Appropriate Prescribing of Oral Beta-Lactam Antibiotics

Author: Keith B. Holten, Edward M. Onusko
Date: August 1, 2000

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.

TABLE 1Oral Beta-Lactam AntibioticsClass DrugNatural penicillin Penicillin VPenicillinase-resistant Cloxacillin (Tegopen) penicillin Dicloxacillin (Dynapen) Nafcillin (Unipen)[*] Oxacillin (Prostaphlin)[*]Aminopenicillin Amoxicillin Ampicillin Bacampicillin (Spectrobid)Beta-lactam-beta- Amoxicillin-clavulanate lactamase inhibitor (Augmentin) combinationAntipseudomonal Carbenicillin (Geocillin) penicillinFirst-generation Cefadroxil (Duricef)cephalosporin Cephalexin (Keflex) Cephradine (Velosef)Second-generation Cefaclor (Ceclor, cephalosporin Ceclor CD) Cefprozil (Cefzil) Cefuroxime axetil (Ceftin)Carbacephem Loracarbef (Lorabid)Third-generation Cefdinir (Omnicef) cephalosporin Cefixime (Suprax) Cefpodoxime (Vantin) Ceftibuten (Cedax)Class Antimicrobial spectrumNatural penicillin Streptococcus species and oral cavity anaerobesPenicillinase-resistant Methicillin-sensitive Staphylococcus aureus penicillin and Streptococcus speciesAminopenicillin Same coverage as penicillin V, plus Listeria monocytogenes, Enterococcus species, Proteus mirabilis and some strains of Escherichia coliBeta-lactam-beta- Same coverage as aminopenicillins, plus beta- lactamase inhibitor lactamase-producing strains of combination methicillin-sensitive S. aureus, Haemophilus influenzae and Moraxella (formerly Branhamella) catarrhalisAntipseudomonal Limited activity against Pseudomonas and penicillin Klebsiella speciesFirst-generation Improved coverage of methicillin-sensitivecephalosporin S. aureus, E. coli, P. mirabilis and Klebsiella speciesSecond-generation Compared with first-generation agents, better cephalosporin coverage of beta-lactamase-producing organisms such as methicillin-sensitive S. aureus, H. influenzae, M. catarrhalis, E. coli, P. mirabilis and Klebsiella speciesCarbacephem Same coverage as second-generation cephalosporinsThird-generation Variable loss of Staphylococcus and Pneumococcus cephalosporin coverage; compared with second-generation cephalosporins, somewhat expanded coverage of gram-negative organisms; enhanced coverage of Proteus vulgaris and Providencia species[*]--Poorly absorbed.TABLE 2Comparison of Oral Cephalosporins and PenicillinsFactors CephalosporinsAllergic reactions Fewer immediate and delayed hypersensitivity reactions; must be avoided in patients with a history of immediate hypersensitivity to penicillinPatient tolerance Better taste, which increases compliance in children; fewer gastrointestinal side effectsCost More expensiveAntimicrobial Broader antibacterial spectrum spectrumFactors Penicillin V[*]Allergic reactions Allergic reactions commonPatient tolerance More gastrointestinal side effectsCost Less expensiveAntimicrobial Narrower antibacterial spectrum; spectrum less likely to induce antimicrobial resistance; some penicillins cover anaerobes, Listeria, Enterococcus or Pseudomonas species[*]--For purposes of comparison, penicillin V is used as theprototype penicillin.Information from references 1, 5, 6, and 9 through 11.TABLE 3Selected Differences Among the Oral CephalosporinsCephalosporins CommentsFirst-generation agentsCefadroxil (Duricef) Kinetics allow once-daily or twice-daily dosing; convenience offset by significantly higher cost than other first-generation cephalosporinsCephalexin (Keflex) Extensive clinical experience with its use; well tolerated; good pharmacokineticsCephradine (Velosef) Similar properties as cephalexin, but not as widely usedSecond-generation agentsCefaclor (Ceclor, May cause serum sickness-like syndrome; absorptionCeclor CD) decreased by food; of second-generation cephalosporins, has highest incidence of Haemophilus influenzae resistanceCefprozil (Cefzil) Absorption not affected by foodCefuroxime axetil Parenteral form available (cefuroxime sodium (Ceftin) [Zinacef]); absorption enhanced by food; only second-generation agent labeled for the treatment of urinary tract infectionsThird-generation agentsCefixime (Suprax) Oral suspension better absorbed than tablets (therefore, less likely to cause diarrhea); single oral dose indicated for the treatment of uncomplicated gonorrheaCefpodoxime (Vantin) Of the third-generation agents, provide best and cefdinir (Omnicef) coverage of penicillin-sensitive Pneumococcus and methicillin-sensitive Staphylococcus aureusCeftibuten (Cedax) Poor efficacy against Streptococcus pneumoniae, which limits its clinical usefulnessInformation from references 1, 5, 6, and 9 through 11.TABLE 5Clinical Indications for Oral Beta-Lactam AntibioticsInfection Preferred drug(s)Otitis media AmoxicillinStreptococcal Penicillin V pharyngitisSinusitis Amoxicillin, trimethoprim- sulfamethoxazoleAnimal and Amoxicillin-clavulanate human bitesBacterial Amoxicillin endocarditis prophylaxisPneumonia Macrolide antibiotics, quinolone antibioticsBronchitis Doxycycline, trimethoprim- (controversial) sulfamethoxazole, amoxicillin-clavulanateSkin and soft First-generation cephalosporins, tissue infections cloxacillin (Tegopen), (cellulitis) dicloxacillin (Dynapen)Urinary tract Quinolone antibiotics, infection trimethoprim- sulfamethoxazoleInfection Alternative drug(s)Otitis media Amoxicillin-clavulanate (Augmentin), trimethoprim- sulfamethoxazole (Bactrim, Septra), second- generation cephalosporins, some third-generation cephalosporins, macrolide antibioticsStreptococcal In patients with penicillin allergy: macrolide pharyngitis antibiotics, first-generation cephalosporinsSinusitis Amoxicillin-clavulanate, second-generation cephalosporins, third-generation cephalosporinsAnimal and Depends on type of bite (e.g., cefuroxime axetil human bites [Ceftin] or doxycycline [Vibramycin] for cat bites)Bacterial In patients with penicillin allergy: clindamycin endocarditis (Cleocin), cephalexin (Keflex), azithromycin prophylaxis (Zithromax), clarithromycin (Biaxin)Pneumonia Amoxicillin-clavulanate, second-generation cephalosporins, third-generation cephalosporinsBronchitis Macrolide antibiotics, quinolone antibiotics, second- (controversial) generation cephalosporins, some third-generation cephalosporinsSkin and soft Macrolide antibiotics, amoxicillin-clavulanate, tissue infections cefpodoxime (Vantin), cefdinir (Omnicef) (cellulitis)Urinary tract Amoxicillin, amoxicillin-clavulanate, cefuroxime axetil infection or other cephalosporins, doxycycline, nitrofurantoin (Furadantin)

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