Antibiotic Therapy

Sasinuch Rutjanawech, MD
Division of Infectious Diseases
Faculty of Medicine
Thammasat University

The Bacteria

Bacteria
Gram
negative

Gram
positive
cocci
In
cluster

Staphylococcus
Micrococcus

cocci

bacilli
In
chain

Streptococcus
Enterococcus

Spore
forming

Bacillus
Clostridium

Non Spore
forming

Lactobacillus
Listeria
Erysipelothrix
Corynebacterium
Propionebacterium
Mycobacteria
Actinomyces
Nocardia

Neisseria
Moraxella

bacilli

Enteobactericeae
Pseudomonas
Burkholderia
Stenotrophomonas
Vibrio
Aeromonas
Hemophilus
ACEK
Acinetobacter

Overview of Antibiotics

Beta lactam: penicillin, cephalosporin, carbapenem

Beta lactam/ Beta lactamase inhibitor
Aminoglycoside
Quinolone
Colistin
Vancomycin

Sites of Action of Antimicrobial

Agents in Clinical Use

Penicillin
Penicillin G (IV)

Penicillin V (PO)

Gram-positive cocci-most
except staphylococci, penicillin-resistant S.pneumoniae (PRSP)
Gram-positive rods most
Spirochetes

Antistaphylococcal Penicillins
Cloxacillin (IV/PO)

- Drug of Choice for MSSA

- Not active against MRSA

Dicloxacillin (PO)

Broad Spectrum (Amino) Penicillins

Ampicillin (IV, PO) Amoxicillin (PO)
Amino side chains enhances diffusion through porin channels
of gram-negative bacilli
Added activity against :
- Escherichia coli
- Proteus mirabilis
- Haemophilus influenzae
- Salmonella spp.,
- Shigella spp.

Broad Spectrum (Ureido) Penicillins

Piperacillin (IV)
More active against Klebsiella, enterococci, and Bacteroides
Active against P. aeruginosa

Risk Factors For Pseudomonas

aeruginosa Infection

Hospital-acquired infection
Neutropenic patients
Structural lung abnormality
Previous broad spectrum antibiotic within one month
Steroid use (> 10 mg/day of prednisolone)
Hemodialysis
Nursing home reidency

Cephalosporins - First Generation

Cefazolin (IV)

Gram-positive cocci
- except enterococci, MRSA, PRSP
Gram-positive bacilli
- except Listeria

Gram-negative cocci
- except Neisseria

Cephalexin (PO)

Gram-negative bacilli
- E.coli, Proteus mirabilis, Klebsiella
- poor against Haemophilus influenza

Anaerobes
- most except Bacteroides

Cephalosporins - Second Generation

Cefuroxime
Cefamandole

(IV,PO)
(IV)

Cefaclor
(PO)
Cefprozil
(PO)
Loracarbef (PO)

Increased activity against Haemophilus influenzae and

Moraxella catarrhalis

Cephalosporins - Second Generation

(Cephamycin)

Cefoxitin (IV)
Increased activity against Bacteroides spp. and
Neisseria gonorrhea

Cephalosporins - Third Generation

Cefotaxime
Ceftriaxone

(IV)
(IV)

Cefixime (PO)

Highly active against Enterobacteriaceae, Neisseria,

H.influenzae, streptococci

Decreased activity against S. aureus (MSSA)

Not active against enterococci, Listeria, MRSA, P. aeruginosa

Cephalosporins Third Generation

(Anti-Pseudomonal)

Ceftazidime (IV)

Cefoperazone (IV)

Highly active against Enterobacteriaceae, Neisseria spp., and H. influenza

Most active against P. aeruginosa
Decreased activity against Gram-positive bacteria

Cephalosporins Fourth Generation

Cefepime (IV)

Cefpirome (IV)

Gram positive, gramnegative include Pseudomonas

No activity against anaerobes

Anti-Bacterial Spectrum of Cephalosporins

Bacteria

Ceph.1 Ceph.2 Ceph.3a Ceph.3b Ceph.4

Streptococci, Staphylococci

4+

2+/3+

3+

0 /1+

3+

Pen.Resist. S.pneumoniae

3+

MRSA

Enterococcus spp.

