Antibiotics: A Review of the Basics

Antibiotics:
Objectives
A Review of the Basics
 Describe the clinical significance of a number of terms
used in antibiotic therapy
 Explain antibiotic pharmacodynamic / pharmacokinetic
principles as they relate to drug choices / dosing
regimens
 Compare & contrast basic & clinical pharm of the most
Alan P. Agins, Ph.D. common classes of antibiotics used in primary care
President: PRN Associates, Ltd
Continuing Medical Education
Tucson, AZ

Antimicrobial Therapy
Disclosures Terms, Definitions And Basic Principles

This speaker has no Bacteriostatic

antibiotics which inhibit the growth of bacteria
financial or other
conflicts of interest to Bactericidal
disclose antibiotics which kill bacteria

“Cidal” vs “Static” (in vitro terms) “Cidal” vs “Static”

 Antibiotics labeled as "bactericidal” may actually  Some antibiotics can be bactericidal against
fail to kill every bacteria on plate within standard certain organisms but only be bacteriostatic
18–24 hours over which the test is conducted against others and vice versa.
 Eg. the inoculum is large  Eg. macrolides, considered bacteriostatic,

 “Bacteriostatic” agents often do kill quite a few
bacteria within the standard testing time
 Sometimes as many as 90%–99% of the inoculum
 Not enough (>99.9%) under laboratory "rules" to be
labeled “bactericidal"
have shown in vitro bactericidal activity
against non-resistant Streptococcus
pneumoniae and S. pyogenes
 At higher concentrations, bacteriostatic agents
are often "cidal' against a number of
susceptible organisms

Alan P. Agins, Ph.D. 2017 1

 Antibiotics: A Review of the Basics

“Cidal” vs “Static” “Cidal” vs “Static”

 Bactericidals most efficacious against dividing bacteria
 Have greatest efficacy with organisms growing rapidly
during the early stages of infection or in mild infections.
 Effectiveness of bactericidal antibiotics often decreases
as colony grows larger, growth tends to slow dramatically
 eg., stationary phase of deep-seeded infections
 Bactericidal activity on freshly inoculated plate may not
translate to the same in a long standing infection in the
host
 Potential advantages to using bacteriostatic drugs
 Most bacteriostatic drugs inhibit protein synthesis
 tetracyclines, clindamycin, macrolides
 Can rapidly diminish synthesis of exotoxins or
endotoxins that are the actual mediators of clinical
symptoms, morbidity and potential mortality

Antimicrobial Therapy Intrinsic resistance examples:

Terms, Definitions And Basic Principles Intrinsic
Organism resistance Mechanism
against
Resistance
Anaerobic Lack of oxidative metabolism to
Inability for antibiotic to affect a bacteria at bacteria Aminoglycosides drive uptake of aminoglycosides

concentrations attainable in host Aerobic Inability to anaerobically reduce drug

bacteria Metronidazole to its active form

• Intrinsic Resistance Gram- Lack of uptake resulting from

• Acquired Resistance negative Vancomycin inability of vancomycin to penetrate
bacteria outer membrane
• Host Resistance Production of beta-lactamases that
Klebsiella spp. Ampicillin destroy ampicillin before the drug
can reach the PBP targets

Host (Site) Resistance Acquired Resistance

 Bacteria may be sensitive and susceptible to a
particular antibiotic in vitro, but infection located
at a site where drug concentrations > MIC may
not be attainable.
 Ocular fluid, CSF, abscess cavity, prostate, and
bone often much lower concentrations than
serum levels.
 Examples: 1st & 2nd generation cephalosporins and
macrolides do not cross the blood-brain barrier
 Low-oxygen, low-pH, and high-protein environment in
abscess may limit ctivity of like the aminoglycosides
 Result from the mutation of genes involved in
normal physiological processes and cellular
structures - or from the acquisition of
resistance genes from other bacteria - or from
a combination of both
 Traits associated with acquired resistance are
found only in some strains or subpopulations
of any particular bacterial species.

