Review of Antimicrobial Agents
Part I
Siriluck Anunnatsiri, MD, MCTM, MPH
Infectious Diseases & Tropical Medicine
Department of Medicine
Khon Kaen University
Classification of Antimicrobial Agents
-lactam antibiotics:
Penicillins, Cephalosporins, Carbapenems,
Monobactams, -lactam/-lactamases inhibitors
Aminoglycosides
Macrolides
Ketolides: Telithromycin, Dirithromycin
Lincosamides: Lincomycin, Clindamycin
Quinolones
Chloramphenicol
Classification of Antimicrobial Agents
Tetracyclines, Tigecycline
Sulfamethoxazole/Trimethoprim (SMX/TMP)
Glycopeptides: Vancomycin, Teicoplanin
Oxazolidinones: Linezolid
Fosfomycin
Fusidic acid
Polymyxins: Polymyxin B, Colistin
Metronidazole
Classification of Antimicrobial Agents
Lipopeptide: Daptomycin
Streptogramins: Quinupristin-Dalfopristin
-lactam antibiotics
Aminoglycosides
Glycopeptides
Antimicrobial Properties
Structure
Spectrum
Mechanisms of action
Mechanism of
resistance
Pharmacokinetic
Absorption
Distribution
Metabolism
Elimination
Pharmacodynamic
Drug interaction
Side effect
Beta-lactams Antibiotic: Basic Structure
Aminoacyl
Thiazolidine ring
Hydroxyethyl
Dihydrothiazine ring
Beta-lactams Antibiotic: General Properties
Inhibit cell wall synthesis
Bactericidal effect
Time-dependent bactericidal action
Inoculum effect on antimicrobial activity is
more prominent
In GNB - No or short PAE for most -lactam
Share -lactam class allergic reaction except
monobactams
PD Parameters affecting Antibiotic Potency
AUC/MIC
>125 for GNB
>25-50 for GPC
Cmax/MIC >10
> 40-50% of dosing interval
Inoculum Effect
The effect of inoculum size on
antimicrobial activity
Dense population can be less
susceptible to -lactams
Failure to express receptor (PBP)
High concentration of -lactamases
Trend to presence of resistant
subpopulation
Postantibitic Effect
A persistent suppression of growth after
levels have fallen below the MIC
Bacterial Cell Wall Synthesis
Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155
Bacterial Cell Wall Synthesis
(Transpeptidase)
Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155
Beta-lactams Antibiotic : Mechanism of Action
Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155
Beta-lactams Antibiotic : Mechanism of Resistance
-lactamases destruction of antibiotic
Failure of antibiotic to penetrate the outer
membrane of gram-negative to reach PBP
target
Efflux of antibiotic across the outer
membrane of gram-negative
Low-affinity binding of antibiotic to PBP
target
Beta-lactams Antibiotic: Adverse Reactions
• Hypersensitivity – 3 to 10 %
• Irritability, jerking, confusion, seizures– especially
with high dose penicillins and imipenem
• Leukopenia, neutropenia, thrombocytopenia –
therapy > 2 weeks
• Interstitial nephritis
• Cephalosporin-specific: cefamandole, cefotetan,
cefmetazole, cefoperazone, moxalactam
 Hypoprothrombinemia - due to reduction in
vitamin K-producing bacteria in GI tract
Penicillins: Classification
Natural penicillins
Penicillin V, Penicillin G
Aminopenicillins
Ampicillin, Amoxicillin
Penicillinase-resistant penicillins
Cloxacillin, Dicloxacillin, Nafcillin, Methicillin
Carboxypenicillins
Carbenicillin, Ticarcillin
Ureidopenicillin
Piperacillin, Azlocillin, Mezlocillin
Natural Penicillins: Spectrum of Activity
Gram-positive
Gram-negative
S. pneumoniae
Streptococcus sp.
Enterococcus sp.
C. diphtheriae
B. anthracis
L. monocytogenes
Neisseria meningitidis
Anaerobes
Above the diaphragm
Clostridium perfringens
Other
Treponema pallidum
Leptospira sp.
