Unipen

Beta-lactam antibiotics include penicillins, cephalosporins and related compounds. As a group, these drugs are active against many gram-positive, gram-negative and anaerobic organisms. Information based on "expert opinion" and antimicrobial susceptibility testing supports certain antibiotic choices for the treatment of common infections, but less evidence-based literature is available to guide treatment decisions. Evidence in the literature supports the selection of amoxicillin as first-line antibiotic therapy for acute otitis media. Alternative drugs, such as amoxicillin-clavulanate, trimethoprim-sulfamethoxazole and cefuroxime axetil, can be used to treat resistant infections. Penicillin V remains the drug of choice for the treatment of pharyngitis caused by group A streptococci. Inexpensive narrow-spectrum drugs such as amoxicillin or trimethoprim-sulfamethoxazole are first-line therapy for sinusitis. Animal and human bites can be treated most effectively with amoxicillin-clavulanate. For most outpatient procedures, amoxicillin is the preferred agent for bacterial endocarditis prophylaxis. Beta-lactam antibiotics are usually not the first choice for empiric outpatient treatment of community-acquired pneumonia. Based on the literature, the role of beta-lactam antibiotics in the treatment of bronchitis, skin infections and urinary tract infections remains unclear. (Am Fam Physician 2000;62:611-20.)

Beta-lactam antibiotics, which are named for the beta-lactam ring in their chemical structure,(1) include the penicillins, cephalosporins and related compounds. These agents are active against many gram-positive, gram-negative and anaerobic organisms. The beta-lactam antibiotics exert their effect by interfering with the structural crosslinking of peptidoglycans in bacterial cell walls. Because many of these drugs are well absorbed after oral administration, they are clinically useful in the outpatient setting.

Resistance to Beta-Lactam Antibiotics

Bacterial resistance against beta-lactam antibiotics is increasing at a significant rate and has become a common problem in primary care medicine. There are several mechanisms of antimicrobial resistance to beta-lactam antibiotics.(1-3) One important mechanism is the production of beta-lactamases, which are enzymes that cleave the beta-lactam ring.(4) Beta-lactamase activity can occur in gram-positive organisms (Staphylococcus aureus and Staphylococcus epidermidis); gram-negative organisms (Haemophilus influenzae, Neisseria gonorrhoeae, Moraxella [formerly Branhamella] catarrhalis, Escherichia coli, and Proteus, Serratia, Pseudomonas and Klebsiella species); and anaerobic organisms (Bacteroides species).

The newer beta-lactam antibiotics can be highly effective in combating infections caused by beta-lactamase-producing organisms. When used alone, beta-lactamase inhibitors (clavulanate, sulbactam and tazobactam) have weak intrinsic antibacterial activity, but their effectiveness increases when they are combined with a beta-lactam antibiotic (e.g., amoxicillin-clavulanate [Augmentin]).

Orally administered beta-lactam antibiotics are divided into classes based on their antimicrobial spectrum(5) (Table 1).

Oral Penicillins

The orally administered penicillins include natural penicillins, penicillinase-resistant penicillins, aminopenicillins, beta-lactam- beta-lactamase inhibitor combinations and antipseudomonal penicillins.(6)

The antibiotic properties of Penicillium mold were first noted by Fleming in 1928.(1) Penicillins first became available commercially in the mid-1940s, and they remain one of the most important classes of antimicrobial agents. Despite the development of bacterial resistance, which was noted shortly after the penicillins were introduced, these drugs are still widely used, and new penicillin derivatives are being developed.

NATURAL PENICILLINS

Penicillin V, the potassium salt of phenoxymethyl penicillin, is well absorbed orally, and peak serum levels are achieved within 60 minutes. Penicillin G is not as well absorbed and is therefore less useful for oral therapy. Penicillin V is indicated for the treatment of mild gram-positive infections of the throat, respiratory tract and soft tissues. This natural penicillin is still the drug of choice for the treatment of group A streptococcal pharyngitis in patients who are not allergic to penicillin.(5) Penicillin V is also useful for anaerobic coverage in patients with oral cavity infections.

PENICILLINASE-RESISTANT PENICILLINS

Penicillinase-resistant penicillins were developed because of the increasing resistance of staphylococci to natural penicillins. These chemically modified penicillins have a side chain that inhibits the action of penicillinase.(6)

The penicillinase-resistant penicillins are active against Streptococcus and Staphylococcus species, but they are not active against methicillin-resistant S. aureus, which is becoming an increasingly common organism.(7) These drugs also do not have activity against gram-negative organisms.

