Antimicrobial Therapies 1 (Cell Wall Inhibitors)

Question 1

Cell Wall Inhibitors

Answer 1

These antibiotics selectively interfere with synthesis of the bacterial cell wall

The cell wall is made of polymer called peptidoglycan that consists of glycan units joined to each other by peptide
cross-links

The antibiotics that inhibit cell walls require actively proliferating microorganisms

Cell Wall Inhibitor Families

Penicillins
Cephalosporins
Carbapenems
Monobactams
ß Lactam Inhibitor + Antibiotic Combinations
Lipoglycopeptides
Other Antibiotics

Question 2

Penicillins

Answer 2

Consist of a core 4 membered ß-lactam ring—which is attached to a thiazolidine ring and an R side chain

Drugs in this family differ from each other in the R substitute attached to the 6-aminopenicillanic acid residue—this side
chain affects the drugs spectrum, stability in the stomach acid, cross-sensitivity and susceptibility to bacterial degradation
enzymes—better known as ß-lactamases

MOA

-Interfere with final stage of cell wall synthesis known as transpeptidation

-PCNs compete for & bind to enzymes called penicillin binding proteins [PBPs] which catalyze transpeptidase and facilitate
cross-linking of the cell wall

-Downstream effect is a weak cell wall and cell death

-PCNs are bactericidal and work in a time-dependent mode

Antibacterial Spectrum

-Gram + microbes have a cell wall easily transversed by PCNs—so unless resistance is present, they are susceptible

-Gram – microbes have an outer lipopolysaccharide membrane surrounding their cell wall that acts as a barrier to PCNs

-However, gram – pathogens do have proteins inserted into this barrier membrane that behave as a water lined channel
[porins] that allow some PCNs to enter via this transmembrane canal

Question 3

Natural Penicillins

Answer 3

Penicillin G and Penicillin V are obtained from fermented fungus of PCN
chrysogenum

PCN G [benzyl penicillin] has activity against many gram +, gram – and spirochetes; it is 5-10 times more potent than PCN V against Neisseria spp. and anaerobes

Most streptococci are sensitive to PCN G, BUT PCN-resistant viridians streptococci and Streptococcus pneumoniae isolates are emerging

More than 90% of Staphylococcus aureus are now penicillinase producing and resistant to PCN G

PCN is DOC for gas gangrene [Clostridium perfringens] and syphilis [Treponema pallidum]

PCN V is only available oral, with a spectrum similar to that of PCN G—not used for severe infections due to limited oral absorption

PCN V more acid stable than PCN G and is oral agent used in less severe infections

Question 4

Semisynthetic Penicillins

Answer 4

Ampicillin and Amoxicillin

Aminopenicillins or extended spectrum penicillins

Created by chemically attaching different R groups to the 6-aminopenicillanic acid nucleus—this extends the gram –
coverage to include Haemophilus influenzae, E. coli and Proteus mirabilis

Ampicillin [+/-Gentamicin]—DOC for Listeria
monocytogenes and some enterococcal species

Extended spectrum agents used in URIs

Ampicillin used by dentists to prevent bacterial endocarditis in high risk patients

These drugs are combined with ß-lactamase inhibitors such as clavulanic acid or sulbactam to treat infections
from ß-lactamase producing pathogens

Without B-lactamase inhibitor, RSSA is resistant to Ampicillin and Amoxicillin

Resistance from plasmid-mediated penicillinases are a problem—this limits the use of these agents with gram - bugs

Question 5

Antistaphylococcal Penicillins

Answer 5

Methicillin [only used in lab testing in US]
Nafcillin
Oxacillin
Dicloxacillin

ß-lactamase [penicillinase]-resistant penicillins

They are used for infections caused by penicillinase-producing staphylococci, including MRSA

MRSA—source of serious community acquired and nosocomial infections and is resistant to most commercially available ß-lactam antibiotics

Penicillinase-resistant penicillins have minimal to no activity against gram - infections

Question 6

Antipseudomonal Penicillins

Answer 6

Piperacillin

-Active against Pseudomonas aeruginosa

-When combined with Tazobactam [Zosyn] extends the antimicrobial spectrum to cover penicillinase-producing organisms [Enterobacteriaceae and
Bacteroides spp.]

