Published
October 15, 2002
Morton
P.
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Newer
Antibacterial Agents: Linezolid
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The feature that distinguishes linezolid (Zyvox) and quinupristin/dalfopristin (Synercid) from other antibiotics is their activity against vancomycin-resistant enterococci (VRE). In addition, either linezolid or quinupristin/dalfopristin may serve as an alternative agent for patients who are intolerant of standard antibiotics and infected with staphylococci or streptococci. The drugs are quite different from one another, particularly in their side effects. Both are quite costly. Table 1 summarizes important distinguishing characteristics.
Linezolid is a member of the oxazolidinone class of antimicrobials. Both quinupristin and dalfopristin are streptogramin antibiotics. They are thus structurally related to macrolides like erythromycin and to lincosamides like clindamycin. The ratio of quinupristin to dalfopristin in Synercid is 30:70.
Linezolid and quinupristin/dalfopristin are active at the level of the 50S portion of the bacterial ribosome, but they bind at different sites on the ribosome. Each drug by itself is bacteriostatic, but because quinupristin and dalfopristin bind at sequential sites on the 50S ribosomal subunit, their combined effect is bactericidal for some organisms. Resistance can develop to both linezolid and quinupristin/dalfopristin through changes at the 23S ribosomal level, and additional mechanisms of resistance have been described for quinupristin/dalfopristin. When the macrolide-lincosamide-streptogramin (MLSb) gene is acquired, the 23S ribosome is methylated, conferring resistance to quinupristin and leading to bacteriostatic activity.
The spectrum of action of linezolid and quinupristin/dalfopristin against gram-positive cocci is similar with one exception. Both are active against staphylococcal species, including methicillin-resistant staphylococci. Likewise, both are active against streptococci. The difference is in the enterococcal group: both linezolid and quinupristin/dalfopristin are active against Enterococcus faecium, but only linezolid is active against E faecalis. VRE are almost always E faecium.
The oral absorption of quinupristin/dalfopristin is negligible. Linezolid, on the other hand, is nearly 100% bioavailable. Linezolid undergoes oxidative metabolism, resulting in two inactive compounds that are excreted in the urine. There are three active metabolites of quinupristin/dalfopristin, all of which are excreted in the bile and feces. In general, the dose of neither drug requires adjustment for patients with renal or hepatic dysfunction.
There are distinct patterns of clinical and laboratory-related adverse reactions associated with each antibiotic in this group. Quinupristin/dalfopristin frequently causes phlebitis when administered through a peripheral vein. Patients receiving quinupristin/dalfopristin may develop arthralgias and myalgias, with reported rates varying from 5% to more than 50%. Linezolid use may be associated with nausea, vomiting, and headaches. In terms of laboratory abnormalities, quinupristin/dalfopristin has been associated with asymptomatic hyperbilirubinemia and elevated hepatic function enzymes, while linezolid is more commonly associated with thrombocytopenia and other hematopoietic disorders. Close monitoring of the complete blood cell count is recommended for patients receiving more than 2 weeks of linezolid therapy.
Because linezolid is a weak monoamine oxidase inhibitor, concomitant use with adrenergic or seratonergic agents may result in hypertensive reactions. Administration of quinupristin/dalfopristin, as an inhibitor of the cytochrome P-450 3A4 enzymatic pathway, may result in elevated levels of substrate drugs such as cyclosporine, nifedipine, midazolam, and terfenidine. These drugs should be avoided, or their levels closely monitored, when quinupristin/dalfopristin is coadministered. Considerations related to drug infusion, including physical incompatibilities, are summarized in Table 1.
The primary use for both linezolid and quinupristin/dalfopristin is in the treatment of infections caused by VRE. As noted above, they may also serve as substitutes for standard antibiotics for antibiotic-intolerant patients with infections caused by other gram-positive cocci. Patient characteristics (such as the presence of preexisting hematologic or hepatic abnormalities), the specific target organism(s), and the site of the infection help to guide antibiotic selection.
The availability of effective antimicrobials for prophylaxis and treatment of Herpes simplex virus, Herpes varicella zoster virus, and cytomegalovirus (CMV) infections has had a notable impact on the care of immunosuppressed patients. The most recent addition to this group, valganciclovir (Valcyte), is an oral prodrug of ganciclovir. The characteristics of valganciclovir are compared with those of parenteral ganciclovir (Cytovene-IV) and oral ganciclovir (Cytovene) in Table 2.
Ganciclovir is a nucleoside guanine analogue that is preferentially phosphorylated in CMV virions. It inhibits viral DNA synthesis through competition with naturally occurring guanine in the replication cycle. Valganciclovir is an ester of ganciclovir that is rapidly absorbed and hydrolyzed to ganciclovir after oral administration. The serum levels of ganciclovir achieved with valganciclovir use are fourfold higher than those with oral ganciclovir because of valganciclovir's superior oral bioavailability. Because the hematologic side effects of ganciclovir are in+ part dose-dependent and the drug is renally excreted, doses of valganciclovir and both forms of ganciclovir must be reduced in patients with renal dysfunction.