The agents in this class with the best oral absorption are cloxacillin (Tegopen) and dicloxacillin (Dynapen). These drugs should be taken one to two hours before meals.(1) Nafcillin (Unipen) and oxacillin (Prostaphlin) come in oral preparations but are poorly absorbed.

Penicillinase-resistant penicillins are primarily indicated for the treatment of skin and soft tissue infections.

AMINOPENICILLINS

The aminopenicillins were the first penicillins discovered to be active against gram-negative rods such as E. coli and H. influenzae.

Amoxicillin is more completely absorbed than ampicillin. As a result, serum amoxicillin levels are twice as high as serum ampicillin levels. Because a smaller amount of amoxicillin remains in the intestinal tract, patients treated with this agent have less diarrhea than those treated with ampicillin. However, the more complete absorption of amoxicillin makes the drug less effective than ampicillin in the treatment of Shigella enteritis. Otherwise, amoxicillin and ampicillin have almost the same spectrum of antimicrobial activity.

Bacampicillin (Spectrobid) does not have any significant advantages over the other aminopenicillins, and it is more expensive.

Orally administered amoxicillin and ampicillin are used primarily to treat mild infections such as otitis media, sinusitis, bronchitis, urinary tract infections and bacterial diarrhea. Amoxicillin is the agent of choice for the treatment of otitis media.(8) Because H. influenzae and E. coli are becoming increasingly resistant to the aminopenicillins, these drugs are becoming somewhat less effective clinically.

BETA-LACTAM-BETA-LACTAMASE INHIBITOR COMBINATION

The only penicillin available in an oral combination with a beta-lactamase inhibitor is amoxicillin-clavulanate.(6) This combination drug provides increased antimicrobial coverage of beta-lactamase-producing strains of S. aureus, H. influenzae, N. gonorrhoeae, E. coli, M. catarrhalis and Proteus, Klebsiella and Bacteroides species. It has little activity against Pseudomonas or methicillin-resistant S. aureus.

In clinical situations in which there is increased development of beta-lactamase- producing organisms, amoxicillin-clavulanate may be the first choice for the treatment of otitis media, sinusitis, bronchitis, urinary tract infections and skin and soft tissue infections. Because of its anaerobic coverage, amoxicillin-clavulanate is an excellent drug for treating infections caused by human and animal bites.

Common side effects include gastrointestinal distress, diarrhea (alleviated by taking the drug with food or water), rashes and Candida superinfection.

ANTIPSEUDOMONAL PENICILLINS

Carbenicillin (Geocillin) is the only available orally administered antipseudomonal penicillin. This drug has excellent oral absorption. However, it is metabolized so rapidly that serum levels remain low, which markedly limits its clinical usefulness.

Oral Cephalosporins

Structurally, the cephalosporins have a beta-lactam ring (which they share with all penicillins) and a thiazolidine ring. These drugs are divided into generations based on their spectrum of antimicrobial activity.

Although the cephalosporins are often thought of as new and improved derivatives of the penicillins, they were actually discovered as naturally occurring substances separate from the penicillins. Brotzu noted the periodic clearing of microorganisms from sea water near a sewage outlet and isolated a substance with antibacterial properties that was produced by the fungus Cephalosporium acremonium.(1) After further study and modification of this substance, the first commercially available cephalosporin (cephalothin) was introduced in 1962.

The effectiveness of an individual cephalosporin depends on its ability to overcome the mechanisms of resistance that bacteria have developed to combat beta-lactam antibiotics. A comparison of cephalosporins and penicillin, using penicillin V as the prototype, is presented in Table 2.(1,5,6,9-11) Selected differences among the oral agents in each cephalosporin generation are given in Table 3.(1,5,6,9-11)

FIRST-GENERATION CEPHALOSPORINS

The first-generation cephalosporins include cefadroxil (Duricef), cephalexin (Keflex) and cephradine (Velosef), which are similar drugs. They are all well absorbed, even in the presence of food, and they achieve high urinary concentrations. Dosages of these agents should be decreased in patients with severe renal failure.

Cefadroxil, cephalexin and cephradine are effective in the treatment of skin and soft tissue infections caused by Streptococcus species and methicillin-sensitive S. aureus. Many physicians consider these drugs to be preferable to the orally administered antistaphylococcal penicillins (cloxacillin and dicloxacillin) because they are associated with a lower incidence of gastrointestinal side effects and have a better taste.