Alan P. Agins, Ph.D. 2017 2

 Antibiotics: A Review of the Basics

Acquired Resistance examples:

Horizontal Transfer Mechanisms
Non-pathogenic
Ab Resistant
Conjugation
Transfer of DNA via
sexual pilus and requires
cell–to-cell contact.
Pathogenic !!!
Ab Sensitive
Image source: Agins
Acquired Resistance observed Mechanism involved
Non-pathogenic
through:
Ab Resistant
E.coli, H. flu Mutations in the chromosomal
phage Transduction resistance to trimethoprim gene specifying dihydrofolate
Plasmid Mutations reductase
Transfer of DNA from one
bacterium into another via S. Pneumonia resistance Mutations in the chromosomal
bacteriophage to penicillins gene specifying PBPs
S. aureus resistance to Via acquisition of genes on
methicillin (MRSA) and mobile genetic element which
Transformation Horizontal other beta-lactams code for PBPs not sensitive to
Uptake of short fragments gene transfer ß-lactam inhibition
of naked DNA by naturally Enterobacteriaceae Transfer of plamids containing
transformable bacteria resistance to b-lactams genes for ESBLs
Non-pathogenic
Ab Resistant

Clinical Aspects of resistance Culture & Sensitivity Report

 MIC Remember: Sensitivities are in vitro
 Lowest concentration of antimicrobial that inhibits Considerations
the growth of the organism after an 18 to 24 hour
incubation period • Tissue penetration
• Patient Factors:
 Interpreted in relation to the specific
- Age / pregnancy / nursing
antibiotic and achievable drug levels - Antibiotic Allergies
 Can not compare MICs between different - Renal / hepatic status
antibiotics - Compliance risk
- Potential drug interactions
 Discrepancies between in vitro and in vivo
• Cost

James H. Jorgensen, JH and Ferraro, MJ. Antimicrobial Susceptibility

Testing: A Review of General Principles and Contemporary Practices.
Clin Infect Dis. (2009) 49 (11): 1749-1755.

Site of Infection Site of Infection

Will the antibiotic get there? Will the antibiotic get there?
 Choice of agent, dose, and route important
 Choice of agent, dose, and route important
 Oral vs. IV administration
 Ability to cross blood-brain barrier
 Bioavailability, severity of infection, site of infection,
function of GI tract  Dependent on inflammation, lipophilicity, low mw, low
protein binding, low degree of ionization
 Blood and tissue concentrations
 3rd or 4th generation cephalosporins, chloramphenicol
 Ampicillin   concentrations in bile

 Fluoroquinolones   concentrations in bone

 Local infection problems
 Quinolones, TMP/SMX, cephalosporins, amoxicillin 
 Aminoglycosides inactivated by low pH and low oxygen
 concentrations in prostate tension
 Macrolides (clarithromycin, azithromycin) 
 Beta-lactams  inoculum effect
concentrations in lung

Alan P. Agins, Ph.D. 2017 3

 Antibiotics: A Review of the Basics

Antimicrobial Therapy
Concomitant Drug Therapy Terms, Definitions And Basic Principles
 Drug interactions
Selective Toxicity
 Pharmacokinetic interactions
use specific, unique targets to destroy or inhibit
  risk of toxicity microorganism without affecting host
 Macrolides and CYP3A4, Cotrimoxazole and CYP2C9
  efficacy of antimicrobial Spectrum
 Divalent cations and fluoroquinolones number of different types of organisms sensitive to
 Pharmacodynamic interactions
an antibiotic
 Cotrimoxazole and ACEI/ARB
Suprainfection
 Selection of combination antibiotics ( 2 agents) secondary infection arising during the course of
requires understanding of the interaction potential primary therapy
 Synergy vs antagonism

Antimicrobial Therapy Antimicrobial Therapy

Terms, Definitions And Basic Principles Terms, Definitions And Basic Principles
Concentration vs Time-dependent killing
Concentration vs Time-dependent killing
Antibiotic Pharmacodynamic Categories
Time-Dependent Concentration- Time Dependent -
(T>MIC) Dependent (concentration enhanced)

No post-antibiotic Cmax/MIC or AUC/MIC AUC24/MIC

Moderate post-
effect (for gram-) Strong post-antibiotic
effect antibiotic effect
Penicillins Aminoglycosides Macrolides
Cephalosporins Fluoroquinolones (Azithromycin)
Erythromycin Metronidazole Clindamycin
Vancomycin
Tetracyclines
>MIC for 40 – 50% of AUC/MIC
dosing interval – max > 125 for gram– bacteria
killing seen when time > 25-50 for gram+ cocci
above MIC is at least Cmax/MIC >10
70% of dosing interval.