Valganciclovir was approved by the US Food and Drug Administration (FDA) for a single indication: treatment of CMV retinitis in patients with acquired immunodeficiency syndrome. Although retinitis is the official indication, the drug is used to treat CMV infections at all sites.
Two new antifungal agents have recently been added to the existing armamentarium of amphotericin, lipid amphotericin products, itraconazole, and fluconazole for treating severe fungal infections. Voriconazole (Vfend) is new triazole antifungal, which recently received FDA approval. Caspofungin (Cancidas), approved by the FDA in 2001, was the first echinocandin available in the United States.
The echinocandins prevent fungal cell-wall formation by 1,3-ß-D-glucan synthase. This enzyme forms glucan polymers in the fungal cell wall; inhibition prevents glucose incorporation into glucan.
Caspofungin is active against Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus. Furthermore, the following Candida species are susceptible to caspofungin: C albicans, C glabrata, and C tropicalis, including azole-susceptible and azole-resistant strains. C krusei, C parapsilosis, and C lusitaniae may have higher minimal inhibitor concentrations, but still remain susceptible to caspofungin. Caspofungin has in-vitro activity against Pneumocystis carinii and Histoplasma capsulatum. However, it is not active against Cryptococcus.
Caspofungin is poorly absorbed and available only in an intravenous preparation. It is highly protein-bound and metabolized by hydrolysis and N-acetylation. Caspofungin and its metabolites are excreted in the feces and urine, with approximately 1.4% excreted unchanged.
Caspofungin appears to be well tolerated and has few drug interactions (Table 3). The combination of caspofungin and cyclosporine is contraindicated due to risk of hepatotoxicity secondary to inhibition of caspofungin metabolism by cyclosporine. Caspofungin decreases tacrolimus by approximately 30%; therefore, levels should be closely monitored.
Voriconazole is a new triazole antifungal with a mechanism of action similar to that of fluconazole and itraconazole. Like itraconazole, voriconazole is active against Aspergillus sp. Voriconazole has in-vitro activity against C albicans, C parapsilosis, C tropicalis, and C krusei. Voriconazole may be active against Cryptococcus sp, the endemic fungi (eg, Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis), and Fusarium sp.
Voriconazole has excellent oral bioavailability and will be available both orally and intravenously. Like other azoles, it is metabolized by the cytochrome P-450 system; therefore, the potential exists for interactions with medications also metabolized by this system. Voriconazole displays nonlinear pharmacokinetics and may accumulate up to eightfold after multiple dosing as a result of saturation of its own metabolism. The main adverse effects with voriconazole appear to be transient visual changes, dose-related increases in liver function test results, and rash.
Few published trials are available for these two agents. Both have been studied in noncomparative trials in patients with invasive aspergillosis who are intolerant or refractory to standard therapy. Voriconazole has also been compared to amphotericin as primary therapy of invasive aspergillosis. Further studies are needed to define their role in the treatment of Candida infections and their use in combination with other antifungals. As further studies are performed, more information regarding adverse effects and drug interactions will also become available.
Nalidixic acid, discovered in 1962 by Lescher and colleagues, was the first in the fluoroquinolone class. The agents of this class have a broad spectrum of antimicrobial activity, good bioavailability, excellent penetration into tissues, and long serum half-lives. Older fluoroquinolone agents (eg, ciprofloxacin, ofloxacin) developed marked resistance to gram-positive organisms, and the utility of these agents is limited to treating gram-negative infections. In recent years, several newer fluoroquinolones have come to market. These agents differ in their spectrum of activity and therefore their clinical applications.
Levofloxacin (Levaquin), gatifloxacin (Tequin), and moxifloxacin (Avelox) have been referred to as second-, third- or next-generation fluoroquinolones. The new fluoroquinolones exhibit increased activity against gram-positive organisms compared with ciprofloxacin, including excellent activity against pneumococci, even penicillin-resistant strains. The newer agents have comparable activity against gram-negative organisms; however, they demonstrate slightly lower activity than ciprofloxacin for Pseudomonas aeruginosa. Gatifloxacin and moxifloxacin appear to have some anaerobic coverage. All fluoroquinolone agents have similar activity against the atypical respiratory pathogens, (eg, Mycoplasma pneumoniae, C pneumoniae, Legionella pneumophila). Most strains of Neisseria gonorrhoeae and C trachomatis are susceptible to fluoroquinolones. The new fluoroquinolones also appear to have some activity against certain mycobacteria.
