intradermally and observing for a local allergic response. A positive test indicates the presence of IgE antibodies, which can mediate severe penicillin allergy. Accordingly, if skin testing is negative, a severe allergic reaction (anaphylaxis) is unlikely.
It is important to note that skin testing can be dangerous:
In patients with severe penicillin allergy, the skin test itself can precipitate an anaphylactic reaction. Accordingly, the test should be performed only if epinephrine and facilities for respiratory support are immediately available.
Current guidelines recommend skin testing with two reagents, which test for the major (more common) and minor (less common) determinants of penicillin allergy. The minor deter- minants, although less common, mediate the majority of severe penicillin reactions.
The major determinant reagent, available commercially as Pre-Pen, contains a single component: benzylpenicilloyl- polylysine. Benzylpenicilloyl-polylysine is a large polymeric molecule that is poorly absorbed. Hence, even in patients with severe penicillin allergy, this skin test carries a low risk of a systemic reaction.
The recommended minor determinant reagent, which is not available commercially, is a mixture of three compounds:
benzylpenicillin G, benzylpenicilloate, and penicilloyl propyl- amine. As noted, the term minor indicates that the antibodies being tested for are relatively uncommon and not that the allergic response mediated by these antibodies is of minor significance. In fact, the minor determinants are responsible for the majority of severe penicillin reactions.
Management of Patients With a History of Penicillin Allergy. All patients who are candidates for penicillin therapy should be asked whether they have an allergy to penicillin.
For patients who answer “yes,” the general rule is to avoid penicillins. If the allergy is mild, a cephalosporin is often an appropriate alternative. However, if there is a history of anaphylaxis or some other severe allergic reaction, it is prudent to avoid cephalosporins as well (because there is about a 1%
risk of cross-sensitivity to cephalosporins). When a cephalo- sporin is indicated, an oral cephalosporin is preferred (because the risk of a severe reaction is lower than with parenteral therapy). For many infections, vancomycin, erythromycin, and clindamycin are effective and safe alternatives for patients with penicillin allergy.
Rarely, a patient with a history of anaphylaxis may have a life-threatening infection (e.g., enterococcal endocarditis) for which alternatives to penicillins are ineffective. In these cases, the potential benefits of penicillin therapy outweigh the risks, and treatment should be instituted. To minimize the chances of an anaphylactic reaction, penicillin should be administered according to a desensitization schedule. In this procedure, an initial small dose is followed at 60-minute intervals by progres- sively larger doses until the full therapeutic dose has been achieved. It should be noted that the desensitization procedure is not without risk. Accordingly, epinephrine and facilities for respiratory support should be immediately available.
Drug Interactions
Aminoglycosides. For some infections, penicillins are used in combination with an aminoglycoside (e.g., gentamicin). By weakening the cell wall, the penicillin facilitates access of the aminoglycoside to its intracellular site of action, thereby increasing bactericidal effects. Unfortunately, when penicillins are present in high concentrations, they interact chemically with Penicillin Allergy
General Considerations. As with most allergic reactions, there is no direct relationship between the size of the dose and the intensity of the response. Although prior exposure to penicillins is required for an allergic reaction, responses may occur in the absence of prior penicillin use. How can this be?
Because patients may have been exposed to penicillins produced by fungi or to penicillins present in foods of animal origin.
Because of cross-sensitivity, patients allergic to one penicillin should be considered allergic to all other penicillins. In addition, a few patients (about 1%) display cross-sensitivity to cepha- losporins. If at all possible, patients with penicillin allergy should not be treated with any member of the penicillin family.
The use of cephalosporins depends on the intensity of allergic response: If the penicillin allergy is mild, the use of cephalo- sporins is probably safe; however, if the allergy is severe, cephalosporins should be avoided.
Individuals allergic to penicillin should be encouraged to wear a medical identification bracelet to alert healthcare person- nel to their condition.
Types of Allergic Reactions. Penicillin reactions are classified as immediate, accelerated, and delayed. Immediate reactions occur 2 to 30 minutes after drug administration;
accelerated reactions occur within 1 to 72 hours; and delayed reactions occur within days to weeks. Immediate and accel- erated reactions are mediated by immunoglobulin E (IgE) antibodies.