Question 7

Resistance

Answer 7

Survival in spite of a ß-lactam antibiotic
can occur by one of three ways—ß-
lactamase production, decreased
permeability of the drug or altered
penicillin binding proteins [PBPs]

Question 8

ß-Lactamase
Production

Answer 8

This family of enzymes breaks down the amide bond of the ß-lactam ring, which causes loss of bactericidal activity—they are the MAJOR cause of resistance to PCNs and are becoming more and more of an issue

Some ß-lactam antibiotics are poor
substrates for ß-lactamases and resist hydrolysis, thus keeping their power over ß-lactamase producing bugs

Gram + organisms secret ß-lactamases
extracellularly

Gram – organisms inactivate ß-lactam drugs in the periplasmic space

Question 9

Decreased Permeability of the Drug

Answer 9

Decreased penetration of the antibiotic through the outer cell membrane of the pathogen prevents the drug from reaching target PBPs

In gram + bugs, peptidoglycan layer is close to surface of bacterium—few barriers for the drug to reach its target

Reduced penetration of the drug into gram – bugs is more of a problem—they have a complex cell wall that includes aqueous channels [porins]

Pseudomonas aeruginosa lacks high permeability porins

Presence of an efflux pump, actively removes the drug from the site of action can also reduce amount of intracellular drug [Klebsiella pneumoniae]

Question 10

Altered Penicillin Binding Proteins [PBPs]

Answer 10

Antibiotic exposure can prevent cell wall synthesis and lead to changes or lysis of susceptible bacteria

Modified PBPs have lower affinity for ß-lactam antibiotics—requiring unobtainable levels of the drug to be present to kill the bug—this mechanism explains MRSA resistance to most available ß-lactams

Question 11

Penicillins

Pharmacokinetics

Answer 11

Administration

Determined by stability of the drug in gastric
acid and severity of infection

Routes

• Ampicillin + sulbactam [Unasyn]; Piperacillin + tazobactam [Zosyn]; Nafcillin and Oxacillin given IV or IM
• PCN V, Amoxicillin, Dicloxacillin are given PO
• All others are available PO, IV or IM
• Amoxicillin + Clavulanic acid is only oral in the US

Depot Forms

• Procaine PCN G and Benzathine PCN G are
given IM as depot injections—they are
slowly absorbed and persist at low levels over long periods

Absorption

• Acidity of the GI tract interferes with absorption of PCNs
• Only 1/3 of PCN V is absorbed orally
• Food decreases absorption of
penicillinase-resistant penicillin
Dicloxacillin—as gastric emptying time increases, the drug is destroyed by HCl, so should be taken on empty stomach
• Amoxicillin is stable in acid environment

Distribution

• ß-lactam antibiotics distribute throughout body
• All PCNs cross the blood-brain barrier—none are teratogenic
• Penetration into bone and CSF not enough for therapy unless these sites are inflamed—
inflamed meninges more permeable to PCNs—resulting in higher levels in CSF than in
serum
• PCN levels in prostate too low to use for treatment

Metabolism

• Host metabolism of the ß-lactam antibiotics usually insignificant; metabolism of PCN G may occur in those with CKD
• Exceptions—Nafcillin and Oxacillin metabolized by liver

Excretion

Primary route is organic acid [tubular]
secretory system in the kidney and GFR
• Those with CKD must have dosages reduced
• Nafcillin and oxacillin metabolized in liver
and do not require dose reductions in CKD
• Probenecid [gout prevention drug] inhibits
secretion of PCNs by competing for active
tubular secretion via the organic acid
transporter and can increase blood levels of
PCNs
• PCNs excreted in breast milk

Question 12

Penicillins

ADE

Answer 12

Hypersensitivity

• 10% will report allergy
• Rashes—angioedema or anaphylaxis have been reported, but are rare
• Cross allergy among the ß-lactams does
occur

Diarrhea

Occurs from disruption of normal balance of intestinal flora
• More common with drugs that are incompletely absorbed and have extended spectrum
• Pseudomembranous colitis from C. difficile
can occur

Nephritis

• PCNs—especially Methicillin [no longer available in US because of this] have the
potential to cause acute interstitial nephritis

Neurotoxicity

• Irritating to neuronal tissue and can provoke seizures if injected intrathecally or if
very high dose blood levels are reached—
epileptics at risk as PCNs can cause GABAergic inhibition

Hematologic Effects

• Decreased coagulation can be seen with high doses of Piperacillin and Nafcillin and perhaps with PCN G
• Cytopenias with therapy longer than 2
weeks—check CBCs weekly in these patients

Question 13

Cephalosporins

Answer 13

ß-lactam drugs related structurally and functionally to PCNs

Most Cephalosporins are semisynthetic by attaching side chains to 7-aminocephalosporanic acid

Changes on the acyl side chain at the 7 position effects the antibacterial power; variations at the 3-position change the pharmacokinetic profile

