Page 836 - Basic _ Clinical Pharmacology ( PDFDrive )

822 SECTION VIII Chemotherapeutic Drugs

Adverse Effects ■ CHLORAMPHENICOL
Common adverse effects are diarrhea, nausea, and skin rashes.
Impaired liver function (with or without jaundice) and neutro- Crystalline chloramphenicol is a neutral, stable compound with
penia sometimes occur. Administration of clindamycin is a risk the following structure:
factor for diarrhea and colitis due to C difficile. OH CH OH O
2
NO 2 C C N C CHCI 2
■ STREPTOGRAMINS H H H
Chloramphenicol
MECHANISM OF ACTION &
It is soluble in alcohol but poorly soluble in water. Chloram-
ANTIBACTERIAL ACTIVITY phenicol succinate, which is used for parenteral administration,
is highly water-soluble. It is hydrolyzed in vivo with liberation of
Quinupristin-dalfopristin is a combination of two free chloramphenicol.
streptogramins—quinupristin, a streptogramin B, and dalfopris-
tin, a streptogramin A—in a 30:70 ratio. The streptogramins share
the same ribosomal binding site as the macrolides and clindamy- Mechanism of Action & Antimicrobial
cin and thus inhibit protein synthesis in an identical manner. Activity
Quinupristin-dalfopristin is rapidly bactericidal for most suscep- Chloramphenicol is an inhibitor of microbial protein synthesis and
tible organisms except Enterococcus faecium, which is killed slowly. is bacteriostatic against most susceptible organisms. It binds revers-
Quinupristin-dalfopristin is active against Gram-positive cocci, ibly to the 50S subunit of the bacterial ribosome (Figure 44–1)
including multidrug-resistant strains of streptococci, penicillin- and inhibits peptide bond formation (step 2). Chloramphenicol
resistant strains of S pneumoniae, methicillin-susceptible and resis- is a broad-spectrum antibiotic that is active against both aerobic
tant strains of staphylococci, and E faecium (but not Enterococcus and anaerobic Gram-positive and Gram-negative organisms. It is
faecalis). Resistance is due to modification of the quinupristin active also against rickettsiae but not chlamydiae. Most Gram-
binding site (MLS-B type resistance), enzymatic inactivation of positive bacteria are inhibited at concentrations of 1–10 mcg/mL,
dalfopristin, or efflux.
and many Gram-negative bacteria are inhibited by concentrations
of 0.2–5 mcg/mL. H influenzae, Neisseria meningitidis, and some
Pharmacokinetics strains of Bacteroides are highly susceptible; for these organisms,
Quinupristin-dalfopristin is administered intravenously at a chloramphenicol may be bactericidal.
dosage of 7.5 mg/kg every 8–12 hours. Peak serum concentra- Low-level resistance to chloramphenicol may emerge from
tions following an infusion of 7.5 mg/kg over 60 minutes are large populations of chloramphenicol-susceptible cells by selection
3 mcg/mL for quinupristin and 7 mcg/mL for dalfopristin. of mutants that are less permeable to the drug. Clinically signifi-
Quinupristin and dalfopristin are rapidly metabolized, with cant resistance is due to production of chloramphenicol acetyl-
half-lives of 0.85 and 0.7 hours, respectively. Elimination is prin- transferase, a plasmid-encoded enzyme that inactivates the drug.
cipally by the fecal route. Dose adjustment is not necessary for
renal failure, peritoneal dialysis, or hemodialysis. Patients with Pharmacokinetics
hepatic insufficiency may not tolerate the drug at usual doses,
however, because of increased area under the concentration The usual dosage of chloramphenicol is 50–100 mg/kg/d divided
curve of both parent drugs and metabolites. This may neces- every 6 hours. It is no longer available in the USA as an oral for-
sitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg mulation. The parenteral formulation is a prodrug, chlorampheni-
every 8 hours. Quinupristin and dalfopristin significantly inhibit col succinate, which is hydrolyzed to yield free chloramphenicol,
CYP3A4, which metabolizes warfarin, diazepam, quetiapine, giving blood levels somewhat lower than those achieved with
simvastatin, and cyclosporine, among many others. Dosage orally administered drug. Chloramphenicol is widely distributed
reduction of cyclosporine may be necessary. to virtually all tissues and body fluids, including the central ner-
vous system and cerebrospinal fluid, such that the concentration
Clinical Uses & Adverse Effects of chloramphenicol in brain tissue may be equal to that in serum.
The drug penetrates cell membranes readily.
Quinupristin-dalfopristin is approved for treatment of infec- Most of the drug is inactivated either by conjugation with gluc-
tions caused by staphylococci or by vancomycin-resistant strains uronic acid (principally in the liver) or by reduction to inactive
of E faecium, but not E faecalis, which is intrinsically resistant, aryl amines. Active chloramphenicol, about 10% of the total dose
probably because of an efflux-type resistance mechanism. The administered, and its inactive degradation products are eliminated
principal toxicities are infusion-related events, such as pain at the in the urine. A small amount of active drug is excreted into bile
infusion site, and an arthralgia-myalgia syndrome. Quinupristin- and feces. There are no specific dosage adjustments recommended
dalfopristin is used to a limited extent in the USA due to the in renal or hepatic insufficiency; however, the drug will accumu-
availability of better-tolerated alternatives. late and should be used with extra caution in these situations.