Anaphylaxis (laryngeal edema, bronchoconstriction, severe hypotension) is an immediate hypersensitivity reaction, mediated by IgE. Anaphylactic reactions occur more frequently with penicillins than with any other drugs. However, even with penicillins, the incidence of anaphylaxis is extremely low (the estimated incidence is between 0.004% and 0.04%). Nonethe- less, when these reactions do occur, the risk of mortality is high (about 10%). The primary treatment is epinephrine (subQ, IM, or IV) plus respiratory support. To ensure prompt treatment if anaphylaxis should develop, patients should be observed for at least 30 minutes after drug injection (i.e., until the risk of an anaphylactic reaction has passed).
Development of Penicillin Allergy. Before discussing penicillin allergy further, we need to review the development of allergy to small molecules as a class. Small molecules, such as penicillin and most other drugs, are unable to induce antibody formation directly. Therefore, to promote antibody formation, the small molecule must first bond covalently to a larger molecule, usually a protein. In these combinations, the small molecule is referred to as a hapten. The hapten-protein combina- tion constitutes the complete antigen that stimulates antibody formation.
The hapten that stimulates production of penicillin antibodies is rarely intact penicillin itself. Rather, compounds formed from the degradation of penicillin are the actual cause. As a result, most “penicillin antibodies” are not directed at penicillin itself. Rather, they are directed at various penicillin degradation products.
Skin Tests for Penicillin Allergy. Allergy to penicillin can decrease over time. Hence, an intense allergic reaction in the past does not necessarily mean that an intense reaction will occur again. In patients with a history of penicillin allergy, skin tests can be employed to assess current risk. These tests are performed by injecting a tiny amount of allergen
only against penicillinase-producing strains of staphylococci (Staph. aureus and Staph. epidermidis). Since most strains of staphylococci produce penicillinase, the penicillinase-resistant penicillins are drugs of choice for the majority of staphylococcal infections. It should be noted that these agents should not be used against infections caused by non–penicillinase-producing staphylococci, since they are less active than penicillin G against these bacteria.
An increasing clinical problem is the emergence of staphy- lococcal strains referred to as methicillin-resistant Staphylococ- cus aureus, a term used to indicate lack of susceptibility to methicillin (an obsolete penicillinase-resistant penicillin) and all other penicillinase-resistant penicillins. Resistance appears to result from the production of PBPs to which the penicillinase- resistant penicillins cannot bind. Vancomycin is the treatment of choice.
Nafcillin
Nafcillin is usually administered IV. Intramuscular use is rare. Absorption from the GI tract is erratic and incomplete, and hence oral formulations have been discontinued.
Oxacillin and Dicloxacillin
These drugs are similar in structure and pharmacokinetic properties. Both are acid stable, but only dicloxacillin is formulated for oral dosing. Oxacillin is administered IV.
Broad-Spectrum Penicillins (Aminopenicillins)
Only two broad-spectrum penicillins are available: ampicillin and amoxicillin. Both have the same antimicrobial spectrum as penicillin G, plus increased activity against certain gram- negative bacilli, including Haemophilus influenzae, Escherichia coli, Salmonella, and Shigella. This broadened spectrum is due in large part to an increased ability to penetrate the gram- negative cell envelope. Both drugs are readily inactivated by beta-lactamases, and hence are ineffective against most infec- tions caused by Staph. aureus.
Ampicillin
Ampicillin was the first broad-spectrum penicillin in clinical use. The drug is useful against infections caused by Enterococ- cus faecalis, Proteus mirabilis, E. coli, Salmonella, Shigella, and H. influenzae. The most common side effects are rash and diarrhea, both of which occur more frequently with ampicillin than with any other penicillin. Administration may be oral or IV. It should be noted, however, that for oral therapy, amoxicillin is preferred (see Amoxicillin). Dosages for patients with normal kidney function are shown in Table 84.2. For patients with renal impairment, dosage should be reduced.
As discussed later, ampicillin is also available in a fixed-dose combination with sulbactam, an inhibitor of bacterial beta- lactamase. The combination is sold as Unasyn.
Amoxicillin
Amoxicillin [Moxatag] is similar to ampicillin in structure and actions. The drugs differ primarily in acid stability, amoxicillin being the more acid stable. Hence, when the two are admin- istered orally in equivalent doses, blood levels of amoxicillin are greater. Accordingly, when oral therapy is indicated, amoxicillin is preferred. Amoxicillin produces less diarrhea than ampicillin, perhaps because less amoxicillin remains unabsorbed in the intestine.
aminoglycosides and thereby inactivate the aminoglycoside.