Bacterial Morphology & Antibiotics Antibiotic Targets

Beta Lactams
Gram POSITIVE Cell Wall Synthesis
Vancomycin
Streptococcus Bacitracin
Enterococcus
DNA Replication
Staphylococcus
Folic Acid Synthesis Metronidazole
Clostridium Fluoroquinolones
Sulfonamides
Listeria / Bacillus Trimethoprim
mRNA synthesis
porins Gram NEGATIVE Protein Synthesis Rifampin
Outer membrane E.Coli
Periplasmic space tRNA activity
Salmonella
Mupirocin
Pseudomonas
H. Influenzae
H. Pylori Macrolides, aminoglycosides Cell Membrane
Neisseria tetracyclines, clindamycin Disruption
Image: Wiki Commons (public domain) Image source: Agins

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 Antibiotics: A Review of the Basics

Antibiotic Generations Beta Lactams

1st Generation 3rd Generation
gram (+) > gram (-) gram (-) > gram (+)

Penicillins, cephalosporins, macrolides

3rd Generation 1st Generation Penicillins Cephalosporins

gram (+) > gram (-) gram (-) > gram (+)

Gram (-) Fluoroquinolones

Clavulanic Acid
Fatty Membrane

Porin

Monobactams Carbapenems

Beta-Lactam Beta Lactam Mechanism

S
Characteristics C C
 Same MOA: Inhibit cell wall synthesis C
 Bactericidal (except against Enterococcus sp.); C N
Penicillin Binding Protein O CH2
 Time-dependent killers (PBP)
• Amount of Time above MIC correlates with efficacy

 Short elimination half-life (few exceptions)

 Cross-hypersensitivity
PBPs catalyze a number of “transpeptidase” reactions involved in the
process of synthesizing cross-linked peptidoglycan (cell-wall)

Beta Lactam Mechanism Types of Resistance

Beta Lactam
antibiotics have S 1. Production of beta-lactamase enzymes
affinity for PBPs
C C  most important and most common
Structurally similar to
peptidoglycan C  hydrolyzes beta-lactam ring = inactivation
building blocks C N
O CH2 2. Alteration in PBPs leading to decreased
PBP
binding affinity or increased expression
Covalent binding to of enzyme (eg., MRSA)
serine residue at
catalytic site

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 Antibiotics: A Review of the Basics

Resistance to Beta-lactams 1. Beta-Lactamase

1. Beta-Lactamase Penicillinases
Cephaosporinases
Penicillinases S Extended-Spectrum S
β-lactamases
Cephaosporinases C C C C
metallo-β-lactamases
Extended-Spectrum C C
β-lactamases O C
C N HN
metallo-β-lactamases
OH
O CH2 CH2

2. Alteration in PBPs Beta-Lactams - Side Effects

Mutations in genes leading to PBPs with decreased
binding affinity for beta-lactams
MRSA
Methacillin resistance staph aureus
PRSP
Penicillin resistant strep pneumonia
• Generally well tolerated –
 Mostly GI – upset stomach, diarrhea, nausea, etc
 Risk of suprainfection (more with broad-spectrum)
 Hypersensitivity – 3 to 9 %
 Mild to severe allergic reactions
 rash to anaphylaxis and death
 Higher incidence with parenteral administration or
procaine formulation
 Cross-reactivity exists among all penicillins and even
other -lactams
 Desensitization is possible

Image source: Agins

New Report on Penicillin Allergy Natural Penicillins

(penicillin G, penicillin VK)
 Penicillin “allergy” history often inaccurate
 Of 30 million US patients reported to be penicillin-allergic,
an estimated 28.5 million actually are not!
Gram-positive Gram-negative
 19 of 20 pts who think they are allergic to penicillin are misinformed S. aureus (pen-sens) negligible
 Subjects with a penicillin “allergy” history: S. pneumoniae (pen-sens)
 Spend significantly more time in the hospital. Group streptococci Anaerobes
 Are exposed to significantly more antibiotics previously viridans streptococci Above the diaphragm
associated with C difficile and VRE. Clostridium sp.
 fluoroquinolones, clindamycin, and vancomycin Atypicals
 Testing for penicillin allergy may result in cost savings, Spirochetes (syphillus, lyme)
improved patient care, and fewer drug-resistant bacteria

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 Antibiotics: A Review of the Basics