Penicillinase-Resistant Penicillins: Spectrum
Gram-positive
MSSA
MSSE
Streptococcus sp.
Aminopenicillins: Spectrum of Activity
Gram-positive
Gram-negative
Streptococcus sp.
Enterococcus sp.
L. monocytogenes
C. diphtheriae
Proteus mirabilis
Salmonella sp.
Shigella
some E. coli
H. influenzae
N. meningitidis
Anaerobes
Above the diaphragm
Clostridium perfringens
Carboxypenicillins: Spectrum of Activity
Gram-positive
Gram-negative
Streptococcus sp.
C. diphtheriae
Proteus mirabilis
Salmonella sp.
Shigella
E. coli
H. influenzae
Neisseria sp.
Enterobacter sp.
P. aeruginosa
Citrobacter sp.
Serratia sp.
Anaerobes
Fairly good activity
Ureidopenicillins: Spectrum of Activity
Gram-positive
Gram-negative
Streptococcus sp.
Enterococcus sp.
L. monocytogenes
Proteus mirabilis
Salmonella sp.
Shigella
E. coli
Klebsiella sp.
H. influenzae
Neisseria sp.
Enterobacter sp.
P. aeruginosa
S. marcescens
Anaerobes
Fairly good activity
Penicillins: Pharmacology
Administration – Oral, IV, IM
Varying oral absorption
40% for Ampicillin  75% for Amoxicillin
Varying protein binding
17% for aminopenicillin  97% for dicloxacillin
More free drugs in the presence of probenecid
Mainly excrete via renal tubular cells, which
can be blocked by probenecid.
Penicillins: Pharmacology
Dose adjustment is needed when CCr < 1020 ml/min, on hemodialysis or CVVH
Biliary excretion is important only for nafcillin
and antipseudomonal penicillins.
Well distributed to most tissues, high
concentration in urine and bile
Relatively insoluble in lipid and penetrate cells
relatively poorly
Cephalosporins: Classification
1st Generation 2nd Generation Cephamycins 3rd Generation 4th Generation
Cefazolin
Cefamandole
Cefmetazole
Ceftriaxone
Cefepime
Cephalothin
Cefonicid
Cefotetan
Cefotaxime
Cefpirome
Cephapirin
Cefmetazole
Cefoxitin
Ceftazidime
Cephradine
Cefotetan
Cefoperazone
Cefadroxil
Cefoxitin
Ceftizoxime
Cephalexin
Cefuroxime
Cefsulodin
Cefprozil
Moxalactam
Loracarbef
Cefdinir
Cefaclor
Cefditoren
Cefixime
Ceftibuten
Cefpodoxime
1st Generation Cephalosporins: Spectrum
Best activity against gram-positive aerobes, with
limited activity against a few gram-negative aerobes
Gram-positive
Gram-negative
MSSA
Enterobacteriaceae
Streptococcus sp.
2nd Generation Cephalosporins/Cephamycins:
Spectrum
More active against gram-negative aerobes
Cephamycin group has activity against gram-negative
anaerobes including Bacteroides fragilis
3rd Generation Cephalosporins: Spectrum
Increase potency against gram-negative
aerobes
Ceftriaxone and cefotaxime have the best
activity against MSSA and Streptococcus sp.
Ceftazidime, moxalactam, cefixime, and
ceftibuten have less activity against MSSA
Ceftazidime, cefoperazone, and cefsulodin
have activity against P. aeruginosa.
4th Generation Cephalosporins: Spectrum
Extended spectrum of activity
 gram-positives: similar to ceftriaxone
 gram-negatives: Enterobacteriaceae
including cephalosporinase-producer,
P.
aeruginosa.