Accordingly, penicillins and aminoglycosides should never be mixed in the same IV solution. Rather, they should be administered separately. Once a penicillin has been diluted in body fluids, the potential for inactivating the aminoglycoside is minimal.
Probenecid. As noted, probenecid can delay renal excretion of penicillin, thereby prolonging antibacterial effects.
Bacteriostatic Antibiotics. Since penicillins are most effective against actively growing bacteria, concurrent use of a bacteriostatic antibiotic (e.g., tetracycline) could, in theory, reduce the bactericidal effects of the penicillin.
However, the clinical significance of such interactions is not known. Nonetheless, combined use of penicillin and bacteriostatic agents is generally avoided.
Preparations, Dosage, and Administration
Preparations and Routes of Administration. Penicillin G is available as four different salts (potassium, procaine, sodium, and benzathine). These salts differ with respect to routes of administration: potassium penicillin G [Pfizerpen] and sodium penicillin G are administered IM and IV; all other salts—benzathine penicillin G [Bicillin LA], procaine penicillin G, and a combination product [Bicillin C-R], composed of benzathine penicillin G plus procaine penicillin G—are administered IM. Check to ensure that the penicillin salt to be administered is appropriate for the intended route. Dosage ranges for penicillins are shown in Table 84.2.
Penicillin V
Penicillin V, also known as penicillin VK, is similar to penicillin G in most respects. The principal difference is acid stability: Penicillin V is stable in stomach acid, whereas penicillin G is not. Because of its acid stability, penicillin V has replaced penicillin G for oral therapy. Penicillin V may be taken with meals.
Penicillinase-Resistant Penicillins (Antistaphylococcal Penicillins)
By altering the penicillin side chain, pharmaceutical chemists have created a group of penicillins that are highly resistant to inactivation by beta-lactamases. In the United States, three such drugs are available: nafcillin, oxacillin, and dicloxacillin. These agents have a very narrow antimicrobial spectrum and are used
Penicillins
Life Stage Patient Care Concerns
Infants Penicillins are used safely in infants with bacterial infections, including syphilis, meningitis, and group A streptococcus.
Children/
adolescents Penicillins are a common drug used to treat bacterial infections in children.
Pregnant women Penicillins are classified in U.S. Food and Drug Administration Pregnancy Risk Category B.a There is no evidence of second- or third-trimester fetal risk.
Breast-feeding
women Amoxicillin is safe for use in breast-feeding mothers. Data are lacking regarding the transmission of some other penicillins from mother to infant via breast milk.
Older adults Doses should be adjusted in older adults with renal dysfunction.
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
aAs of 2020, the FDA will no longer use Pregnancy Risk Categories.
Please refer to Chapter 9 for more information.
Piperacillin can cause bleeding secondary to disrupting platelet function.
The drug is acid labile and hence must be administered parenterally, usually IV. Dosages for patients with normal kidney function are shown in Table 84.2. Dosage should be reduced in patients with renal impairment. As discussed in the next section, piperacillin is also available in a fixed-dose combination with tazobactam, a beta-lactamase inhibitor. The combination is marketed as Zosyn.
Penicillins Combined With a Beta-Lactamase Inhibitor
As their name indicates, beta-lactamase inhibitors are drugs that inhibit bacterial beta-lactamases. By combining a beta- lactamase inhibitor with a penicillinase-sensitive penicillin, we can extend the antimicrobial spectrum of the penicillin. In the United States, three beta-lactamase inhibitors are used:
sulbactam, tazobactam, and clavulanic acid (clavulanate). These drugs are not available alone. Rather, they are available only in fixed-dose combinations with a penicillin. Three such combination products are available:
• Ampicillin/sulbactam [Unasyn]
• Amoxicillin/clavulanate [Augmentin, Clavulin ]
• Piperacillin/tazobactam [Zosyn, Tazocin ]
Because beta-lactamase inhibitors have minimal toxicity, any adverse effects that occur with the combination products are due to the penicillin.
As discussed later, amoxicillin is also available in a fixed- dose combination with clavulanic acid, an inhibitor of bacterial beta-lactamases. The combination is marketed as Augmentin.
Amoxicillin, by itself, is one of our most frequently prescribed antibiotics.
Extended-Spectrum Penicillin (Antipseudomonal Penicillin)
Only one extended-spectrum penicillin is available: piperacillin.