Same MOA as PCNs and affected by same resistance mechanisms

Tend to be more resistant than PCNs to certain ß-lactams

Question 14

Cephalosporins

Antibacterial Spectrum

Answer 14

Regardless of generation—Cephalosporins are ineffective for Listeria, C. difficile and Enterococcus

1st Generation

• Like PCN G substitute except they cover MSSA; isolates of Strep pneumonia resistant to PCN G will be resistant to these drugs
• Modest activity against:
• Proteus mirabilis
• E. coli
• Klebsiella pneumoniae
• Oral cavity anaerobes, such as Peptostreptococcus
• Bacteroides fragilis is resistant to these drugs

2nd Generation

• More activity against gram – bugs:
• H. influenzae
• Klebsiella spp.
• Proteus spp.
• E. coli
• M. catarrhalis
• Gram + coverage is less than 1st generation drugs
• Cefotetan [Cefotan] and Cefoxitin [Mefoxin] covers
anaerobes [Bacteroides fragilis]—only cephalosporins with good activity against gram – anaerobes; however neither is 1st line for B. fragilis—currently, a lot of resistance

3rd Generation

• Important players in treating ID
• Yet, they are less potent against 1st generation drugs when treating MSSA
• Enhanced coverage of gram – bacilli, including ß-lactamase producing H. influenzae and Neisseria gonorrhea
• Covers Serratia marcescens and Providencia spp.
• Ceftriaxone [Rocephin] and Cefotaxime [Claforan] are DOC in meningitis
• Ceftazidime [Fortaz] covers Pseudomonas aeruginosa [resistance is increasing]
• Use these drugs cautiously—they can foster bacterial resistance and cause C. difficile infection

4th Generation

• Cefepime [Maxipime]
• Must be given parenterally
• Wide spectrum with coverage of Staph and
Strep [that are methicillin sensitive]
• Also covers aerobic gram negative bugs—
Enterobacter spp., E. coli, K. pneumoniae, P.
mirabilis and Pseudomonas [refer to local
antibiograms to assess coverage of
Pseudomonas]

Advanced Generation

• Broad spectrum—only ß-lactam in the US that covers MRSA
• Indicated to treat complicated skin and skin structure infections and CAP
• It binds to PBPs in MRSA and Penicillin resistant
Streptococcus pneumoniae
• Covers gram + pathogens and gram – coverage similar to
3rd generation Ceftriaxone
• Does not cover— P. aeruginosa, certain strains of
Enterobacteriaceae and Acinetobacter baumannii

• Ceftaroline [Teflaro]
• Twice day dosing limits its use outside
of a hospital setting

Question 15

Pearls for Practice for
Cephalosporins

Answer 15

Sanford Guide is your bible to assist in
learning what drugs cover what bugs—and
it is updated yearly based on resistance
patterns and CDC recommendations…

1st generation drugs—gram + bugs

2nd generation drugs—gram – bugs

3rd generation drugs—covers both but you
lose some gram + coverage

4th generation—broader coverage and
covers some aerobes and Pseudomonas

Question 16

Cephalosporins

Resistance

Answer 16

Develops from:

Hydrolysis of the beta-lactam ring by
ß-lactamases

Reduced affinity for PBPs

Question 17

Cephalosporins

Pharmacokinetics

Answer 17

Administration

• Many have to be given IV or IM because of
poor oral absorption

Distribution

• Distributes well in body fluids
• Adequate levels in the CSF, regardless of inflammation, are obtained with only a few
of these drugs
• Ceftriaxone [Rocephin] and Cefotaxime [Claforan] used in treating neonatal and
childhood meningitis from H. influenzae
• Cefazolin [Ancef; Kefzol] used for surgery prevention due to its coverage of
penicillinase-producing S. aureus getting good tissue and fluid penetration

Elimination

• Through tubular secretion and/or GFR
• Dose reduction in renal disease
• Ceftriaxone is excreted through the bile into the feces, no dose reduction on those with CKD

Question 18

Cephalosporins

ADEs

Answer 18

• Generally well-tolerated
• Those who have had anaphylaxis, Stevens-
Johnson Syndrome or Toxic Epidermal Necrolysis to PCNs should not be prescribed a Cephalosporin
• Use with caution in those with PCN allergy
• Cross-reactivity between Cephalosporins and PCNs is 5-10%
• Highest chance of cross-sensitivity between PCN is with 1st generation Cephalosporins