Natural Penicillins Aminopenicillins

(penicillin G, penicillin VK) (ampicillin, amoxicillin)
Common Clinical Uses Increased activity against gram (-) aerobes
Streptococcal infections (without bacteremia) Gram-positive Gram-negative
Mild-to-moderate infections of the upper respiratory H. influenzae ( L neg )
tract, scarlet fever, mild erysipelas
S. aureus (pen-sens)
Pneumococcal infections Group streptococci M. Caterrhalis
Mild to moderately severe infections of the viridans streptococci N. meningitidis
respiratory tract Enterococcus sp. Proteus mirabilis
Staphylococcal infections (pen-sensitive). E. coli (some strains)
Mild infections of the skin and soft tissues Atypicals
Salmonella
Spirochetes (syphillus, lyme)

Aminopenicillins Carboxypenicillins
(carbenicillin, ticarcillin)
Common clinical uses
 Infections of the ear, nose, and throat Developed to further increase activity
against resistant gram-negative aerobes
 Infections of the genitourinary tract
 Infections of the skin and skin structure Gram-positive Gram-negative
 Infections of the gastrointestinal tract (ampicillin) marginal Proteus mirabilis
 Infections of the lower respiratory tract Salmonella, Shigella
some E. coli
H. influenzae ( L neg )
Enterobacter sp.
Pseudomonas aeruginosa

Ureidopenicillins -Lactamase Inhibitor –

(piperacillin, azlocillin) Penicillin Combinations
Developed (from Ampicillin) to further increase activity
against resistant gram-negative aerobes Beta-Lactamase

Gram-positive Gram-negative Clavulanic Acid

viridans strep Proteus mirabilis
Group strep Salmonella, Shigella
+
some Enterococcus E. coli Amoxicillin
H. influenzae
Anaerobes Enterobacter sp. Augmentin
Fairly good activity Pseudomonas aeruginosa • Amp +S = Unasyn
Serratia marcescens • Pip +T = Zosyn
some Klebsiella sp. • Tic +C = Timentin

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 Antibiotics: A Review of the Basics

Cephalosporins  First Generation

Cephalosporins
Best activity against gram-positive aerobes,
• Divided into 5 groups with limited activity against a few gram-negatives
“Generations”
Gram-positive Gram-negative
• Generations differ in ~
 Antimicrobial activity
3rd S. aureus* (meth-sens) E. Coli (some)
 Spectrum S. pneumoniae* (pen-sens) K. pneumoniae
 Resistance to beta-lactamase Group streptococci P. mirabilis
 CNS penetration 1st viridans streptococci

* May retain activity with B-lactamase producing strains

 First Generation
Cephalosporins  Second Generation
Cephalosporins
General Clinical Uses: In general, less active against gram (+) aerobes,
but more active against gram (-)
Uncomplicated, community-acquired cefalotin (Keflin) Cephamycins & Carbacephems also included in the group
infections of the skin and soft tissue cefalexin (Keflex) po
Gram-positive Gram-negative
and urinary tract. cefadroxil (Duricef) po
S. aureus* (meth-sens) E. Coli (some)
cephazolin (Ancef) K. pneumoniae
Respiratory tract infections caused S. pneumoniae* (pen-sens)
P. mirabilis
by penicillin-sensitive S. pneumonia. Group streptococci H. influenzae
viridans streptococci M. Catarrhalis
Parenteral 1st generation agents are E. aerogenes
used for surgical wound prophylaxis Neisseria sp. (some)
(ie. Ancef).

 Second Generation
Cephalosporins  Third Gen Cephalosporins

• Less active against gram-positive, but greater

General Clinical Uses:
 Treating upper and lower
respiratory tract infections,
sinusitis and otitis media
 Alternatives for treating
urinary tract infections caused Cephamycins
by E coli, Klebsiella and
Proteus
cefprozil (Cefzil) po activity against gram-negative aerobes
cefuroxime (Ceftin) po / im • Ceftriaxone (Rochephin) and cefotaxime (Claforen)
cefaclor (Ceclor) po retain good activity against gram-positive aerobes,
including pen-resistant S. pneumoniae
Carbacephem
loracarbef (Lorabid) po • Those with anti-pseudomonal activity have
decreased activity against Gram-positive organisms
• Several agents are strong inducers of extended
Next slide spectrum beta-lactamases (ESBLs)

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 Antibiotics: A Review of the Basics