2+/4+

3+/4+

4+

4+

4+

0 /1+

1+/2+

3+/4+

2+/3+

4+
3+/4+

3+/4+

Enterobacteriaceae
Community-Acquired
Hospital-Acquired
P. Aeruginos

4+

B. fragilis

0*

Ceph.3a = Cefotaxime, Ceftriaxone

* Cefoxitin

Ceph.3b = Ceftazidime

Carbapenems
Imipenem(+cilastatin) (IV) Meropenem(IV)
Doripenem (IV)
Ertapenem (IV)
Broadest spectrum Gram-positives, Gram-negatives, anaerobes,

Nocardia

Stable to all -lactamases except carbapenemases

No activity to MRSA, Stenotrophomonas , Enterococcus faecium
Drug of choice for ESBL-producing strain

ESBL

One class of beta lactamase

Report only in E.coli, K.pneumoniae, K.oxytoca,

P.mirabilis

Risk factors: hospital-acquired infection, 3rd gen

cephalosporin, quinolones

Carbapenems
Meropenem: approved for treatment of meningitis, less neurotoxicity, more
active against gram negative bacilli

Doripenem: has lower MIC for Pseudomonas, data in prolonged infusion

Imipenem: has activity to Enterococcus faecalis, nephrotoxicity from cilastatin
Ertapenem: narrowest spectrum, not active against Pseudomonas

Organisms Resistant to
Imipenem and Meropenem
Stenotrophomonas maltophilia
Burkholderia cepacia
Enterococcus faecium
MRSA
Diphtheroids

Beta Lactam/ Beta Lactamase

Inhibitor

Amoxicillin/Clavulanic acid (Augmentin)

Ampicillin/ Sulbactam (Unasyn)

Piperacillin/ Tazobactam (Tazocin)

Cefoperazone/ Sulbactam (Sulperazon, Sulcef)

-Lactamase Inhibitors
Clavulanate Sulbactam Tazobactam
Little intrinsic antibacterial activity
Irreversible binding to -lactamases of :
- Staphylococcus aureus
- Haemophilus influenzae
- Neisseria gonorrhoeae
- Bacteroides spp.
- Some Enterobacteriaceae

Rational for Beta-Lactam / BetaLactamase Inhibitor Combination

Beta-Lactamase Enzyme

Bacteria

Beta-Lactam

Rational for Beta-Lactam / BetaLactamase Inhibitor Combination

Beta-Lactamase Enzyme
Beta-Lactamase Inhibitor

Bacteria

Beta-Lactam

Aminoglycoside

Antibacterial activity

rapidly bactericidal against a broad range of

aerobic gram-negative bacilli including P.

aeruginosa

used for combination therapy such as

enterococci and staphylococci with betalactam antibiotics and vancomycin to achieve
synergistic bactericidal activity
Lack activity against anaerobes

Nephrotoxicity

Toxicity

Oto-vestibular toxicity - cochlear and

vestibular bodies of the inner ear
Neuromuscular blockade - interference
of neurotransmission at neuromuscular
junctions

Clinical implication

Combination therapy with other antimicrobial

agents for serious gram-negative bacillary
infections

Mycobacterial infections
Less common pathogens -Yersinia pestis,
Brucella spp, and Francisella tularensis

Clinical implication

Combination with cell-wallactive antibiotics

synergistic bactericidal activity for serious
gram-positive coccal infections
- staphylococcal, enterococcal, streptococcal
endocarditis

Quinolones

Generation
1st

2nd

3rd

Drug Names

Spectrum

nalidixic acid

Gram- but not

Pseudomonas species

norfloxacin
ciprofloxacin
ofloxacin

Gram- (including
Pseudomonas species),
some Gram+ (S. aureus)
and some atypicals

levofloxacin
moxifloxacin

Same as 2nd generation

with extended Gram+ and
atypical coverage

*withdrawn from the market in 1999

Quinolones

Antibacterial activities

Aerobic gram-negative bacilli:

**Enterobacteriaceae and Haemophilus spp.
Gram-negative cocci such as Neisseria spp.
and Moraxella (Branhamella) catarrhalis.