The good urinary concentrations of first-generation cephalosporins make them second-line agents (after quinolone antibiotics and trimethoprim-sulfamethoxazole [Bactrim, Septra]) for the treatment of urinary tract infections caused by susceptible gram-negative organisms, although they are not effective against Pseudomonas or Enterococcus species. Their relative safety in pregnancy makes them a reasonable alternative for the treatment of urinary tract infections in pregnant women.

Cefadroxil, cephalexin and cephradine may be used to treat streptococcal pharyngitis in patients with delayed-reaction penicillin allergy. Indications for these agents in the treatment of other upper respiratory tract infections (bronchitis, pneumonia, otitis media and sinusitis) are unclear. First-generation cephalosporins are generally not effective against H. influenzae, M. catarrhalis and other gram-negative beta-lactamase-producing organisms.

SECOND-GENERATION CEPHALOSPORINS AND CARBACEPHEM

The second-generation cephalosporins include cefaclor (Ceclor), cefprozil (Cefzil) and cefuroxime axetil (Ceftin). Compared with first-generation cephalosporins, these drugs have improved activity against common beta-lactamase-producing respiratory pathogens such as H. influenzae and M. catarrhalis.

As a result of their widespread use, bacterial resistance to second-generation cephalosporins has greatly increased.1 In addition, second-generation cephalosporins are generally much more expensive than first-generation agents or penicillins.

Structurally, loracarbef (Lorabid) is a carbacephem rather than a cephalosporin. However, loracarbef is so similar to cefaclor in spectrum of antimicrobial activity and side effects that it is usually listed as a second-generation cephalosporin.

The second-generation cephalosporins are heavily promoted for their coverage of relatively resistant organisms (e.g., H. influenzae) that cause respiratory tract infections such as otitis media, bronchitis and sinusitis. Much less expensive agents, such as trimethoprim-sulfamethoxazole, may be preferred. Cefuroxime axetil may be considered a second-line agent for the treatment of urinary tract infections.

THIRD-GENERATION CEPHALOSPORINS

Third-generation cephalosporins include cefdinir (Omnicef), cefixime (Suprax), cefpodoxime (Vantin) and ceftibuten (Cedax). Secondary to better resistance to some plasmid-mediated beta lactamases, the third-generation agents demonstrate somewhat expanded coverage of gram-negative organisms compared with first- and second-generation cephalosporins. They have the advantage of convenient dosing schedules, but they are expensive.

The third-generation agents have variable loss of efficacy against gram-positive organisms, particularly Streptococcus pneumoniae and Staphylococcus species. Lack of gram-positive coverage limits the usefulness of ceftibuten in the treatment of otitis media and respiratory tract infections, except perhaps as a second-line agent when antibiotics with better gram-positive coverage have failed.(11) Poor coverage of Staphylococcus species precludes the use of cefixime and ceftibuten in the treatment of skin and soft tissue infections.

Cefpodoxime and cefdinir retain good coverage of Staphylococcus and Streptococcus species.(12) Thus, they are probably the more useful third-generation cephalosporins.

Practical Clinical Applications

Because of all the drugs that are available to treat common infections in the primary care setting, choosing an antibiotic can be difficult. The decision is individualized, based on the cost of treatment and the patient's financial resources, formulary restrictions from insurance companies, the availability of drug samples in the physician's office, the likelihood of a resistant organism, the severity of the infection, comorbid conditions in the patient and the risk of drug side effects.

Dosages and average wholesale costs for 10 days of treatment with orally administered beta-lactam antibiotics are given in Table 4.13 Clinical indications for beta-lactam antibiotics are summarized in Table 5.

Although information based on "expert opinion" and antimicrobial susceptibility testing is available to support certain antibiotic choices for the treatment of common infections, the literature contains much less evidence-based information on the treatment of clinical syndromes. However, clinical treatment guidelines(14-16) demonstrate some consensus on antibiotic therapy for various infections.

OTITIS MEDIA

In the United States, acute otitis media is routinely treated with antibiotics despite the lack of consistent supporting data and the risk of promoting drug resistance.(17) When antibiotics are used, amoxicillin is considered first-line therapy in children.

