1 (immediate) allergic reactions (1-72 hrs post admin)* IgE abs interact with PCN/PCN degradation products-->become fixed to mast cells of the skin, GI and RT-->release *histamine and other vasoactive mediators* upon reaction with sp. Ags-->may cause anaphylaxis, angioedema, and urticaria, rhinitis, asthma‐like symptoms, and laryngeal edema.

Question 43

symptoms of T1 allergic rxn

Answer 43

skin rxns: rash, antioedema, urticaria, pruritis GI manifestations: N/V/D ,abd. pain respiratory tract involvement: dyspnea or wheezing CV manifestations: hypotnsn, tachy, arrhythmias *fatality is rare but when it occurs, usually due to laryngeal edema or CV collapse T1 most common, but can cause other hypersensitivity rxns: (TII: hemolytic anemia, TIII: vasculitis, TIV: interstitial nephritis, drug fever, contact dermatitis)

Question 44

skin testing for PCN allergy

Answer 44

only useful for Type 1 hypersensitivity Pre-Pen commercial product used for testing, contains benzyl penicilloyl (major Ag determinant) and polylysine (major Ag determinant) + test indicates individual is likely to have T1 immediate hypersn reaction to PCN no commercial product of minor Ag determinants available for skin testing, but pharmacies at larger clinical sites usually can prepare a mixture of the minor Ag determinants

Question 45

what to do if pt has bacterial endocarditis, etc. and will benefit from PCN but are allergic to it?? what other drugs should you have on hand??

Answer 45

desensitization protocol 15 min intervals btw dosing, increasing dose each time get slow release of histamine from mast cells at end of protocol, in therapeutic range have anti-histamine, epinephrine, corticosteroids in case of allergic reaction

Question 46

other adverse reactions to PCNs

Answer 46

- GI upset, N/V/D (large oral doses) - superinfections due to PCNs killing off the NF (probiotics helps) i.e. pseudomembranous colitis, fungal infection - high blood levels can cause seizures, so *should not be injected DIRECTLY into the CSF* (GABA antagonist affect in CSF if high enough blood concentration: at risk for drug interactions (Probenicid) and impaired metab/excr (renal failure))

Question 47

serious Methicillin SE (no longer used in US anymore)

Answer 47

*interstitial nephritis* (nephron destruction and dec. renal function) Type IV hypersensitivity reaction mediated by T-lymphocytes

Question 48

other PCN adverse rxns: dispensed as K+ or Na+ salts, so problematic for ??

Answer 48

CHF and renal failure

Question 49

Ampicillin, Amoxicillin SE

Answer 49

non-allergic skin rashes (1-28 days after tx) esp. if have viral infection (EBV) diarrhea (more from ampicillin) decrease effectiveness of OCTs

Question 50

case: acute OM what is the most likely causative organism? how would you tx?

Answer 50

*S. pneumo (35-40%)* (definitely need to target: less likely to resolve on own) Hib (30-35%) Moraxella (15-18%) -viruses may be the cause of 40-75% tx if younger than 6 mos even if uncertain dx tx 6 mo-2yr if certain dx, uncertain if severe illness >2 yrs abx if certain dx and severe illness, otherwise observation tx: Amoxicillin 80-90 mg/kg/day, s/s may not go away after initiating; may imply resistance S. pneumo: involves PBPs H. flu and M. cat involves B-lactamase how tx this pt? Augmentin 90 mg/kg/day OR Ceftriaxone OR Clindamycin (not against G-) if allergic to amoxicillin? Cephalosoprin (2/3) clarithromycin, azithromycin, clindamycin (no longer TMP-SMX, erythromycin + sulfisoxazole) OM + effusion: does not need to be tx w. abx if

Question 51

natural PCN spectrum of activity: G+

Answer 51

G+: non-resistant Staph and Streph *90% of S. aureus are resistant!*: not good choice - pneumococcal pneumonia: 25% resistant: until shown sensitive, use macrolide, FQ or 3rd gen. ceph (ceftriaxone) - pneumococcal meningitis: usually sensitive, until known use 3rd gen ceph - Strep pharyngitis: resistance not a problem - Entercoccal endocardidtis: PCN G + aminoglycoside for synergistic effect

Question 52

natural PCN spectrum of activity: G-

Answer 52

- can use for: anaerobes: activity against C. perfringes (gas gangrene) and C. tetani - do NOT use for: N. meningitides, N. gonorrhea, Pasteurella Multocida (resistant): use 3 gen ceph instead

Question 53

natural PCN spectrum of activity: other microorgs.

