Antibiotics for MDR Pathogens
Dr. Hossein Khalili
Ampicillin/Sulbactam
• First developed and marketed in US in 1987.
• Sulbactam sodium is a derivative of the basic
penicillin nucleus.
• Chemically, sulbactam is sodium penicillinate
sulfone
Dosage Forms
Ampicillin/Sulbactam
• Both agents have similar time-to-peak
plasma concentrations
• Both have similar profile of elimination halftime (∼ 1 h), which supports a 6 – 8 h
i.v./intramuscular dosing schedule
• Optimal application form of 3 – 4 h infusion
Ampicillin/Sulbactam
• High tissue/fluid concentrations, which
exceed the MICs of important bacterial
pathogens, have been demonstrated in
cerebrospinal fluid with sulbactam to
increase ampicillin’s penetration, particularly
in the presence of inflamed meninges
Tissue penetration of
Ampicillin/Sulbactam
• Sufficient penetration in peritoneal fluid,
intestinal mucosa, prostatic and appendiceal
tissue, sputum and peritonsillar abscess pus
has also been shown
Metabolism and elimination
• Half-lifes of both agents are similar and
approximately equal to 1 h.
• They are eliminated primary by urinary
excretion
• Tubular secretion plays a major role in
excretion of sulbactam
Excretion
• Based on half-life, a dosing schedule of 6 – 8
h is indicated for the parenteral route
• Hemodialysis removes 30% of the given
doses of ampicillin-sulbactam, and
supplemental doses are recommended after
dialysis
Pharmacodynamics
• The bacteriological efficacy of β-lactams
agents, and as such of ampicillin-sulbactam,
is particularly dependent on the time (T) that
free serum concentration of the drugs exceed
the MIC for the target pathogen (T > MIC)
• For ampicillin-sulbactam, a T > MIC of 30 –
40% of the dosing interval is required for
maximal bacteriological efficacy against
respiratory pathogens
Ampicillin/Sulbactam Efficacy
• Favorable clinical outcomes have been
reported with ampicillin-sulbactam therapy
in patients with various types of nosocomial
infections caused by MDR A. baumannii,
including ventilator-associated pneumonia,
bactaeremia, meningitis and UTIs.
Ampicillin/Sulbactam ADRs
• Other adverse reactions were skin disorders
(1.2%), diarrhoea (1.6%) and minor increase
in serum transaminase levels (serum
aspartate aminotransferase, 6.2%; serum
alanine aminotransferase, 6.9%)
Ampicillin Sodium and Sulbactam
Sodium
• Administer by slow IV injection, IV infusion or
by IM injection
Ampicillin-Sulbactam Adminestration
• Reconstitution and Dilution IV solutions are
prepared by reconstituting vials containing
1.5 or 3 g of combined ampicillin and
sulbactam with sterile water for injection to
provide solutions containing 375 mg/mL (250
mg of ampicillin and 125 mg of sulbactam per
mL)
Ampicillin-Sulbactam Adminestration
• An appropriate volume of the reconstituted
solution should then be immediately diluted
with a compatible IV solution to yield
solutions containing 3–45 mg/mL (2–30 mg
of ampicillin and 1–15 mg of sulbactam per
mL)
Ampicillin Sodium and Sulbactam
Sodium
• For IV injection, given slowly over a period of
≥10–15 minutes.
• IV infusions should be infused slowly over
15–30 min
Ampicillin Sodium and Sulbactam
Sodium
• Reconstitution IM solutions are prepared by
reconstituting vials containing 1.5 or 3 g of
combined ampicillin and sulbactam with 3.2
or 6.4 mL, respectively, of sterile water for
injection or 0.5 or 2% lidocaine hydrochloride
injection to provide a solution containing 375
mg of the drug per mL (250 mg of ampicillin
and 125 mg of sulbactam per mL).
Renal Impairment
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Clcr ≥30 ml/min: No dose adjustment
Clcr 15–29 ml/min: Dose every 12h
Clcr 5–14 ml/min: Dose every 24 h
In hemodialysis dose should preferably be
given immediately after dialysis
Hepatic Impairment
• No dose adjustment
Maximum Dose of Sulbactam
• For the treatment of less-susceptible
pathogens, the dosage regimen of sulbactam
should be increased to a 4-h infusion of 3 g
q8h.
• However, the prolonged infusion of 4 g of
sulbactam q8h and the continuous infusion
of 12 g sulbactam q24h did not achieve
higher PTAs than a prolonged infusion of 3 g
of sulbactam q8h
Colistin (polymyxin E1 and E2)
• Colistin methanesulfonate (CMS) also known
as colistimethate (for intravenous,
intramuscular, intraventricular, intrathecal
and inhalation use)
• Colistin sulfate (used for topical and
inhalation purposes)
Colistin Dosage Forms
Colistin Dosage Forms
Colistin Dosage Forms
Colistin Dosage Forms
Colistin
• Colistin binds to lipopolysaccharide moieties
of cell membrane of Gram-negative bacteria,
changes cell membrane permeability and
displaces divalent cations
• Colistin also has antitoxin and anti-biofilm
activity
Excretion
• Approximately 60–70% of CMS is cleared
unchanged by kidney through glomerular
filtration and tubular secretion
• Colistin base is eliminated through unknown,
non-renal pathways
Colistin Pharmacokinetic
• Pharmacokinetic study in healthy volunteers
showed that (30%) of parent drug is
metabolized to its active form, colistin
• Therefore, non-renal clearance may be
important in patients with renal failure.