Quinolones

Antibacterial activities

Norfloxacin, ciprofloxacin, and ofloxacin: limited activity against streptococci and

many anaerobes
Ciprofloxacin, ofloxacin, levofloxacin, and moxifloxacin: active against M.
tuberculosis, Mycobacterium fortuitum, Mycobacterium kansasii, and some strains of
Mycobacterium chelonae but fair or poor activity against Mycobacterium aviumintracellulare

Quinolones
Antibacterial activities
Ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin:
active against
- Atypical pneumonias, including Legionella

pneumophila,
Mycoplasma pneumoniae, and Chlamydophila
pneumoniae
- genital pathogens such as Chlamydia trachomatis,
Ureaplasma urealyticum, and Mycoplasma hominis.

Moxifloxacin:
increased potency against anaerobes

Colistin

Polymyxins
Colistin: Polymyxin E
Spectrum of Activity
Narrow spectrum
Most aerobic gram-negative bacilli
including P. aeruginosa &
Acinetobacter spp.

Parenteral colistin
dosing

CCr > 40

150 mg iv q 12 h

CCr 31-40

100 mg iv q 12 h

CCr 21-30

75 mg iv q 12 h

Ccr 11-20

100 mg iv OD

Ccr < 10

75 mg iv OD

*** loading 300 mg not related to Cr Cl

Aerosolized
polymyxins

To improve concentrations of polymyxins in the distal airway

and reduce the systemic toxicity

Dosing 75-300 mg/day of colistin base, q 4-12 h for inhalation

Aerosolized therapy as an adjunct to systemic treatment

appears promising

Current published data; too limited to allow determination

Intrathecal colistin administration

Central nervous system infection

Generally, intravenous treatment with
polymyxins alone is not recommended, since
they are considered to penetrate poorly in
CSF.

Intrathecal use of colistin is a potentially safe,

effective, and viable treatment option for MDR
GNB infection.

Intrathecal colistin administration

Case report
Dosing
Variable doses of intrathecal colistin,
ranging from 1.6 to 20 mg/day (q12-48h)
J Clin Microbiol. 2005;43:4916-7
J Antimicrob Chemother. 2004;54:290-2
Clin Infect Dis. 1999;28:916-7
J Clin Microbiol. 2000;38:3523
J Infect. 2005;50: 348-52

Adverse Effects

Nephrotoxicity (10% - 20%) : ATN

Neurotoxicity (7%) : Dizziness, weakness,

facial paresthesia, vertigo, visual disturbances,
ataxia, confusion, neuromuscular blockade
which can lead to respiratory failure or apnea
Dose dependent & reversible

Adverse Effects

Polymyxins in nebulization

Induce bronchospasm
Other minor symptoms - reported
cough, sore throat, chest tightness

Glycopeptides

Mechanism of Action

Inhibits bacterial cell wall synthesis by

blocking glycopeptide polymerization through
binding tightly to D-alanyl-D-alanine precursor
of the cell wall

Bactericidal

Glycopeptides

Agents

Vancomycin
Teicoplanin

Spectrum of Activity

Gram Positive

Staphylococcus
MRSA
Streptococcus
Enterococcus
Coagulase negative
staphylococcus
No coverage of VRE
Clostridium difficile

Gram Negative

No coverage

VANCOMYCIN

VANCOMYCIN

Constant activity against all common gram-positive

bacteria
- Staphylococci, Streptococci,
Enterococci,Corynebacteria,
Bacillus spp, Listeria monocytogenes, anaerobic cocci,
Actinomyces, and Clostridia
First line treatment for MRSA infection
combination of vancomycin and gentamicin is synergistic
against S. aureus and Enterococci, Streptococci

Pharmacodynamic

Total trough serum vancomycin concentrations

of 1520 mg/L are recommended in S. aureus
infection of
bacteremia
endocarditis
osteomyelitis
meningitis
hospital acquired pneumonia

Pharmacodynamic
In order to achieve rapid attainment
of this target concentration for seriously
ill patients ->
loading dose of 2530 mg/kg
(based on ABW)