Stability against -lactamases; poor inducer
of extended-spectrum  -lactamases
Cephalosporins: Pharmacology
Polar, water-soluble compounds
Administration – IM, IV, oral, intraperitoneum
High oral bioavailability
Varying protein binding – 10% -> 98%
Largely confined to extracellular
compartment, relatively poor intracellular
concentration
Good CNS penetration – Only 3rd & 4th gen.
cephalosporins
Almost excrete via renal tubular secretion,
except ceftriaxone and cefoperazone are
largely eliminated via biliary route
Carbapenems
Imipenem
N-formimidoyl derivative of thienamycin
Need to combine with cilastatin to prevent
renal dehydropeptidase I hydrolysis and
nephrotoxic effect
Meropenem, Ertapenem
-1-methyl, 2-thio pyrrolidinyl derivative of
thienamycin
Carbapenems: Spectrum of Activity
Most broad spectrum of activity of all
antimicrobials
Have activity against gram-positive and gramnegative aerobes, anaerobes, Nocardia sp.,
rapid-growing mycobacteria
Bacteria not covered by carbapenems include
MRSA, MRSE, E. faecium, C. difficile, S.
maltophilia, B. cepacia
Ertapenem not active against P. aeruginosa and
Acinetobacter sp.
Carbapenems: Pharmacology
Absorbed poorly after oral ingestion
T1/2:
Imipenem, Meropenem 1 hr
Ertapenem 4 hr
Well distributed to body compartment and
penetrate well into the most tissues
Excrete via renal, dosage adjustment is
required in patient with impaired renal
function.
Need supplement dose in patient performing
CVVH, hemodialysis
-Lactam/-Lactamase Inhibitor
Ampicillin/sulbactam (A/S)
Amoxicillin/clavulanate (A/C)
Ticarcillin/clavulanate (T/C)
Piperacillin/tazobactam (P/T)
Cefoperazone/sulbactam (C/S)
-Lactam/-Lactamase Inhibitor: Spectrum
Maintain spectrum of -Lactams but enhance
activity against -Lactamase (Ambler class A)
producing organisms
Activity against MSSA, Streptococcus sp.,
Enterococcus sp. (Except C/S), -Lactamase
producing Enterobactericeae, P. aeruginosa
(Only P/T, C/S), Anaerobes.
-Lactam/-Lactamase Inhibitor: Pharmacology
Clavulanate, Sulbactam – Moderately well
absorbed
Good tissue distribution
Penetration into inflamed meninges
Clavulanate, Sulbactam – Poor
Tazobactam – Good in animal model
Excretion
Clavulanate – Lung, feces, urine
Sulbactam, Tazobactam - Urine
Monobactams





Aztreonam
Bind primarily to PBP 3 in Enterobacteriaceae, P.
aeruginosa, and other gram-negative aerobes
No activity against gram-positive or anaerobic
bacteria
Low incidence of drug hypersensitivity; no crossreaction with other -Lactams
Weak -Lactamase inducer
Aminoglycosides: Basic Chemical Structure
Aminocyclitol Ring
Aminoglycosides: Classification
Family
Member
Streptidine aminocyclitol ring
Streptomycin
Spectinomycin
Streptomycin
2-deoxystreptamine aminocyclitol ring
Kanamycin
Kanamycin, Amikacin,
Tobramycin, Dibekacin
Gentamicin
Gentamicin, Netilmicin,
Sisomicin, Isepamicin
Neomycin, Paromomycin
Neomycin
Aminoglycosides: Mechanism of Action
Aminoglycosides: Mechanism of Resistance
Adenyltransferase
Phosphotransferases
Acetyltransferases
Aminoglycosides: Spectrum of Activity
Gram-Negative Aerobes
Enterobacteriaceae, P. aeruginosa,
Acinetobacter sp.- Kanamycin & Gentamicin
groups
F. tularensis, Brucella sp., Y. pestis Streptomycin, gentamicin
N. gonorrhoeae - Spectinomycin
Mycobacteria
M. tuberculosis – Streptomycin, kanamycin,
amikacin
Non-tuberculous – Amikacin, streptomycin
Aminoglycosides: Spectrum of Activity
Gram-Positive Aerobes (In vitro synergy)
S. aureus, S. epidermidis, viridans streptococci,
Enterococcus sp.