The antimicrobial spectrum of this drug includes organisms that are susceptible to the aminopenicillins plus Pseudomonas aeruginosa, Enterobacter species, Proteus (indole positive), Bacteroides fragilis, and many Klebsiella. Piperacillin is susceptible to beta-lactamases, and hence is ineffective against most strains of Staph. aureus.
Piperacillin is used primarily for infections with P. aeru- ginosa. These infections often occur in the immunocompromised host and can be very difficult to eradicate. To increase killing of Pseudomonas, an antipseudomonal aminoglycoside (gen- tamicin, tobramycin, amikacin, netilmicin) may be added to the regimen. When these combinations are employed, the penicillin and the aminoglycoside should not be mixed in the same IV solution because high concentrations of penicillins can inactivate aminoglycosides.
Generic Name Brand Name
Usual Routes
Dosing Interval (hr)
Total Daily Dosagea
Adults Children
NARROW-SPECTRUM PENICILLINS: PENICILLINASE-SENSITIVE Penicillin G Bicillin C-R, Bicillin LA,
Pfizerpen IM, IV 4 1.2–24 million
unitsb 100,000–400,000 units/kgb
Penicillin V Generic only PO 4–6 0.5–2 gm 25–50 mg/kg
NARROW-SPECTRUM PENICILLINS: PENICILLINASE-RESISTANT (ANTISTAPHYLOCOCCAL PENICILLINS)
Nafcillin IV 4–6 2–12 gm 100–200 mg/kg
Oxacillin IV 4–6 1–12 gm 100–200 mg/kg
Dicloxacillin PO 6 0.5–4 gm 12.5–25 mg/kg
BROAD-SPECTRUM PENICILLINS (AMINOPENICILLINS)
Ampicillin Generic only PO 6–8 2–4 gm 50–100 mg/kg
IV 6–8 4–12 gm 50–400 mg/kg
Ampicillin/sulbactam Unasyn IV 6 4–8 gmc 150–600 mg/kgc
Amoxicillin Generic only PO 8 750–1750 mg 20–90 mg/kg
Amoxicillin, ER Moxatag PO 24 775 mg 775 mg
Amoxicillin/clavulanate Augmentin, Clavulin PO 8–12 250–1750 mgd 20–90 mg/kgd
Augmentin ES-600 PO 12 — 90 mg/kg
Augmentin XR PO 12 4000 mg —
EXTENDED-SPECTRUM PENICILLINS (ANTIPSEUDOMONAL PENICILLINS)
Piperacillin/tazobactam Zosyn, Tazocin IV 4–6 12–18 gme 80–100 mg/kge
TABLE 84.2 ■ Dosages for Penicillins
aDoses vary widely, depending upon the type and severity of infection; doses and dosing intervals presented here may not be appropriate for all patients.
b10,000 units = 6 mg.
cDose based on ampicillin content.
dDose based on amoxicillin content.
eDose based on piperacillin content.
ER, Extended release.
KEY POINTS
■ Penicillins weaken the bacterial cell wall, causing lysis and death.
■ Some bacteria resist penicillins by producing penicillinases (beta-lactamases), enzymes that inactivate penicillins.
■ Gram-negative bacteria are resistant to penicillins that cannot penetrate the gram-negative cell envelope.
■ Penicillins are the safest antibiotics available.
■ The principal adverse effect of penicillins is allergic reaction, which can range from rash to life-threatening anaphylaxis.
■ Patients allergic to one penicillin should be considered cross-allergic to all other penicillins. In addition, they have about a 1% chance of cross-allergy to cephalosporins.
■ Vancomycin, erythromycin, and clindamycin are safe and effective alternatives to penicillins for patients with penicil- lin allergy.
■ Penicillins are normally eliminated rapidly by the kidneys, but can accumulate to harmful levels if renal function is severely impaired.
■ The principal differences among the penicillins relate to antibacterial spectrum, stability in stomach acid, and duration of action.
■ Penicillin G has a narrow antibacterial spectrum and is unstable in stomach acid.
■ Benzathine penicillin G is released very slowly following IM injection and thereby produces prolonged antibacterial effects.
■ The penicillinase-resistant penicillins (e.g., nafcillin) are used primarily against penicillinase-producing strains of Staph. aureus.
■ In contrast to penicillin G, the broad-spectrum penicillins, such as ampicillin and amoxicillin, have useful activity against gram-negative bacilli.
■ The extended-spectrum penicillin—piperacillin—is useful against P. aeruginosa.