 Third Gen Cephalosporins

Gram-negative aerobes
 Third Gen Cephalosporins
General Clinical Uses
E. coli, K. pneumoniae, P. mirabilis, H. influenzae, For infections involving gram- cefdinir (Omnicef) (PO)
M. catarrhalis, N. gonorrhoeae (incl beta-lactamase +) negative bacteria, particularly cefixime (Suprax) (PO)

hospital-acquired infections ceftibuten (Cedax) (PO)

N. meningitidis, Citrobacter sp., Enterobacter sp.,
- or - cefpodoxime (Vantin) (PO)
Acinetobacter sp., M. morganii, S.marcescens
cefditoren (Spectracef) (PO)
Pseudomonas ceftazidime (Fortaz) Complicated community-
cefotaxime (Claforan)
acquired infections of the
ceftizoxime (Cefizox)
Gram+ cocci ceftriaxone (Rochephin) respiratory tract, blood, intra-
cefotaxime (Claforen) abdominal, skin and soft tissue ceftriaxone (Rocephin)
and urinary tract. cefoperazone (Cefobid)
cefpodoxime (Vantin)
ceftazidime (Fortaz)
cefixime (Suprax) Drugs of choice for Menningitis

 Fourth Gen Cephalosporins Cephalosporin Side Effects

 GI - diarrhea, nausea, electrolyte disturbances, and/or
• Greater activity against both Gram-negative & pain and inflammation at injection site, suprainfection
Gram-positive organisms than 3rd-gen agents
 Hypersensitivity –
 Good activity against Pseudomonas aeruginosa,  Studies suggest 1% to 3% incidence of allergic rx’s
Staphylococcus aureus, and multiple drug resistant independent of history of PCN allergy
Streptococcus pneumoniae
 Cross rx with PCN allergy reported as high as 10%
 Stability against -lactamases Penicillin and cephalosporins known to
 Poor inducer of extended-spectrum  -lactamases have a risk of allergic cross reaction.
These cephalosporins should be
• cefepime (Maxipime) - currently only one available avoided in patients who are allergic to
penicillin.

vancomycin
 Glycopeptide antibiotic obtained from the
actinobacteria species Amycolatopsis orientalis
 Inhibits synthesis of cell wall phospholipids and
prevents cross-linking of peptidoglycans at a
different site than B-lactams
 Active against gram positive bacteria only
 Highly resistant Strep. pneumo, Clostridia,
Enterococcus, Staph. epi and MRSA
vancomycin
Common Clinical Uses:
 Serious infections caused by susceptible
organisms resistant to penicillins
 methicillin-resistant Staph aureus [MRSA]
 multi-resistant Staph epidermidis (MRSE)
 Pseudomembranous colitis (relapse or
unresponsive to metronidazole treatment)
 Treatment of infections caused by gram-positive
microorganisms in patients with serious allergies to
beta-lactam antimicrobials

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 Antibiotics: A Review of the Basics

vancomycin Tetracylines
 Adverse effects From various Streptomyces strains
 Pain / thrombophlebitis (IV administration) “Broad Spectrum” antibiotics
 Red man syndrome • gram (+) (except Enterococcus)
 due to histamine release (non-IgE mediated) • gram (-)
 pruritus, erythematous rash that involves the face, • Atypicals
neck, and upper torso. • Inhibit protein synthesis / Bacteriostatic
 Slow injection and prophylactic antihistamines
 Ototoxic – may potentiate known ototoxic agents. Naturally-occurring Semi-synthetic
 Renal excretion (90-100% glomerular filtration). Short-acting (t½ 6 - 8 hrs) Long-acting (t½ >16 hrs)
 Normal half-life 6-10 hours. Tetracycline Doxycycline
 Half life is over 200 hours in pts with ESRD Oxytetracycline Minocycline
Demeclocycline (10 hr)