Question 19

Other ß-Lactam
Antibiotics

Answer 19

Carbapenems

Synthetic ß-lactam antibiotics that differ from PCNs in that sulfur atom of the thiazolidine ring has be externalized and replaced by a carbon atom

Imipenem [Primaxin] is prototype drug
Meropenem [Merrem]
Doripenem [Doribax]
Ertapenem [Invanz]

Question 20

Carbapenems

Antibacterial Spectrum

Answer 20

Imipenem

• Resists breakdown by ß-lactamases, but
not metallo-ß-lactamases
• Can be used empirically as it is active against gram + and gram – ß-lactamase producing pathogens, anaerobes and
Pseudomonas

Meropenem

• Bacterial coverage similar to Imipenem

Doripenem

• Bacterial coverage similar to Imipenem
• May be active against resistant strains of
Pseudomonas

Ertapenem

• Does not cover Pseudomonas,
Enterococcus spp. or Acinetobacter spp.

Question 21

Carbapenems

Pharmacokinetics

Answer 21

• All carbapenems are given IV
• Imipenem, Meropenem and Doripenem penetrate well into tissues, fluids and CSF [when meninges are inflamed]
• Meropenem reaches therapeutic levels in the meninges even without inflammation
• Excreted by glomerular filtration
• Because Imipenem is cleaved by a dehydropeptidase in the brush border of the proximal tubule, it is combined with cilastin to protect the drug from this cleavage

Other Carbapenems do not require co-
administration
• Ertapenem is given once per day [IV]
• All of these agents must be dose reduced
in CKD

Question 22

Carbapenems

ADEs

Answer 22

• Nausea, Vomiting and Diarrhea can be seen with Imipenem
• Eosinophilia and neutropenia are less than with other ß-lactams
• High levels of Imipenem can cause seizures [less chance with other carbapenems]
• Because carbapenems and PCNs share a common bicyclic core cross sensitivity may occur
• Use carbapenems cautiously in those with PCN allergy [cross sensitivity rate is <1%]

Question 23

Monobactams

Answer 23

Disrupt bacterial cell wall synthesis—
unique because ß-lactam ring is not fused
to another ring

Aztreonam [Azactam] is the prototype
drug

Aztreonam mainly covers gram – bugs—Enterobacteriaceae and Pseudomonas

Does not cover gram + or anaerobic bacteria

Given IV or IM

Can accumulate in those with CKD

Relatively non-toxic, but can cause phlebitis, rash and elevated LFTs [rare]

Shows little cross-sensitivity with other ß-lactams—so can be used in those allergic to PCN, Cephalosporins or Carbapenems

Question 24

ß-Lactamase Inhibitors

Answer 24

Hydrolysis of the ß-lactam ring—either by cleavage with a ß-lactamase or by acid, destroys the antimicrobial effect

ß-lactamase inhibitors, such as Clavulanic acid, Sulbactam and Tazobactam contain a ß-lactam ring, but alone have not antimicrobial effects or cause any SE

Avibactam and Vaborbactam are also ß-lactamase inhibitors, but they lack the core ß-lactam ring

ß-lactamase inhibitors function by inactivating ß-lactamases, and protecting the antibiotics that are normal substrates for these enzymes

ß-lactamase inhibitors are combined with ß-lactamase- sensitive antibiotics, such as Amoxicillin, Ampicillin and Piperacillin

Question 25

Cephalosporin + ß-lactamase Inhibitor Combinations

Answer 25

Ceftolozane + Tazobactam [Zerbaxa]

3rd generation cephalosporin + ß-lactamase inhibitor

IV medication used to treat resistant Enterobacteriaceae and multi-drug resistant Pseudomonas aeruginosa

It has some activity against some ß-lactamase-producing bacteria [select strains of extended spectrum ß-lactamases; ESBLs]

This agent has narrow gram + and limited anaerobic activity

Ceftazidime + Avibactam [Avycaz]

3rd generation cephalosporin + ß-lactamase inhibitor

IV medication with broad gram – activity including Enterobacteriaceae and Pseudomonas aeruginosa

Adding Avibactam allows the drug to resist hydrolysis against broad spectrum ß-lactamases

Little activity against Acinetobacter, anaerobes and gram + bugs

Both of these drugs are used to treat
intra-abdominal infections [with
Metronidazole] and for management of complicated UTIs

These agents are reserved for the treatment of infections due to multiple-drug resistant pathogens

Question 26

Carbapenem + ß-lactamase Inhibitor Combinations

Answer 26

Meropenem + Vaborbactam [VaBomere]