■ Beta-lactamase inhibitors, such as clavulanic acid, are combined with certain penicillins to increase their activity against beta-lactamase–producing bacteria.
■ Penicillins should not be combined with aminoglycosides (e.g., gentamicin) in the same IV solution.
Please visit http://evolve.elsevier.com/Lehne for chapter- specific NCLEX® examination review questions.
Summary of Major Nursing Implications
aPENICILLINS Amoxicillin
Amoxicillin/clavulanate Ampicillin
Ampicillin/sulbactam Dicloxacillin
Nafcillin Oxacillin Penicillin G Penicillin V Piperacillin
Piperacillin/tazobactam
Except where indicated otherwise, the implications here apply to all members of the penicillin family.
Preadministration Assessment Therapeutic Goal
Treatment of infections caused by sensitive bacteria.
Baseline Data
The prescriber may order tests to identify the infecting organism and its drug sensitivity. Take samples for micro- biologic culture before starting treatment.
In patients with a history of penicillin allergy, a skin test may be performed to determine current allergic status.
Identifying High-Risk Patients
Penicillins should be used with extreme caution, if at all, in patients with a history of severe allergic reactions to penicillins, cephalosporins, or carbapenems.
Implementation: Administration Routes
Penicillins are administered orally, IM, and IV. Before giving a penicillin, make sure the preparation is appropriate for the intended route.
Dosage
Doses for penicillin G are prescribed in units (1 unit equals 0.6 mg). Doses for all other penicillins are prescribed in milligrams or grams.
Administration
During IM injection, aspirate to avoid injection into an artery.
Take care to avoid injection into a nerve.
Instruct the patient to take oral penicillins with a full glass of water 1 hour before meals or 2 hours after. Penicillin V, amoxicillin, and amoxicillin/clavulanate may be taken with meals.
Instruct the patient to complete the prescribed course of treatment, even though symptoms may abate before the full course is over.
Continued
aPatient education information is highlighted as blue text.
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects
Monitor the patient for indications of antimicrobial effects (e.g., reduction in fever, pain, or inflammation; improved appetite or sense of well-being).
Monitoring Kidney Function
Renal impairment can cause penicillins to accumulate to toxic levels, and hence monitoring kidney function can help avoid injury. Measuring intake and output is especially helpful in patients with kidney disease, acutely ill patients, and the very old and very young. Notify the prescriber if a significant change in intake/output ratio develops.
Minimizing Adverse Effects
Allergic Reactions. Penicillin allergy is common. Very rarely, life-threatening anaphylaxis occurs. Interview the patient for a history of penicillin allergy.
For patients with prior allergic responses, a skin test may be ordered to assess current allergy status. Exercise caution:
The skin test itself can cause a severe reaction. When skin tests are performed, epinephrine and facilities for respiratory support should be immediately available.
Advise patients with penicillin allergy to wear some form of identification (e.g., Medic Alert bracelet) to alert emergency healthcare personnel.
Instruct outpatients to report any signs of an allergic response (e.g., skin rash, itching, hives).
Whenever a parenteral penicillin is used, keep the patient under observation for at least 30 minutes. If anaphylaxis
occurs, treatment consists of epinephrine (subQ, IM, or IV) plus respiratory support.
As a rule, patients with a history of penicillin allergy should not receive penicillins again. If previous reactions have been mild, a cephalosporin (preferably oral) may be an appropriate alternative. However, if severe immediate reactions have occurred, cephalosporins should be avoided too.
Rarely, a patient with a history of anaphylaxis nonetheless requires penicillin. To minimize the risk of a severe reaction, administer penicillin according to a desensitization schedule.
Be aware, however, that the procedure does not guarantee that anaphylaxis will not occur. Accordingly, have epinephrine and facilities for respiratory support immediately available.
Sodium Loading. High IV doses of sodium penicillin G can produce sodium overload. Exercise caution in patients under sodium restriction (e.g., cardiac patients, those with hypertension). Monitor electrolytes and cardiac status.
Hyperkalemia. High doses of IV potassium penicillin G may cause hyperkalemia, possibly resulting in dysrhythmias or cardiac arrest. Monitor electrolyte and cardiac status.
Effects Resulting From Incorrect Injection. Take care to avoid intra-arterial injection or injection into peripheral nerves because serious injury can result.
