Box 2 Amikacin

Drug class Aminoglycoside

Usual dose

15 mg/kg or 1 g (IV) every 24 h* Pharmacokinetic parameters

• Peak serum level: 65-75 mg/mL (q 24 h dosing); 20-30 mg/mL (q 12 h dosing)

• Bioavailability: Not applicable

• Excreted unchanged: 95%

• Serum half-life (normal/end-stage renal disease): 2/50 h

Primary mode of elimination Renal

Comments

Dose for synergy is 7.5 mg/kg (IV) q 24 h or 500 mg (IV) q 24 h. Single daily dosing virtually eliminates nephrotoxic/ototoxic potential.

Therapeutic serum concentrations

Cerebrospinal fluid penetration

• Noninflamed meninges: 15%

Traditional uses Combination therapy for

• Aerobic gram-negative bacilli

Increased/New uses Combination therapy for

• MDR P aeruginosa

• MDR Klebsiella pneumoniae

• MDR Acinetobacter baumannii

• MDR M tuberculosis

* In adults with normal hepatic/renal function, not intolerant/allergic to the drug. Adapted from Cunha BA, editor. Antibiotic essentials. 5th edition. Royal Oak (MI): Physicians' Press; 2006.

Because of the increase over the past decade in MDR P aeruginosa, Kpneu-moniae, and A baumannii strains, there has been renewed interest in and use of colistin and polymyxin B to treat infections due to these highly resistant aerobic gram-negative bacilli (GNB). Based on our current understanding of pharmacokinetics and pharmacodynamics, colistin and polymyxin B have been re-evaluated and dosing regimens optimized. Recent studies indicate that colistin and polymyxin B, dosed properly, have minimal nephrotoxic potential. Both colistin and polymyxin B display concentration-dependent killing kinetics (ie, the higher the dose, the more effective the microbial killing at nontoxic concentrations). Colistin and polymyxin B are increasingly relied on because there are so few antibiotics that have or maintain activity against these MDR GNB. Colistin and polymyxin B are antibiotics with a "low resistance potential'' and argue against the common myth that resistance is inevitable with high volume and prolonged use of all antibiotics [1,3,15,30,32].

Pharmacokinetic principles have guided the determination of optimal dosing regimens for systemic infections in various body compartments. Intrathecal (IT) administration ofcolistin/polymyxin B is given with these antibiotics in full systemic doses. Administration ofcolistin/polymyxin B by the IT route does not lower the seizure threshold and is not epileptogenic [1,29,4651]. To treat peritonitis in patients who have renal failure and chronic ambulatory peritoneal dialysis, intraperitoneal polymyxin B is supplemented with full systemic doses to maintain therapeutic concentrations in intraperitoneal fluid [52]. The uses and applications of colistin and polymyxin B for MDR GNB infections will grow in number (eg, ventilator-associated pneumonia, cystic fibrosis, orthopedic infections) [52-57]. The place of colistin and poly-myxin B in the therapeutic armamentarium is assured, given that virtually no new anti-GNB antibiotics are in development. Few antibiotics are currently available against MDR GNB (eg, tigecycline against extended spectrum b-lactamase-producing K pneumonia, meropenem against MDR P aeruginosa, A baumannii) [15].

When colistin/polymyxin B is used for MDR GNB and synergy may be demonstrated, amikacin is the preferred aminoglycoside in combination therapy. Monotherapy with colistin and polymyxin B is usually used because of their high degree of anti-GNB activity and their "low resistance potential.'' If a nonaminoglycoside is added to colistin or polymyxin B for enhanced activity, rifampin may be synergistic against aerobic MDR GNB [1,2,58-60]. Polymyxin B also inhibits cytokines/endotoxin release from aerobic GNB (Box 3) [15,61].

Doxycycline and minocycline Doxycycline

Doxycycline is effective against a wide variety of microbial pathogens, ranging from rickettsia to parasites [62-80]. Doxycycline is a second-generation extended spectrum tetracycline. It differs from conventional tetracyclines

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