Answer 53

- spirochetes: Teponema pallidum (syphilis) parenteral PCN G is tx of choice! - Actinomyces israelii - do NOT use for: B. anthraces (resistance): use ciprofloxacin

Question 54

PCN G procain and PCN G benzathine

Answer 54

IM injection in glut max or midlat thigh do not inject into or near nerve: can result in permanent neuro damage IM inj. provides slow release into blood and prolonged duration of action (repository forms) -also provide local anesthetic effect (procaine, benzathine) PCN G procaine (600,000 units) can last for several days PCN G benzathine (1.2 million units) : 26 days! increase compliance

Question 55

Penicillinase Resistant Penicillins

Answer 55

bulky side group (R group) makes them *resistant to breakdown by Staphylococcal B-lactamases* Nafcillin the most! *do not need to adjust the dose for renal failure!* may need to for liver failure

Question 56

Penicillinase Resistant Penicillins spectrum

Answer 56

v. narrow window of activity - less active than PCN G against PCN G susc. bac and anaerobes - B-lactamase producing S. aureus: skin/ST infections, osteomyelitis, acute endocarditis * not effective agains G- bac* * beware of MRSA!*: use VANCOMYCIN or doxycycline

Question 57

Extended Spectrum Penicillins (Aminopenicillins)

Answer 57

* able to penetrate G- outer membrane, better for G-s than PCN G* - are susceptible to breakdown by B-lactamases - can be combined with B-lactamase inhibitors i. e. augmentin (Amoxicillin + clavulanate)

Question 58

Extended Spectrum PCN mnemonic: HELPS ME

Answer 58

(see slide) H. influenzae (Hib): URIs (sinusitis, otitis) (30-55% resistance, may use augmentin) E. coli: UTIs (30-50% resistance) L isteria mono: meningitis in immcompr. and in kids younger than 2 months, bacteremia P roteus mirabilis: UTIs (10% resistance) S almonell: typhoid fever, bacteremia, acute gastroenteritis (Ampicillin is an alternative to Salmonella and Shigella due to increasing resistance) S trep pyogenes and PCN-susc Strep. pneumoniae, URIs M oraxella Catarrhalis: RTIs, but around 100% resistance: use augmentin! E nterococcus faecalis

Question 59

Extended Spectrum PCNs SEs (amoxicillin, ampicillin)

Answer 59

decreased effectiveness of oral contraceptives ethinyl estradiol: conjugated in liver to sulfate and glucuronide metabolites by intestinal bacterial enzymes-->conjugates excreted in bile amoxicillin/ampicillin kills off flora that hydrolyze the ethinyl estradiol conjugates, so more ethinyl estradiol is reabsorbed

Question 60

antipseudomonal PCNs

Answer 60

- effective against Pseudomonas (Ticarcillin more than Carbenicillin) - also effective against PCN -resist. anaerobes (B. Fragilis) * major use is in combo w. aminoglycoside for pseudomonal (or amp-resist. proteus) infections such as septicemia and UTIs - used for mixed aerobic anaerobic infections (intra-abdominal) - Prostatitis – Caused by E. coli, P. mirabilis, Enterobacter, Enterococcus - NOT effective against most S. aureus infections tox: high sodium, may interact w. platelets to prolong bleeding time, hypokalemia (Carbenicillin)

Question 61

toxicity of Ticarcillin

Answer 61

high sodium can be problematic for pts w. CHF | -prolonged bleeding time

Question 62

Piperacillin + Tazobactam uses

Answer 62

- often used in combo w. aminoglycoside for synergistic killing effect - CAP: B-lactamase-producing H. flu or P. aeruginosa (+FQ, or + aminoglycoside + azithromycin, or aminoglygocoside + FQ) - Nosocomial pneumonia: B-lactamase producing H. flu, Kleb, pseudomonas: *empiric tx w. aminoglycoside* (discontinue if pseudomonas is ruled out) - serious G- infections: septicemia, burns, UTIs, OB/Gyn infections (E. coli), intraabdominal, skin/ST