Minimizing Adverse Interactions
Aminoglycosides. When present in high concentration, penicillins can inactivate aminoglycosides (e.g., gentamicin).
Do not mix penicillins and aminoglycosides in the same IV solution.
Summary of Major Nursing Implications
a—cont’d
85 Drugs That Weaken the Bacterial Cell Wall II:
Cephalosporins, Carbapenems, Vancomycin, Telavancin,
Aztreonam, and Fosfomycin
Cephalosporins, p. 1039 Carbapenems, p. 1043
Imipenem, p. 1043
Other Inhibitors of Cell Wall Synthesis, p. 1044 Vancomycin, p. 1044
Telavancin, p. 1045 Aztreonam, p. 1045 Fosfomycin, p. 1047 Key Points, p. 1048
Summary of Major Nursing Implications, p. 1048 Box 85.1. Clostridium difficile Infection, p. 1046
(2) activate autolysins (enzymes that cleave bonds in the cell wall). The resultant damage to the cell wall causes death by lysis. Like the penicillins, cephalosporins are most effective against cells undergoing active growth and division.
Resistance
The principal cause of cephalosporin resistance is the production of beta-lactamases, enzymes that cleave the beta-lactam ring and thereby render these drugs inactive. Beta-lactamases that act on cephalosporins are sometimes referred to as cephalo- sporinases. Some of the beta-lactamases that act on cephalo- sporins can also cleave the beta-lactam ring of penicillins.
Not all cephalosporins are equally susceptible to beta- lactamases. Most first-generation cephalosporins are destroyed by beta-lactamases; second-generation cephalosporins are less sensitive to destruction; and third-, fourth-, and fifth-generation cephalosporins are highly resistant.
In some cases, bacterial resistance results from producing altered PBPs that have a low affinity for cephalosporins.
Methicillin-resistant staphylococci produce these unusual PBPs and are resistant to most cephalosporins as a result. Ceftaroline, a fifth-generation cephalosporin, has demonstrated activity against methicillin-resistant Staphylococcus aureus (MRSA).
Classification and Antimicrobial Spectra
The cephalosporins can be grouped into five “generations”
based on the order of their introduction to clinical use. The generations differ significantly with respect to antimicrobial spectrum and susceptibility to beta-lactamases (Table 85.1).
In general, as we progress from first-generation agents to fifth-generation agents, there is (1) increasing activity against gram-negative bacteria and anaerobes, (2) increasing resistance to destruction by beta-lactamases, and (3) increasing ability to reach the cerebrospinal fluid (CSF).
First Generation. First-generation cephalosporins, represented by cephalexin, are highly active against gram-positive bacteria. These drugs are the most active of all cephalosporins against staphylococci and nonenterococ- cal streptococci. However, staphylococci that are resistant to methicillin-like drugs are also resistant to first-generation cephalosporins (and to most other cephalosporins as well). The first-generation agents have only modest activity against gram-negative bacteria and do not reach effective concentrations in the CSF.
Second Generation. Second-generation cephalosporins (e.g., cefoxitin) have enhanced activity against gram-negative bacteria. The increase is due to a combination of factors: (1) increased affinity for PBPs of gram-negative
Like the penicillins, the drugs discussed here are inhibitors of cell wall synthesis. By disrupting the cell wall, these drugs produce bacterial lysis and death. Much of the chapter focuses on the cephalosporins, our most widely used antibacterial drugs.
With only three exceptions—vancomycin, telavancin, and fosfomycin—the agents addressed here are beta-lactam drugs.
CEPHALOSPORINS
The cephalosporins are beta-lactam antibiotics similar in struc- ture and actions to the penicillins. These drugs are bactericidal, often resistant to beta-lactamases, and active against a broad spectrum of pathogens. Their toxicity is low. Because of these attributes, the cephalosporins are popular therapeutic agents and constitute our most widely used group of antibiotics.
Chemistry
All cephalosporins are derived from the same nucleus. This nucleus contains a beta-lactam ring fused to a second ring.
The beta-lactam ring is required for antibacterial activity.
Mechanism of Action
The cephalosporins are bactericidal drugs with a mechanism like that of the penicillins. These agents bind to penicillin-binding proteins (PBPs) and thereby (1) disrupt cell wall synthesis and
Pharmacokinetics
Absorption. Because of poor absorption from the GI tract, many cephalosporins must be administered parenterally (IM or IV). Of the cephalosporins used in the United States, only 10 can be administered by mouth (Table 85.2). Of these, only one—cefuroxime—can be administered orally and by injection.