Nocardia sp. - Amikacin
E. histolytica, C. parvum - Paromomycin
Aminoglycosides: Pharmacology
Bactericidal effect
Concentration dependent killing
Little influence by inoculum effect
Presence of PAE effect
Administration – IV, IM, intrathecal,
intraperitoneum, inhale, oral (neomycin,
paromomycin), topical
Low level of protein binding (10%), high
water solubility, lipid insolubility
Aminoglycosides: Pharmacology
99% of drug is excreted unchanged by
glomerular filtration
5% of excreted drug is reabsorbed at
renal proximal tubule
Once-Daily Aminoglycosides
Equal efficacy compared to multiple-dose
administration
May lower but not eliminate risk of drug-induced
nephrotoxicity and ototoxicity
Simple, less time consuming, and more cost
effective
Does not worsen neuromuscular function in
critically ill ventilated patients
Probably should not be used in enterococcal
endocarditis
Need further study in pregnancy, cystic fibrosis,
GNB meningitis, endocarditis, and osteomyelitis
Aminoglycosides: Adverse Effects
Neuromuscular blockage
Nephrotoxicity
Reversible if detection early
Risk factors: prolonged trough level, volume
depletion, hypotension, underlying renal
dysfunction, elderly, other nephrotoxins
Ototoxicity
Cumulative dose
8th cranial nerve damage - irreversible
Vestibular toxicity: dizziness, vertigo, ataxia
Auditory toxicity: tinnitus, decreased
hearing (high frequency)
Glycopeptides
Vancomycin
Teicoplanin
Glycopeptides: Mechanism of Action
Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155
Glycopeptides: Mechanism of Resistance in S. aureus
Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155
Glycopeptide-resistant S. aureus
NCCLS
BSAC
S
I
R
S
R
Vancomycin
<4
8-16
>32
<4
>8
Teicoplanin
<8
16
>32
<4
>8
NCCLS = The National Committee for Clinical Laboratory Studies
BSAC = The British Society for Antimicrobial Chemotherapy
Glycopeptide-resistant S. aureus
Recommend using MIC determination for
confirmation of VISA, GISA, or VRSA isolates
Heteroresistance phenomenon: Hetero-VRSA
Only a subpopulation of S. aureus can grow on
vancomycin-containing agar (>8 g/ml)
Precursor of VISA/VRSA isolates
Population analysis is needed to identify heteroVRSA
Glycopeptide-resistant Enterococci
Acquired resistance level, Type
Stain
Characteristics
High,
VanA
Low
Variable, Moderate,
VanB
VanD
VanG
VanE
Intrinsic
resistance,
low level,
Type
VanC1, C2,
C3
MIC, mg/L
Vancomycin
64-100
4-1000
64-128
16
8-32
2-32
Teicoplanin
16-512
0.5-1
4-64
0.5
0.5
0.5-1
Modified
Target
D-AlaD-Lac
D-AlaD-Lac
D-AlaD-Lac
D-AlaD-Ser
D-AlaD-Ser
D-AlaD-Ser
Courvalin P. Clin Infect Dis 2006; 42: S25-S34.
Glycopeptide-resistant Enterococci
VanS = Membrane-associated sensor kinase
VanR = Cytoplasmic response regulator
Glycopeptides: Spectrum of Activity
Gram-positive bacteria
MSSA, MRSA, MSSE, MRSE
S. pneumoniae (including PRSP)
Streptococcus sp.
Enterococcus sp.
Corynebacterium, Bacillus, Listeria, Actinomyces
Rhodococcus equi
Clostridium sp. (including C. difficile),
Peptococcus, Peptostreptococcus
No activity against gram-negative aerobes or
anaerobes
Vancomycin: Pharmacology
Bactericidal effect except for Enterococcus spp.
Time-dependent bactericidal action
Short PAE effect
Administration: IV, oral (poor oral absorption),
intraperitoneum, intrathecal, intraventricular,
intraocular
Protein binding 30-55%
Poor CSF/aqueous humor penetration
Primarily excrete unchanged by glomerular filtration,
higher clearance in burn patients
Vancomycin: Pharmacology
IV administration
Concentration < 5 mg/ml
Rate < 15 mg/min
Dosage in normal renal function:
30 mg/kg/day divided into 2-4 dosages
Intraperitoneal administration
In CAPD patient, therapeutic serum level can be obtained.