Question 63

Piperacillin + Tazobactam (Zosyn); Piperacillin (Pipracil) SEs

Answer 63

- less Na+ than Ticarcillin, better for pts w. CHF, heart failure - less effect on bleeding time than Ticarcillin, better

Question 64

Aztreonam SEs

Answer 64

patients allergic to PCNs appear *NOT to react to Aztreonam*

Question 65

Carbapenems

Answer 65

*wide spectrum of activity* imipenem broken down by dehydropeptidases in prox. tubule of kidney -Cilastatin is compound that inhibits this enzyme and prev. breakdown of Imipenem, inc. renal concentration -Meropenem, Ertapenem, Doripenem: resistant to breakdown, don't need Cilastatin * resistant to breakdown by most B-lactamases, (Trans configuration of the hydroxyethyl side chain). The metallo‐beta‐lactamases will inactivate carbapenems like Imipenem* - eliminated by renal excretion, adjust dose w. renal failure

Question 66

Carbapenem (imipenem) spectrum how is it broad spectrum?? orgs active against?

Answer 66

> 90% of clinically important bacteria * increased perm. thru porin channels in G- bacteria, resistant to B-lactamases, high affinity binding to PBPs - G+ aerobes: strep (even PCN res. strains, staph (MSSA) - G- aerobic bac (N. meningitidis and N. gonorrhoeae, Pseudomonas aeruginosa, Enterobacter) - anaerobes: excellent activity against strict anaerobes, e.g. B. fragalis - some potentially resistant bugs: MRSA, enterococcus faecium, C. diff

Question 67

Carbapenem uses

Answer 67

- not for CA infections, reserved for serious HA inf., mixed aerobic/ana. inf (intraabd.) - infections resistant to other PCNs - add aminoglycoside for serious pseudomonas inf resistant to other B-lactam abx

Question 68

Carbapenem SEs

Answer 68

* induction of B-lactamases : inc. resistant to other B-lactam abx (seen w. pseudomonas)* - GI upset: N/V/D - seizures (esp. *Imipenem*), esp. with renal failure, - allergic (like other PCNs) - bac/fungal superinfections

Question 69

B-lactamase inhibitors

Answer 69

Clavulanic acid sulbactam Tazobactam - little intrinsic antibac. on own, prevent degradation - more active agains plasmid encoded b-lactamases vs. inducible B-lactamases

Question 70

uses of Augmentin

Answer 70

(amoxicillin + clavulanic acid) (S. aureus, H. flu, gonococci, E. coli M. catarrhalis) -UTIs caused by resistant bacteria: E. coli, Kleb, enterobacter, P. mirabilis -RTIs (ear and sinus): *OM (drug of choice)*, sinusitis, S. pyogenes -human and animal bite wounds : good activity against S. aureus and oral anaerobes (*drug of choice*) -Gonorrhea: some success

Question 71

Aztreonam uses

Answer 71

* highly resistant to breakdown by B-lactamases produced by G- bacteria* - ONLY active against G- bac (like aminoglycosides): E. coli, Kleb, MDR Pseudomonas, S. marcescens, H. influenza, Enterobacter sp. - septicemia, skin inf., intra‐abdominal and gene inf., bone/joint inf., Empiric therapy in febrile neutropenic patient (+ vancomycin for staph). *used for G-infections when there is prior history of allergic reactions to beta‐lactam antibiotics. If the infection also has G+ involvement then another abx with G+coverage must be included

Question 72

Imipenem specific uses

Answer 72

- Complicated UTIs - Serious RTIs (e.g. S. aureus, S. pneumoniae, Enterobacter, E. coli, Klebsiella, S marcescens, Ps. aeruginosa involvement) - Anaerobic/mixed aerobic‐anaerobic infections (e.g. peritonitis, intra‐abd, and gyne infections) - Empiric therapy in Febrile neutropenic patients - Other – skin/ST, bone/joint infections, septicemia - NOT used for surgical prophylaxis - NOT used for MRSA - NOT to be used ALONE to treat serious Pseudomonas infections because of the possibility for selection of resistant microorganisms during therapy. (add aminoglycoside)