Tetracylines
 Doxycycline / Minocycline
 absorption less affected by food, somewhat lower
potential for causing photosensitivity, no dosage
adjustments required in renal impairment
 Minocycline 5x more lipophilic than doxycycline
 may not distribute into tissues like the bladder or
prostate, may be less effective for UTIs, prostatitis or
epididymitis.
 Both shown to have potent anti-inflammatory effects on
neutrophil chemotaxis and inhibitory effects on
Tetracylines
 Respiratory tract infections [CAP or bronchitis]
 due to Mycoplasma, S pneumoniae, H influenzae,
Klebsiella species)
 UTIs caused by mycoplasma or chlamydia
 Genital chlamydial infections
 SSSIs
 Acne, infections due to S. aureus, including CA-MRSA
 Doxycycline one of three choices for (early-stage)
treatment Lyme Disease
 Drug of choice for treatment of rickettsial infections like

cytokines and matrix metalloproteinases Rocky Mountain Spotted Fever

Tetracylines
Macrolides
Adverse Effects: Erythromycin
 GI irritation
 derived from Streptomyces erythreus
 Suprainfection (esp. Candida, also C.diff) Clarithromycin & Azithromycin
 Photosensitivity (esp. natural tetracyclines) Structural analogs
 May worsen renal failure (except doxy / mino)  Broader spectrum of activity

 Dizziness / headaches (minocycline)  Better pharmacokinetic properties –

 better bioavailability, better tissue penetration,
 dose-related, typically appear in 2 – 3 days, women > men
prolonged half-lives
 In children - discoloration of teeth, depression of  Improved tolerability
bone growth

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 Antibiotics: A Review of the Basics

Macrolides
Mechanism of Action
 Inhibit bacterial protein synthesis
 Macrolides typically are bacteriostatic
 May be bactericidal when present at high
concentrations against susceptible organisms
Macrolides
 Antibacterial spectrum:
Erythromycin
 Gram positives: Staph.(MRSA is resistant), Strep.,
Treponema, Corynebacteria.
 Atypicals: Mycoplasma, Ureaplasma, Chlamydia
Clarithromycin- similar to erythromycin
 Increased activity against gram negatives (H. flu,

 Time-dependent activity Moraxella, H. pylori) & atypicals (above plus MAV)

Azithromycin
 Decreased activity against gram positive cocci.
 Increased activity against H. flu and M. cat.

Macrolides
 Empiric use in URIs
1. Spectrum (particularly for C and A) covers S.
pneumoniae, H. influenzae, and M. catarrhalis -
three most common pathogens causing
community-acquired pneumonia (CAP), otitis and
bacterial sinusitis
2. Coverage of atypicals (mycoplasma, chlamydia
and legionella) also associated with CAP
3. Ability to concentrate in respiratory tract tissue
and upper airways.
Macrolides
Side Effects
• Gastrointestinal – up to 33 %
 Nausea, vomiting, diarrhea, dyspepsia
 Most common with erythro; less with others
• Cholestatic hepatitis - rare
> 1 to 2 weeks of erythromycin estolate
• Other: Bad Taste - Clarithromycin
• ototoxicity (high dose erythro in patients with URI);
QTc prolongation (all 3); hypersensitivity rare

Macrolides Co-trimoxazole
Drug Interactions sulfamethoxazole + trimethoprim
[SXT, TMP-SMX, TMP-SMZ,
Erythromycin and Clarithromycin –
powerful inhibitors of CYP 3A4 Bactrim, Septra]
Synthetic antimicrobial agents
Some Statins buspirone
not derived from a “natural” source
(ator, sim, lov) methadone, oxycodone
carbamazepine cyclosporine Fixed dose ratio 5:1 (S:T)
warfarin (R) PDE5 Inhibitors Agents block two different steps in folic acid
OAB drugs some Benzos synthetic pathway
CCBs others No concensus - bactericidal or bacteriostatic

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 Antibiotics: A Review of the Basics

Co-trimoxazole Co-trimoxazole
 Folate necessary for one-carbon transfer in  Broad Spectrum:
purines and pyrimidine de novo synthesis  S. aureus, S. pneumonia, H. flu, Neisseria species, E.Coli,
 Thymidine (for DNA) and Uridine (for mRNA) Shigella, Pneumocystis carinii
most sensitive to blockade  Common Clinical Uses:
 upper and lower RTIs, GU and UTIs, GI infections, skin and
Bacteria Bacteria & Human
wound infections, septicemias, etc
Thymidylate
O
 UTIs, prostititis
=

H 2N C - OH

PABA X DHF X THF THF-C  AOM, AECB, etc

Methionine
Purines
 CA-MRSA, impetigo,
 Shigellosis, PCP (acute and prophylaxis in HIV), Traveler's
Diarrhea, toxoplasmosis, etc
Sulfa Trimethoprim