Fluoroquinolones inhibit bacterial DNA gyrase (topoisomerase II), resulting in inhibition of DNA replication, recombination, and transcription. The newer agents also bind to topoisomerase IV, an enzyme involved in the separation of interlinked chromosomes after replication. Topoisomerase IV appears to be the primary target of newer fluoroquinolones in gram-positive organisms, thereby explaining their increased activity compared to ciprofloxacin.
The most common mechanism of resistance to quinolones is due to chromosomal mutations of DNA gyrase and topoisomerase IV. Decreased cell-membrane permeability also plays a role in the development of resistance. Cross-resistance is seen among fluoroquinolones, particularly in gram-negative bacteria. Most ciprofloxacin-resistant pneumococci, however, remain susceptible to the new fluoroquinolones. In-vitro studies have demonstrated that fluoroquinolones with a methoxy group at C-8 (moxifloxacin and gatifloxacin) have a decreased propensity for development of resistance.
The pharmacokinetic parameters of selected fluoroquinolones are listed in Table 4.
| Table 4: | ||||
Pharmacokinetic
Parameters of Selected Fluoroquinolones |
||||
Quinolone |
Oral
Bioavailablity % |
Cmax (mg/L) |
Half-life
(h) |
% Excreted Unchanged in Urine |
| Ciprofloxacin (Cipro) |
70 |
2.5 |
4 |
40 |
| Gatifloxacin (Tequin) |
96 |
4.2 |
8 |
70 |
| Levofloxacin (Levaquin) |
99 |
5.1 |
7 |
87 |
| Moxifloxacin (Avelox) | 90 |
4.5 |
12 |
20 |
The fluoroquinolones have been reported to cause mild gastrointestinal adverse effects, central nervous system effects, skin reactions, tendon rupture, and arthropathies and osteochondrosis in juvenile animals. The FDA requires product information for new quinolones to include a statement regarding the possibility of QTc prolongation. Levofloxacin and gatifloxacin do not appear to prolong the QTc interval. It is estimated that 15 cases of QT-related ventricular arrhythmias per 10 million patients treated with levofloxacin would occur. Additionally, two cases of torsades de pointes per 1.2 million patients treated with gatifloxacin and nine cases of torsades de pointes per 10 million patients treated with ciprofloxacin are estimated. Moxifloxacin prolongs the QTc interval to a greater degree than other currently marketed quinolones, but the clinical significance is unknown. Significant phototoxicity with the newer agents has not been reported. Hepatotoxicity has not been reported to date with moxifloxacin, gatifloxacin, or levofloxacin, unlike with trovafloxacin.
Levofloxacin, gatifloxacin, and moxifloxacin do not appear to have clinically significant interactions with drugs metabolized via cytochrome P-450. Divalent or trivalent cations may reduce the oral absorption of quinolones. Agents that prolong the QTc interval could have additive toxicities with gatifloxacin or moxifloxacin. (See Table 5). Table 6 provides dosage and administration information.
Ertapenem (Invanz) is a new intravenously administered carbapenem that can be administered once daily. Like the other agents in its class, ertapenem has activity against a wide range of microorganisms that include gram-positive cocci, gram-negative bacilli, and anaerobes; however, it is not active against P aeruginosa or enterococci. It is indicated in the treatment of adult patients with complicated intra-abdominal infections, acute pelvic infections (including postpartum endometritis, septic abortion, and postsurgical gynecologic infections), complicated skin and skin structure infections, community-acquired pneumonia, and complicated urinary tract infections. The major advantage of ertapenem is the 1-gram-once-daily dosing regimen. This agent is not approved for any pediatric indication. A comparison of properties of the available carbapenems can be found in Table 8.
Amoxicillin/clavulanate (Augmentin), a beta-lactam/beta-lactamase inhibitor combination, is indicated for the treatment of lower respiratory tract infections, otitis media, sinusitis, skin and skin structure infections, and urinary tract infections. Dosing becomes confusing with the wide variety of dosage forms and variety of dosing schedules. The newest form is a 600-mg suspension for every-12-hour dosing. Table 9 outlines these dosage forms and clarifies the ability for interchange.
Four macrolides are available on the US market: erythromycin, clarithromycin, azithromycin, and dirithromycin. These agents work by inhibiting RNA-dependent protein synthesis at the chain elongation step, binding to the 50S ribosomal subunit, resulting in blockage of transpeptidation. Macrolides have activity against many gram-positive bacteria (excluding enterococci and methicillin-resistant Staphylococcus aureus), and have variable activity against respiratory gram-negative pathogens, Mycobacterium avium infections, gonorrhea, and Chlamydia infections. Significant cytochrome P-450 metabolic drug interactions occur with the macrolides, but to a minor extent with azithromycin. Additional features of this class are outlined in Table 10. Of note is a new once-a-day dosage form of clarithromycin (Biaxin XL).
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