Amoxicillin is given in an initial dosage of 40 to 45 mg per kg per day for 10 days.(8) A higher dosage (80 to 90 mg per kg per day) may be used in children who are at increased risk for drug-resistant S. pneumoniae infection, such as children younger than two years, children who spend time in day care settings and children who have received an antibiotic within the previous three months. Amoxicillin can be given twice daily.(18)

If treatment failure is evident after amoxicillin has been given for three days, use of an alternative drug should be considered to provide more effective coverage of resistant organisms. Alternatives include amoxicillin-clavulanate, trimethoprim-sulfamethoxazole and cefuroxime axetil.

One meta-analysis(19) supports the use of a shortened antibiotic course (five days) in patients with otitis media. This approach is associated with only a slight increase in treatment failures.

PHARYNGITIS

Penicillin V remains the drug of choice for the treatment of streptococcal pharyngitis.(5) Erythromycin or first-generation cephalosporins may be used in patients who are allergic to penicillin. Once-daily dosing with amoxicillin has compared favorably with thrice-daily dosing of penicillin V.(20)

SINUSITIS

Many patients with sinusitis improve spontaneously,(21) but it may be appropriate to prescribe antibiotics for patients who are sicker or at higher risk for complications.(22) Inexpensive narrow-spectrum drugs such as amoxicillin or trimethoprim-sulfamethoxazole are the first choices.(21) Alternative agents for the treatment of resistant infections include amoxicillin-clavulanate and second- and third-generation cephalosporins.

HUMAN AND ANIMAL BITES

Amoxicillin-clavulanate is the drug of choice in patients who have been bitten by another human or an animal.(5)

BACTERIAL ENDOCARDITIS PROPHYLAXIS

In patients who are able to take oral medications, amoxicillin is the preferred agent to prevent bacterial endocarditis after dental, oral, respiratory tract and esophageal procedures. If a patient is known to be allergic to penicillin, alternative antimicrobials include clindamycin (Cleocin), cephalexin, cefadroxil, azithromycin (Zithromax) and clarithromycin (Biaxin).(23) Prophylactic regimens are given in Table 6.(23)

PNEUMONIA

The beta-lactam antibiotics are not the preferred first-line agents for empiric outpatient treatment of community-acquired pneumonia.(24) Quinolone antibiotics with enhanced S. pneumoniae coverage (e.g., levofloxacin [Levaquin]) or macrolide antibiotics are preferred.

Amoxicillin-clavulanate may be used for outpatient treatment of suspected aspiration pneumonia.

LESS CLEAR INDICATIONS

The benefits of beta-lactam antibiotics in the treatment of bronchitis, skin and soft tissue infections, and urinary tract infections are less clear in the evidence-based literature. The marginal benefit of antibiotics in bronchitis must be weighed against the adverse effects of the drugs and the development of antibiotic resistance.(25) Penicillinase-resistant penicillins and first-generation cephalosporins are first-line choices for the treatment of skin and soft tissue infections, with macrolide antibiotics, amoxicillin-clavulanate, cefpodoxime and cefdinir as second-line agents. Quinolone antibiotics and trimethoprim-sulfamethoxazole are preferred agents for the treatment of uncomplicated urinary tract infections.

The authors thank Karen Mandell, Pharm.D., University of Cincinnati, and Kalvis Danenbergs, R.Ph., Clinton Memorial Hospital, Wilmington, Ohio, for editorial assistance with the manuscript.

REFERENCES

(1.) Mandell GL, Perti WA. Antimicrobial agents: penicillins, cephalosporins, and other b-lactam antibiotics. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, et al., eds. Goodman & Gilman's The pharmacologic basis of therapeutics. 9th ed. New York: McGraw-Hill, Health Professions Division, 1996:1073-101.

(2.) Tenover FC, McGowan JE. The epidemiology of bacterial resistance to antimicrobial agents. In: Evans AS, Brachman PS, eds. Bacterial infections in humans: epidemiology and control. 3d ed. New York: Plenum, 1998:85.

(3.) McManus MC. Mechanisms of bacterial resistance to antimicrobial agents. Am J Health Syst Pharm 1997;54:1420-33.

(4.) Bush K, Jacoby GA, Medeiros AA. A functional classification scheme for beta-lactamases and its correlation with molecular structure. Antimicrob Agents Chemother 1995;39:1211-33.

(5.) Gilbert DN, Moellering RC Jr, Sande MA, eds. The Sanford guide to antimicrobial therapy. 29th ed. Hyde Park, Vt.: Antimicrobial Therapy, 1999:33,52-3,64.

(6.) Wright AJ. The penicillins. Mayo Clin Proc 1999;74:290-307 [Published erratum appears in Mayo Clin Proc 1999;74:1184].