Therapeutic monitoring of
vancomycin

Monitoring of trough serum vancomycin

concentrations to reduce nephrotoxicity is
best suited to patients receiving aggressive
dosing
targeted to produce sustained trough drug
concentrations of 1520 mg/L or who
are at high risk of toxicity

Appropriate use of
Vancomycin

Serious infections due to beta-lactam-resistant GP

pathogens
GP infections in patients with serious beta-lactam
allergies
Antibiotic-associated colitis

Toxicity & Adverse

Reaction
-

Fever
Rash
Phlebitis
Neutropenia
Nephrotoxicity
Auditory toxicity
Interstitial nephritis
Infusion-related reactions

Linezolid

Bind to 50S rRNA,

inhibiting protein
synthesis
Bacteriostatic
Used for MRSA and VRE
infections
IV and PO bioavailabilities are similar
May cause dose
dependent, reversible
thrombocytopenia and
anemia

Quinupristin/Dalfopristin

Inhibits protein synthesis

at 50S rRNA
May be bacteriostatic and
cidal
Active against grm +,
including VRE (not E.
fecalis), MRSA
May cause
thrombocytopenia,
hepatitis, injecting site
irritation

Chloramphenicol

Exhibits dose-related bone marrow

suppression
Idiosyncratic aplastic anemia, may be
weeks to months following treatment
(1:30,000 patients)
Grey baby syndrome: Abdominal
distension, flaccidity, cyanosis, shock due
to neonates inability to conjugate drug
Achieves high CSF levels
Low cost and good availability

Tetracyclines

Inhibit protein synthesis at 30S rRNA sub-unit

Bacteriostatic
Have broad spectrum of activity against gram +,
gram -, some anaerobes, spirochetes,
mycoplasmas, chlamydiae, and rickettsiae
May cause depression of skeletal growth and
tooth enamel hypoplasia in children, in addition
to brown/grey discoloration and should not be
used in children under 8

Macrolides

Erythromycin, azithromycin, clarithromycin

Broad spectrum, including activity against
chlamydia, mycoplasma, rickettsia, legionella,
some mycobacteria and actinomycetes
New macrolides are longer lasting, less GI side
effects.
May decrease metabolism of drugs metabolized
by CYP3A subclass of P-450 system. Has led to
ventricular arrhythmias with terfenadine and
astemizole

Clindamycin

Good gram positive and anaerobic

coverage
Good for aspiration pneumonia, intraabdominal infections
Adverse reaction include
rash/hypersensitivity, diarrhea
C. difficile colitis in 0.1 to 10% of patients
treated with Clindamycin

Tigecycline

Mechanism of Action

Inhibits bacterial protein synthesis by binding

the 30S and possibly the 50S ribosomal
subunits

Bacteriostatic

Tigecycline

Spectrum of Activity
Gram Positive
Streptococcus
Staphylococcus including MRSA
Enterococcus including VRE
Covers listeria
Gram Negative
Broad gram negative activity except
Pseudomonas
Providencia
Proteus
ESBL
Atypicals
Legionella
Mycoplasma
Chlamydia
Rickettsia

Trimethoprim-Sulfamethoxazole

Act synergistically to
inhibit bacterial folic
acid synthesis resulting
in decreased nucleotide
synthesis

TMP-SMX cont.

Bacteriostatic
Similar PO/IV bioavailability
Used often for UTIs, PCP, bronchitis, nocardia,
S. maltophilia, toxoplasmosis
Resistance may be occur via export of drug,
over-production of PABA or decreased binding
of drug

Metronidazole

Potent bactericidal agent that lead to

generation of toxic mediates
Used chiefly for anaerobic and protozoan
infections
Well absorbed orally
Rare reversible neutropenia, peripheral
neuropathy, may have metallic taste

Daptomycin

Mechanism of Action

Potassium efflux causing loss of membrane

potential

Bactericidal

Daptomycin

Spectrum of Activity

Gram Positive
Staphylococcus
MRSA
Coagulase negative staphylococcus
Streptococcus
Enterococcus
VRE

Gram Negative

No gram negative coverage