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Fosfomycin Tromethamine

Interest in oral antibiotics has been renewed, and a number of factors have contributed to this. Various “negative” features are associated with infusion of an antibiotic (discomfort, restriction, phlebitis, bacteremia, excess fluid administration, and cost), and the new oral antimicrobial agents offer excellent absorption. The “pressure” to provide cost effective treatment has influenced clinicians to reconsider their practice patterns, and physicians have recently observed that oral antibiotic treatment (either initially or as a follow-up to IV infusion) is effective management for patients with such infections as chronic osteomyelitis, pyelonephritis, and community-acquired pneumonia, disorders previously considered indications for exclusively parenteral treatment.
This chapter explores specific themes that relate to the new oral antibiotics. Why does a need exist to develop new antibiotics? What factors must be considered when an oral antibiotic is selected? What have we learned concerning patient compliance? What are the clinically meaningful differences between the newer FDA-approved compounds, and what are their advantages and/or limitations? An effort will be made to examine critically the following newer compounds: cephalosporins, loracarbef, macrolides/azalide, fluoroquinolones, and fosfomycin tromethamine.
New antimicrobial agents need to be developed for several reasons: drug allergy, untoward events attributed to available compounds, the potential for drug-drug interactions, the discovery of new pathogens, limited present therapeutic options, and bacterial resistance. During the last few years, researchers have identified numerous novel infectious organisms, including hepatitis G virus, Chlamydia-like microorganism Z, Legionella-like amebal pathogens (LLAPs), Ehrlichia species, and Bartonella species. In addition, there are serious concerns worldwide about the emerging antimicrobial resistance of numerous bacteria, including Streptococcus pneumoniae, Enterococcus species, gram-negative bacilli, and Mycobacterium tuberculosis. Recently, quinolone-resistant Escherichia coli, gonococci, and Campylobacter, multidrug-resistant Salmonella typhimurium, and methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility have all been recognized.
Some of the most important features of an oral drug that influence the selection process include efficacy, track record of safety, potential for drug-drug interactions, compliance concerns, safety during pregnancy, and cost. Although numerous studies have evaluated additional features of antibiotics, such as protein binding, post-antibiotic effect, and bactericidal-bacteriostatic status, it has been difficult to relate these characteristics to the therapeutic efficacy of each compound in the clinical arena.
A frequent observation is the failure of patients to comply with an oral medication regimen. Numerous patients do not follow the medication schedule, do not complete the course of therapy, or inform their physician that they have not taken the medication as recommended. Researchers have consistently demonstrated that patient compliance is enhanced when oral antibiotics are prescribed to be taken no more frequently than twice a day. Each of the new compounds reviewed in this article (cephalosporins, loracarbef, macrolides, azalide, fluoroquinolones, and fosfomycin tromethamine) achieves this goal.
Three new cephalosporin compounds have been approved by the FDA for clinical administration. These drugs are cefprozil (Cefzil), cefpodoxime (Vantin), and ceftibuten (Cedax). They are indicated for the treatment of otitis media, streptococcal pharyngitis/tonsillitis, and exacerbation of chronic bronchitis by susceptible strains of bacteria.
Cefprozil, prescribed as 500 mg taken twice daily, is also approved for the management of acute maxillary sinusitis. Ceftibuten is prescribed as 400 mg taken once a day or as 200 mg taken twice daily. Cefpodoxime is prescribed as 200 mg taken twice daily and is FDA-approved for the management of gonococcal urethritis and community-acquired pneumonia caused by susceptible strains of S. pneumoniae and Haemophilus influenzae. Cefpodoxime rivals cefixime as an effective single-dose therapy for the patient with uncomplicated cervicitis or urethritis caused by Neisseria gonorrhoeae. The most common untoward event attributed to these safe compounds is diarrhea. These three cephalosporins do not, however, appear to add any unique feature or advantage to the present antibiotic arsenal and cannot be recommended as initial treatment of any established infection. They should not be prescribed for the patient who has experienced an immediate or accelerated hypersensitivity reaction to a member of the penicillin or cephalosporin family of drugs.
FDA approval has recently been given to a new, extended-spectrum oral cephalosporin, cefdinir, a compound that inhibits the growth of three bacterial respiratory pathogens: S. pneumoniae, H. influenzae, and Moraxella (Branhamella) catarrhalis. Cefdinir is a safe, effective treatment for patients with acute community-acquired sinusitis, exacerbation of chronic bronchitis, and community-acquired pneumonia. The most common untoward event attributed to this compound is diarrhea.