Co-trimoxazole Co-trimoxazole
Interactions
Adverse Effects  Highly protein bound
 GI Upset and allergic rashes most common  Neonates - Kernicterus
 Photodermatitis  Can displace other protein bound drugs –
 Hypersensitivity (incl SJ syndrome) warfarin, phenytoin, lamotrigine, valproate, NSAIDs
 Hematologic:  TMP may  hyperkalemic effect of ACEIs/ARBs
 Hemolytic anemia (G6PDH deficient pts.), neutropenia,  Both Sulfa and TMP are inhibitors of CYP2C9
thrombocytopenia  Phenytoin
 Renal: toxic nephrosis  S-warfarin
 Some antidiabetic drugs
 others

Fluoroquinolones Fluoroquinolones
Mechanism: First-generation - Nalidixic acid, etc.
• Discovered during synthesis of Chloroquine
Synthetic – not from microorganism • No gram pos. activity
• Poor oral absorption & tissue-penetration
Inhibit bacterial replication / transcription • UTIs – E.coli, Proteus, Shigella, Enterobacter, etc
Bactericidal !!!!
Second-generation (1st gen Fluoro)
Conc–dependent killing / Post Antibiotic effect • Ciprofloxacin, Norfloxacin, Ofloxacin
• Gram Negative Rod coverage (inc. pseudomonas)
Serum concentrations need to average 4X the
• Some Gram Positive coverage
MIC for each 24-hr period to produce almost • Limited atypical coverage
100% kill

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 Antibiotics: A Review of the Basics

Fluoroquinolones Fluoroquinolones
Common Clinical Uses
Third-generation Quinolones  Acute bacterial exacerbations of chronic bronchitis
Levofloxacin (Levaquin)  Community-acquired pneumonia
• Active enantomer of ofloxacin
 Uncomplicated skin and skin structure infections
• Spectrum similar to 2nd-gen – plus -
"atypicals" & gram+  Nongonococcal urethritis and cervicitis
- Strep, Staph, Enterococci  Mixed Infections of the urethra and cervix
 Acute pelvic inflammatory disease
Fourth-generation Quinolones  Uncomplicated cystitis
Moxifloxacin (Avelox)  Complicated urinary tract infections
• Greater gram+ coverage  Prostatitis
• Less effective against pseudomonas and  Acute, uncomplicated urethral & cervical gonorrhea
enterobacter

Fluoroquinolones Adverse Effects
• Gastrointestinal – 5 %
- Nausea, vomiting, diarrhea, dyspepsia
• Central Nervous System
- Headache, dizziness, confusion, tremors,
restlessness, agitation, insomnia, anxiety,
paranoia, panic attacks, hallucinations, toxic
psychosis, seizures
- Peripheral neuropathy (rare)
- Can be irreversible (new FDA WARNING)
Fluoroquinolones
• Hepatic
• Hepatotoxicity, hepatic failure, cholestatic hepatitis -
levofloxacin, ciprofloxacin and moxifloxacin
• Dermatologic
• Severe hypersensitivity reactions
• Phototoxicity - uncommon with current FQs
• Dematologic ADR to a fluoroquinolone can sensitize
a patient to more severe adverse reactions
• Cardiac
• Variable prolongation in QTc interval
• Moxifloxacin causes greatest QT prolongation,
ciprofloxacin least likely

Fluoroquinolones Fluoroquinolones
Drug Interactions Interactions / Warnings
• Divalent / trivalent cations • NSAIDs increase risk of severe CNS adverse
• Impair PO absorption of fluoroquinolones– can lead to
Clinical Failure reactions, including but not limited to seizures
• Ca, Fe, Mg, Al, Zn, etc
• Benzodiazepine-dependent pts may
• Antacids, enteral feedings
experience precipitated withdrawal symptoms
• Administer doses 2 to 4 hours apart; FQ first
• Cytochrome P450 CYP1A2 inhibition • Suprainfection
• Caffeine, theophylline, cyclosporine, (R) warfarin -  levels,  • Quinolones in comparison to other antibiotic
toxicity classes rank amongst the highest for risk of
• ciprofloxacin most likely causing colonization with MRSA and C Difficile