Carbapenem + ß-lactamase Inhibitor

Approved for the treatment of complicated UTIs including pyelonephritis

Drug has activity against Enterobacteriaceae producing a broad spectrum of B-lactamases, except mettallo- ß-lactamases

Question 27

Vancomycin

Answer 27

Tricyclic glycopeptide active against aerobic
and anaerobic gram + pathogens—MRSA,
MRSE, Enterococcus spp., Clostridium
difficile

The drug is bactericidal

Used in skin and soft tissue infections,
infective endocarditis, nosocomial
pneumonia

Dosing frequency depends on GFR—
monitoring creatinine clearance is needed
to optimize exposure while minimizing
toxicity

Best cure rates occur when trough is 10-20 mcg/mL

For activity against Staph aureus—AUC/MIC ratio is used—this ratio should be >/= 400

Initial trough levels are drawn before the 4th or 5th dose to ensure proper dosing

ADEs—nephrotoxicity, infusion related reactions [“Red-Man” Syndrome and phlebitis], ototoxicity

Resistance to Streptococcus and Staphylococcus spp. is common, but is occurring in Enterococcus faecium—
resistance is caused by alterations in binding affinity to peptidoglycan precursors

Because resistance is now being seen—prudent use of the drug should take place

Oral vancomycin is limited to the management of Clostridium difficile infection

Question 28

Lipoglycopeptides

Answer 28

Telavancin [Vibativ]

Oritavancin [Orbactiv]

Dalbavancin [Dalvance]

Bactericidal concentration-dependent
semi-synthetic lipoglycopeptide drugs
active against gram + pathogens

Spectrum is similar to Vancomycin— staphylococcus, streptococcus and
enterococcus

Agents are MORE potent than
Vancomycin and may cover VR isolates

These drugs inhibit bacterial cell wall synthesis; lipid tail is essential to anchor the drug to the cell walls to improve target site binding

Telavancin and Oritavancin disrupt membrane potential

These actions improve spectrum and minimize resistance

Telavancin is an alternative to Vancomycin for acute bacterial skin and skin structure infections [ABSSSIs], hospital acquired pneumonia from resistant gram + organisms, including MRSA

Use of Telavancin may be limited by ADEs—nephrotoxicity, risk of fetal harm, interactions with drugs that prolong the QTc interval [Quinolones, Macrolides]—renal function and pregnancy test must the evaluated before prescribing this drug

Oritavancin and Dalbavancin have long ½ lives [245° and 187° respectively]—can be used as single doses for managing ABSSSs as outpatients

As with other glycopeptides—infusion reactions may occur; Oritavancin and Telavancin are known to interfere with
phospholipid reagents used in managing coagulation—so other agents should be prescribed if patient is on heparin or other anti-coagulants that must have blood monitoring

Question 29

Daptomycin

Answer 29

Bactericidal concentration-dependent cyclic lipopeptide antibiotic that is an alternative to other agents, such as Vancomycin or Linezolid, to treat infections caused by resistant gram + organisms, such as MRSA and VRE

Used to treat complicated SSSIs and bacteremia from S. aureus, including those with right sided infective endocarditis [not used for left sided BE]

This drug is inactivated by pulmonary surfactants—so it cannot be used to treat pneumonia

Given IV once a day

Question 30

Fosfomycin

Answer 30

Bactericidal synthetic derivative of phosphonic acid—blocks cell wall synthesis by inhibiting a key step in peptidoglycan synthesis

Used for UTIs from E. coli or E. faecalis—and is considered 1st line for acute cystitis
Cross resistance is not likely because of its unique MOA

Rapidly absorbed after oral ingestion—distributes well into kidneys, bladder and prostate

Excreted in active form in urine and maintains high levels for days—allowing for one time dosing

ADEs—diarrhea, vaginitis, nausea and headache

Question 31

Polymyxins

Answer 31

Polymyxin B—prototype drug
Colistin[Coly-Mycin M]

Cation polypeptides that bind to
phospholipids on bacterial cell membrane of
gram – pathogens

Detergent like effects that disrupt cell
membrane and cause cell death

Concentration dependent bactericidal
agents

Active against Pseudomonas aeruginosa, E.
coli, K. pneumoniae, Acinetobacter spp.,
Enterobacter spp.

Proteus and Serratia are resistant

Polymyxin B is available parenteral, ophthalmic, otic and topical

Colistin is available as a prodrug, colistimethate sodium, given IV or nebulized

Use of these drugs is limited due to renal and neurotoxicity [when used systemically]

However, with increasing gram – resistance, these agents are now used as salvage therapy for multi-drug resistant infections