Loracarbef (Lorabid), technically a carbacephem, is a b-lactam antibiotic that resembles a cephalosporin and has a spectrum of activity similar to that of cefaclor and cefuroxime. Loracarbef is FDA-approved for the treatment of otitis media, sinusitis, exacerbation of chronic bronchitis, community-acquired pneumonia, streptococcal pharyngitis/tonsillitis, skin infections, and uncomplicated urinary tract infections caused by susceptible pathogens.
The compound, which is prescribed as 200 mg taken twice daily, is a safe agent. The major untoward events produced by loracarbef are headache and diarrhea. This drug is not indicated for the penicillin-allergic patient, and it is not appropriate therapy for the patient with pneumonia caused by Legionella species, Mycoplasma pneumoniae, or Chlamydia pneumoniae.
Loracarbef is an expensive compound that is comparable in therapeutic efficacy to traditional agents, and thus it does not appear to be the preferred treatment for any established infection.
The new macrolides (clarithromycin, dirithromycin) and azalide (azithromycin) offer a therapeutic advance in comparison with erythromycin. The newer compounds require less frequent dosing, are better tolerated, and have expanded indications. They are, however, considerably more expensive.
Dirithromycin (Dynabac) is taken once a day, but because this macrolide does not inhibit the growth of H. influenzae, its empiric administration to patients with an exacerbation of chronic bronchitis or community-acquired pneumonia is severely restricted.

Clarithromycin (Biaxin) and azithromycin (Zithromax) are FDA-approved for the treatment of streptococcal pharyngitis/tonsillitis (disorders for which penicillin is the drug of choice), acute exacerbation of chronic bronchitis, community-acquired pneumonia, and uncomplicated skin infections caused by susceptible pathogens. In addition, each of these compounds is appropriate prophylaxis for disseminated infection with Mycobacterium avium complex in the severely immunocompromised, HIV-infected patient.
Azithromycin is also an effective treatment for patients with Chlamydia trachomatis-related urethritis/cervicitis, genital ulcer disease caused by Haemophilus ducreyi, and moderate or severe shigellosis caused by multidrug-resistant Shigella strains. Azithromycin should not be taken with food. Azithromycin has two particularly desirable features. Treatment durations, compared with those of traditional drug courses, can be abbreviated, and this compound, unlike clarithromycin and erythromycin, does not appear to have a potential for drug-drug interaction. Of interest, because of the possibility of a role of C. pneumoniae in the pathogenesis of coronary artery disease, azithromycin is being evaluated to determine its ability to interfere with the development of coronary artery disease.
In contrast to azithromycin, clarithromycin can be ingested with food, and it has been approved to treat acute maxillary sinusitis and, in conjunction with additional agents, disseminated M. avium complex infection in AIDS patients and peptic ulcer disease caused by Helicobacter pylori. Clarithromycin appears to be the preferred compound to treat patients with cutaneous, disseminated Mycobacterium chelonei infections. Unfortunately, however, clarithromycin has the potential to precipitate drug-drug interactions when it is coadministered with cisapride, digoxin, carbamezepine, ergotamine, theophylline, terfenadine, astemizole, cyclosporine, felodipine, warfarin, and buspirone.
The fluoroquinolones have held a great appeal for clinicians for various reasons: These compounds have a broad spectrum of activity, are bactericidal, are administered infrequently, can be prescribed to penicillin-allergic patients, are safe, rarely cause antimicrobial-related C. difficile pseudomembranous colitis, and constitute effective treatment for a wide range of infections.
Prime indications for treatment with fluoroquinolones include chronic bacterial prostatitis, complicated urinary tract infection, bacterial enterocolitis, and gram-negative osteomyelitis. Additional unique indications for the use of fluoroquinolones include the prevention of spontaneous bacterial peritonitis and the treatment of an acute infectious exacerbation superimposed on cystic fibrosis. In combination with additional antibiotics, fluoroquinolones have been prescribed to treat selected outpatients with pelvic inflammatory disease or with solid tumors complicated by fever and neutropenia. The fluoroquinolones have also been widely used as therapy for patients with respiratory tract infections and urinary tract infections.