Colistin Pharmacokinetic
• Steady state serum concentration is achieved
about 60 h after conventional dosing
methods
• To attain rapid steady state, loading dose is
required (i.e., 9–12 million international units
[MIU]
Colistin Pharmacokinetic
Terminal half-lives:
• 2.3–11h:CMS
• 9.1–14.4h: Colistin
Colistin Pharmacokinetic
• Colistin exerts concentration-dependent
activity against P. aeruginosa and A.
baumannii
• Modest post-antibiotic effect against P.
aeruginosa is only seen at high serum colistin
concentrations
Dosing
• Colomycin and Coly-Mycin M are two main
commercially available forms of CMS
• Colomycin package insert recommends a
dose of 1–2 MU of CMS every 8 h
• While Coly-Mycin M recommends 2.5–5
mg/kg of colistin base per day.
Dose equivalent
• Each one MIU of CMS equals to 80 mg CMS
and about 30 mg colistin base
• 1 MU CMS = 80 mg CMS = 30 mg CBA
Colistin Base activity equivalent
• 1 mg of CMS =12,500 IU
• 1 mg of colistin = 32,500 IU (30,000IU)
Colistin
• The recommended dosages are 2.5–5.0
mg/kg per day of colistin base given in 2–4
divided doses
• OR 6.67–13.3 mg/kg per day of CMS)
For MDR pathogens and severe
infections
-A loading: 9 MIU loading
-Maintenance Dose: 4.5 MIU twice-daily doses
of CMS starting 12 h after
Colistin-induced nephrotoxicity
• Incidence: from 0 to 54%
• Mean times to happen colistin AKI were
different; however, most cases happened
within the first 2 weeks of drug
administration
Colistin induced neurotoxicity
• Colistin interacts with lipid contents of
neurons and may subsequently cause
paresthesia, vertigo, visual disturbances,
hallucinations, mental confusion, ataxia or
seizures
Colistin induced neurotoxicity
• The most important neurotoxicity of colistin
is neuromuscular blockade that may induce
apnea.
• It may occur due to inhibition of
acetylcholine release or interfere with
acetylcholine receptors and calcium
depletion
• In recent studies colistin neurotoxicities have
been reported in less than 6% of participants
IV Administration
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Powder for IV injection
Reconstituted with 2ml SW
Slow IV injection (3-5 minutes)
Short IV Infusion (30-60 minutes)
IM?
Compatible with all IV Fluids
Inhalation
• Although not approved, CMS intravenous
formulation are widely dissolved in 4–6 ml of
isotonic saline or sterile water for injection
and administered as nebulized form
• More commonly used dose is 1–2 MIU every
8h
Different Dosing Methods
• 3 MIU every 8 h
• 4.5 MIU every 12 h
• 9 MIU every 24 h
Renal Dose Adjustment
• Serum creatinine level 1.3–1.5 mg/dl: 2 MIU
(160 mg) of CMS every 8 h
• Serum creatinine level 1.6–2.5 mg/dl: 2 MIU
(160 mg) of CMS every 12 h
• Serum creatinine level ≥2.6 mg/dl: 2 MIU (160
mg) of CMS every 24 h
• 2 MIU (160 mg) of CMS after each hemodialysis
• 2 MIU (160 mg) of CMS daily during peritoneal
dialysis
Renal Dose Adjustment of high dose
colistin
Method of administration of
Antibiotics
• Concentration dependent antibiotics:
Aminoglycosides, Colistin
• Time dependent antibiotics: Beta-lactams
Once-daily dosing of Antibiotics
• Aminoglycosides (Level of evidence B)
• Colistin (less PAE)???
Continuous infusion of Antibiotics
• Pipracillin-Tazobactam (The most evidencebased, B)
• Meropenem (level of evidence, C)
• Ampicillin-Sulbactam (level of evidence, C)
• Imipenem???
• Continuous infusion method (24h or 3-4h)?
Continuous infusion and Resistance
• It is unknown whether the use of extendedinfusion carbapenems will reduce the
emergence of antibiotic resistance in
Acinetobacter
• however, promising results exist for
Pseudomonas aeruginosa
IT /IV Antibiotics
Antibiotic
Vancomycin
Gentamicin
Amikacin
Colistin
Dose
5-20mg
4-8mg
15-50mg
10mg (125000500,000)
Amphotericin 0.1-0.5 mg
Aerosolized Antibiotics
Vancomycin Dosing
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Concentration or time dependent antibiotic?
AUC/MIC>400
Trough or Peak level?
Trough 10-15 or 15-20 mg/l?
Dose 15mg/kg every 8 or 12 h?
Continuous or intermittent infusion?
Sanford 2010 & Aronoff 2007
• Vancomycin:
normal renal
function
ClCr:50-90
1 g q 12h 1 g q 12h
ClCr:10-50 < 10
1 g q 24-96h
Hemodialysi
s, CAPD
Comments
1 g q 4-7 Dose for ClCr
days < 10
New
Hemodialysi
s
membranes
increase
Clearance:
Check level
Vancomycin Dose Adjustment
• Sanford 2012:
Normal Renal Function
1 g q 12h
CrCl: 50-90
15-30 mg/kg q 12h
CrCl: 10-50
15 mg/kg q 24-96h
CrCl < 10
7.5 mg/kg q 2-3 days
Hemodialysis
7.5 mg/kg q 2-3 days