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 half-time (∼ 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 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 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 8 h

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 evidence-based, 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 extended-infusion carbapenems will reduce the emergence of antibiotic resistance in Acinetobacter however, promising results exist for Pseudomonas aeruginosa

IT /IV Antibiotics Antibiotic Dose Vancomycin 5-20mg Gentamicin 4-8mg Amikacin 15-50mg Colistin 10mg (125000-500,000) Amphotericin 0.1-0.5 mg

Aerosolized Antibiotics

Vancomycin Dosing 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 ClCr:10-50 < 10 Hemodialysis, CAPD Comments 1 g q 12h 1 g q 24-96h 1 g q 4-7 days Dose for ClCr < 10 New Hemodialysis 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