Four new fluoroquinolones have recently been marketed: sparfloxacin (Zagam), levofloxacin (Levaquin), grepafloxacin (Raxar), and trovafloxacin (Trovan). Sparfloxacin has been approved by the FDA for the management of community-acquired pneumonia and exacerbation of chronic bronchitis. Levofloxacin is FDA-approved for these indications and also for the treatment of acute maxillary sinusitis, skin infections, and urinary tract infections. Each of these compounds is prescribed to be taken once a day, does not interact with theophylline (in contrast to some other fluoroquinolones), and possesses activity against some penicillin-resistant S. pneumoniae. In addition, both compounds inhibit the growth of “traditional” bacterial respiratory pathogens, as well as the growth of what are occasionally referred to as “atypical” pathogens namely, Legionella species, C. pneumoniae, and M. pneumoniae.
Certain features of these two new fluoroquinolones distinguish them further. Levofloxacin is available for IV as well as oral administration. Sparfloxacin has the potential to produce severe and protracted phototoxicity, and this compound can increase the risk for arrhythmias, such as torsade de pointes, when prescribed with selected antiarrhythmic agents. It would thus appear that levofloxacin is the preferred agent, particularly when patients receive disopyramide, amiodarone, quinidine, procainamide, sotalol, and bepridil. Sparfloxacin should not be used in patients with known QTc prolongation or in patients receiving QTc-prolonging drugs. Levofloxacin dosage requires adjustment in patients with renal compromise.
Grepafloxicin has a spectrum of activity similar to that of the other quinolones, but it does display enhanced activity, in comparison with ciprofloxacin, against S. pneumoniae. Grepafloxacin is administered once a day and is an effective treatment for patients with lower respiratory tract infections caused by traditional respiratory pathogens and in patients with gonococcal/chlamydial urethritis and cervicitis. The most common untoward event produced by this medication is nausea. Grepafloxicin is contraindicated for patients who have hepatic failure, in whom the QTc interval is prolonged, or who are receiving QTc-prolonging drugs.
Trovafloxacin (Trovan), another fluoroquinolone, is available as both an IV and an oral preparation. Compared with ciprofloxacin, trovafloxacin exhibits enhanced in vitro activity against staphylococci, streptococci, penicillin-resistant S. pneumoniae, Bacteroides, Clostridium, and C. trachomatis. This compound has been noted to be an effective treatment for upper and lower respiratory tract infections and uncomplicated urinary tract infections caused by traditional bacterial pathogens, and for genital infections caused by N. gonorrhoeae and C. trachomatis. The main untoward event produced by this drug is dizziness. Because trovafloxacin can produce dizziness, it is probably contraindicated for people who must operate heavy machinery, drive a car, or engage in activities that require mental alertness and coordination. A desirable feature of the drug is that its absorption is not altered by concomitant food intake or concurrent enteral feeding. Furthermore, dose reduction is not required in cases of renal insufficiency, and drug interactions do not occur when the drug is given concomitantly with cimetidine, theophylline, digoxin, warfarin, or cyclosporine. Finally, photoxicity rarely occurs.
Fosfomycin Tromethamine
Fosfomycin tromethamine (Monuril) is a phosphoric acid bactericidal single-dose agent designed for the management of women with acute symptomatic bacterial cystitis caused by E. coli. The favorable features of this compound include excellent compliance, safety (transient adverse events, mild diarrhea), and lack of cross-sensitization with other antibacterials. This agent produces clinical and microbiologic responses that are comparable with those achieved by standard, traditional, single- or multiple-dose treatments. The compound has been given a category B pregnancy status. Fosfomycin is prescribed as a single, 3-g dose of dissolved granules, to be taken without regard to food.
A number of concerns are relevant to fosfomycin tromethamine. It is an expensive treatment, and the agent cannot be coadministered with metoclopramide, as this gastrointestinal motility agent reduces the urinary concentration of fosfomycin tromethamine.
Perhaps the major disadvantage of fosfomycin tromethamine, however, is the fact that it does not inhibit the growth of Staphylococcus saprophyticus. This is important because numerous studies have identified S. saprophyticus as the second most common cause of acute, symptomatic bacterial cystitis in young women.
The newer antimicrobial agents should be reserved for judiciously selected indications. There is no compelling reason to prescribe these newer compounds to patients with streptococcal pharyngitis, acute maxillary sinusitis, acute bronchitis, an exacerbation of chronic bronchitis, or bacterial cystitis. Many time-honored, safe, effective, and less expensive drugs are available to manage patients with these infections. Excessive and inappropriate use of the newer agents will result in exorbitantly expensive medicine and foster the emergence of drug-resistant pathogens. (R.A.G.)
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