Intrathecal or intraventricular administration
Recommend for treatment of shunt infection/ventriculitis
Dosage: 10-20 mg/day (diluted up to 2 ml in 0.9% NSS;
conc. 2.5-25 mg/ml)
Monitor CSF trough level: 10-20 g/ml
Vancomycin Dosage in Renal Insufficiency
Hemodialysis: 15 mg/kg q 7-10 days
If high-flux membrane is used, 20 mg/kg loading
dose with 500 mg after each dialysis
CVVH: 0.5-1.5 g q 24 hours
CVVHD: 0.8-1.75 g q 24 hours
Renal impairment
Loading dose 15 mg/kg, followed by
Dose (mg/day) = 15.4 x CCr (mL/min)
Loading dose 25 mg/kg, followed by 19 mg/kg at
calculated interval
Interval = normal interval (86 ÷ [0.689 x CCr + 3.66])
Indications for Vancomycin Dosage Monitoring
Concomitantly received another nephrotoxic agents
Receiving high-dose vancomycin
Rapidly changing renal function
Undergoing hemodialysis
Receiving vancomycin for treatment CNS infection
Neonate
Extremely ill patients
Suspected therapeutic failure
Morbid obesity
Burn patient
Optimal Targets
Peak serum concentration
Trough level
Average steady state
30-40 g/ml
10-15 g/ml
15 g/ml
Teicoplanin: Pharmacology
Administration: IV, IM, oral (poor absorption),
intraperitoneum, intrathecal
90% protein binding, highly bound in tissue
Better bone concentration compared to
vancomycin
More active against Streptococci, including
Enterococci than vancomycin
Eliminated by kidney
Teicoplanin: Pharmacology
IV/IM administration
Loading 6 mg/kg q 12 hours x 3 doses then q 24 hours
In S. aureus endocarditis or septic arthritis, and in burn pt.
12 mg/kg q 12 hours x 3 doses then q 24 hours
Intraperitoneal administration
In CAPD patient, therapeutic serum level can be obtained.
20 mg/L in each exchange (4 times daily) x 10 days or for
5 days after bacterial clearance
Intrathecal or intraventricular administration
Dosage: 10-20 mg/day q 24-48 hours
Teicoplanin Dosage in Renal Insufficiency
Hemodialysis: 6-12 mg/kg q 72 hours
CVVHD: 800 mg D1, 400 mg D2 & 3 then
400 mg q 48-72 hours
Renal impairment
CCr 40-60 mL/min: 6-12 mg/kg q 48 hours
Maintenance daily dose = normal dose x
[pt’s CCr/normal CCr]
Extended Interval = normal CCr/pt’s CCr
Indications for Teicoplanin Dosage Monitoring
Receiving high-dose teicoplanin
Rapidly changing renal function
Undergoing CVVHD
Suspected therapeutic failure
Trough level < 20 g/ml is correlated with
treatment failure.
IVDU with endocarditis
Burn patient
Glycopeptides: Adverse Reaction
Ototoxicity
Rare, Reversible
Co-administer with AG augment this event
Vertigo and tinnitus may precede hearing loss
Nephrotoxicity: Vancomycin > Teicoplanin
Rate increase when co-administer with AG
Acute interstitial nephritis has been reported.
Neutropenia, Thrombocytopenia
Thrombophrebitis
Glycopeptides: Adverse Reaction
“Red neck” or “Red man” syndrome
Infusion-related reaction from vancomycin, rarely
from teicoplanin
Anaphylactoid reaction
Rapid onset of erythematous rash and/or pruritus
affecting head, face, neck, and upper trunk with
or without angioedema and hypotension
Probably related to histamine release
Prevention by
• Decreasing infusion rate or concentration
• Using antihistamine (H1 receptor antagonist)
Drug rash, Drug-related fever
Glycopeptides: Drug Interaction
Drug precipitation when mixed with
ceftazidime, heparin, chloramphenicol,
corticosteroid, aminophylline, barbiturate,
diphenylhydantoin, sodium bicarbonate
Anion-exchange resins can bind
vancomycin and decrease activity of
vancomycin in the gut lumen.