(7.) Rolinson GN. Forty years of beta-lactam research. J Antimicrob Chemother 1998;41:589-603.

(8.) Dowell SF, Butler JC, Giebink GS, Jacobs MR, Jernigan D, Musher DM, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance--a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J 1999;18:1-9 [Published erratum appears in Pediatr Infect Dis J 1999;18:341].

(9.) Stohlmeyer LA, Kraus DM. Oral cephalosporins: focus on new agents. J Pediatr Health Care 1996; 10:289-94.

(10.) Rodman DP, Knight JT, Anderson RL. A critical review of the new oral cephalosporins. Considerations and place in therapy. Arch Fam Med 1994;3:975-80 [Published erratum appears in Arch Fam Med 1995;4:723].

(11.) Ceftibuten--a new oral cephalosporin. Med Lett Drugs Ther 1996;38:23-4.

(12.) Cefdinir--a new oral cephalosporin. Med Lett Drugs Ther 1998;40:85-7.

(13.) The choice of antibacterial drugs. Med Lett Drugs Ther 1999;41:95-104.

(14.) The Cochrane Library, CD-Rom version. Issue 2. Oxford, England: The Cochrane Collaboration and Update Software Ltd., 1999.

(15.) POEMs for Primary Care. Retrieved May 5, 2000, from the World Wide Web: http://www.infopoems.com/POEMs/poems_home.htm.

(16.) National Guideline Clearinghouse. Retrieved May 5, 2000, from the World Wide Web: http://www. guideline.gov.

(17.) Damoiseaux RA, van Balen FA, Hoes AW, de Melker RA. Antibiotic treatment of acute otitis media in children under two years of age: evidence based? Br J Gen Pract 1998;48:1861-4.

(18.) Principi N, Marchisio P, Bigalli L, Massironi E. Amoxicillin twice daily in the treatment of acute otitis media in infants and children. Eur J Pediatr 1986; 145:522-5.

(19.) Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE, Wincott JL, Sitar DS, Klassen TP, et al. Treatment of acute otitis media with a shortened course of antibiotics: a meta-analysis. JAMA 1998;279: 1736-42.

(20.) Feder HM, Gerber MA, Randolph MF, Stelmach PS, Kaplan EL. Once-daily therapy for streptococcal pharyngitis with amoxicillin. Pediatrics 1999; 103:47-51.

(21.) de Ferranti SD, Ioannidis JP, Lau J, Anninger WV, Barza M. Are amoxycillin and folate inhibitors as effective as other antibiotics for acute sinusitis? A meta-analysis. BMJ 1998;317:632-7.

(22.) de Bock GH, Dekker FW, Stolk J, Springer MP, Kievit J, van Houwelingen JC. Antimicrobial treatment in acute maxillary sinusitis: a meta-analysis. J Clin Epidemiol 1997;50:881-90.

(23.) Dajani AS, Taubert KA, Wilson W, Bolger AF, Bayer A, Ferrieri P, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 1997;277:1794-801.

(24.) Bartlett JG, Breiman RF, Mandell LA, File TM. Community-acquired pneumonia in adults: guidelines for management. The Infectious Diseases Society of America. Clin Infect Dis 1998;26:811-38.

(25.) Smucny JJ, Becker LA, Glazier RH, McIsaac W. Are antibiotics effective treatment for acute bronchitis? A meta-analysis. J Fam Pract 1998;47:453-60.

Richard W. Sloan, M.D., R.Ph., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.

KEITH B. HOLTEN, M.D., is director of the family practice residency program at Clinton Memorial Hospital, Wilmington, Ohio. He is also associate professor of clinical family medicine at the University of Cincinnati College of Medicine. Dr. Holten received his medical degree from the University of Louisville (Ky.) School of Medicine and completed a residency in family medicine at St. Elizabeth's Hospital, Dayton, Ohio.

EDWARD M. ONUSKO, M.D., is associate director of the family practice residency program at Clinton Memorial Hospital and assistant professor of clinical family medicine at the University of Cincinnati College of Medicine. Dr. Onusko graduated from Case Western Reserve University School of Medicine, Cleveland, and completed a residency in family medicine at University Hospitals of Cleveland.

Address correspondence to Keith B. Holten, M.D., Family Practice Residency Program, Clinton Memorial Hospital, 825 W. Locust St., Wilmington, OH 45177. Reprints are not available from the authors.

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