Alan P. Agins, Ph.D. 2017 13


Fluoroquinolones warnings
 QTc interval prolongation
 CNS effects – neuro / psychiatric
 Hypoglycemia
 Hepatotoxicity
 Hypersensitivity reactions
 Peripheral neuropathy
 Photosensitivity/phototoxicity
 Suprainfection (C. difficile and CDAD)
 Tendon inflammation/rupture [Boxed]
Fluoroquinolones & dysglycemia
 Caused removal of gatifloxacin (Tequin) from market
 More likely to occur in diabetic patients
-- especially elderly + renal insufficiency
 Hypoglycemia (early) > hyperglycemia (later)
 hypoglycemia may be profound/difficult to manage
 Moxifloxacin (1%) > levofloxacin (.9%) > cipro(.8%)
 Use caution when using FQs in diabetic patients
Clindamycin
 Semi-synthetic derivative of Lincomycin
 Inhibits protein synthesis (including toxin production)
 Bacteriostatic
 Covers gram- anaerobes & some gram+ aerobes
 aerobic gram (-) bacteria resistant to clindamycin
 Pseudomonas, Legionella, H. influenzae and Moraxella)
 Used for respiratory, skin and soft tissue infections,
peritonitis, oral infections, acne, BV
 Option for CA-MRSA
Alan P. Agins, Ph.D. 2017
Antibiotics: A Review of the Basics
Fluoroquinolones & Neuropathy
 Fluoroquinolones (all) pose risk for producing
permanent peripheral neuropathy
 Onset is rapid, often within few days of treatment
initiation
- FDA stated some patients who d/c drug continued to
experience nerve damage symptoms for > a year
 FDA advises clinicians to switch patients to another
class of antibiotics if they develop symptoms of
peripheral neuropathy
- unless the clinician believes the benefits of
fluoroquinolone treatment outweigh the risks
Fluoroquinolones & Tendons
 Fluoroquinolones use increases the likelihood
of tendon rupture by 3 to 4 fold
 Most at risk:
 Pts > 60 yrs old
 Pts taking corticosteroids (systemic)
 Transplantation pts (kidney, heart or lung)
 Patients who experience pain, swelling,
inflammation of a tendon or tendon rupture should
stop taking the medications and call their provider
Clindamycin
 Topical, PO, IV
 Side effects:
 Diarrhea, vomiting, and nausea
 More common if the individual lies down for an
extended period of time within 30 minutes of taking
Clindamycin.
 Rash, neutropenia / thrombocytopenia,
 Most noted antibiotic for causing
pseudomembranous colitis
14

Metronidazole
 Bactericidal –
 Pro-drug, need to be “reduced” to active drug
 Causes uncoiling of DNA
 Will work in both growing and dormant infections
Anaerobic Bacteria –
Bacteroides sp., Clostridium sp., Helicobacter pylori
Facultative Anaerobe –
Gardnerella (vaginalis)
Anaerobic Parasites / Protozoa –
Trichomonas vaginalis, Giardia lamblia
Metronidazole
Drug Interactions
An inhibitor of CYP2C9 hepatic enzymes
Warfarin  anticoagulant effect
Phenytoin  phenytoin concentrations
The issue with Alcohol
Disulfiram reaction ???
No evidence for  acetaldehyde in serum
May be due to Serotonin Syndrome
More likely in pts taking SSRIs/SNRIs
Nitrofurantoin
Side Effects:
• Nausea,vomiting, fever, rash
• Peripheral neuropathy
• Hypersensitivity pneumonitis
• Chronic use may cause progressive pulmonary
interstitial fibrosis
- Watch for pulmonary involvement early
• SEs much more common in the elderly
• Colors urine a dark orange-brown
Alan P. Agins, Ph.D.
Antibiotics: A Review of the Basics
Metronidazole
Adverse Effects
Gastrointestinal
• Nausea, vomiting, stomatitis, metallic taste
CNS – most serious
• Peripheral neuropathy, seizures, encephalopathy
• Use caution in preexisting CNS disorders
• Requires discontinuation of metronidazole
Other
 Possibly carcinogenic [Black Boxed Warning]
 based on animal data
Nitrofurantoin
Macrodantin, Macrobid
Uses: UTIs, UTI prophylaxis
 Only clinically proven for use against
 E. coli or Staph. saprophyticus
 Concentrates in urine
 Renal impairment - concentration achieved in urine
may be sub-therapeutic
 Inhibits several bacterial enzyme systems including
acetyl coenzyme A interfering with metabolism and
possibly cell wall synthesis
2017 15