Distribution. Cephalosporins distribute well to most body fluids and tissues. Therapeutic concentrations are achieved in pleural, pericardial, and peritoneal fluids. However, concentra- tions in ocular fluids are generally low. Penetration to the CSF by first- and second-generation drugs is unreliable, and hence these drugs should not be used for bacterial meningitis.
In contrast, CSF levels achieved with third-, fourth-, and fifth-generation drugs are generally sufficient for bactericidal effects.
bacteria, (2) increased ability to penetrate the gram-negative cell envelope, and (3) increased resistance to beta-lactamases produced by gram-negative organisms. However, none of the second-generation agents is active against Pseudomonas aeruginosa. These drugs do not reach effective concentrations in the CSF.
Third Generation. Third-generation cephalosporins (e.g., cefotaxime) have a broad spectrum of antimicrobial activity. Because of increased resistance to beta-lactamases, these drugs are considerably more active against gram- negative aerobes than are the first- and second-generation agents. Some third-generation cephalosporins (e.g., ceftazidime) have important activity against P. aeruginosa. Others (e.g., cefixime) lack such activity. In contrast to first- and second-generation cephalosporins, the third-generation agents reach clinically effective concentrations in the CSF.
Fourth Generation. Cefepime, the only fourth-generation cephalosporin, is highly resistant to beta-lactamases and has a very broad antibacterial spectrum.
Activity against P. aeruginosa equals that of ceftazidime. Penetration to the CSF is good.
Fifth Generation. Ceftaroline [Teflaro]—has a spectrum like that of the third-generation agents, but with one important exception: ceftaroline is the only cephalosporin with activity against MRSA.
Class Activity Against
Gram-Negative Bacteria Resistance to
Beta-Lactamases Distribution to Cerebrospinal Fluid First generation
(e.g., cephalexin) Low Low Poor
Second generation
(e.g., cefoxitin) Higher Higher Poor
Third generation
(e.g., cefotaxime) Higher Higher Good
Fourth generation
(cefepime) Highest Highest Good
Fifth generation
(ceftaroline) High Highest Good
TABLE 85.1 ■ Major Differences Between Cephalosporin Generations
Class Drug Routes of
Administration Major Route of Elimination
Half-Life (hr) Normal Renal
Function Severe Renal Impairment
First Generation Cefadroxil PO Renal 1.2–1.3 20–25
Cefazolin IM, IV Renal 1.5–2.2 24–50
Cephalexin PO Renal 0.4–1 10–20
Second Generation Cefaclor PO Renal 0.6–0.9 2–3
Cefotetan IM, IV Renal 3–4.5 13–35
Cefoxitin IM, IV Renal 0.7–1 13–22
Cefprozil PO Renal 1.3 5–6
Cefuroxime PO, IM, IV Renal 1–1.9 15–22
Third Generation Cefdinir PO Renal 1.7 16
Cefditoren PO Renal 1.6 —
Cefixime PO Renal 3–4 11.5
Cefotaxime IM, IV Renal 0.9–1.4 3–11
Cefpodoxime PO Renal 2–3 9.8
Ceftazidime IM, IV Renal 1.9–2 —
Ceftibuten PO Renal 2 Increased
Ceftriaxone IM, IV Hepatic 5.8–8.7 15.7
Fourth Generation Cefepime IM, IV Renal 2 Increased
Fifth Generation Ceftaroline IV Renal 2.6 Increased
TABLE 85.2 ■ Pharmacokinetic Properties of the Cephalosporins
cause of pseudomembranous colitis due to colonic overgrowth with Clostridium difficile. If this superinfection develops, the cephalosporin should be discontinued and, if necessary, oral vancomycin should be given.
With one cephalosporin—cefditoren—there are two unique concerns. First, the drug contains a milk protein (sodium caseinate), and hence should be avoided by patients with milk-protein hypersensitivity (as opposed to lactose intolerance). Second, cefditoren is excreted in combination with carnitine, and hence can cause carnitine loss. Accordingly, the drug is contraindicated for patients with existing carnitine deficiency or with conditions that predispose to carnitine deficiency.
Drug Interactions
Probenecid. Probenecid delays renal excretion of some cephalosporins and can thereby prolong their effects. This is the same interaction that occurs between probenecid and penicillins.
Alcohol. Two cephalosporins—cefazolin and cefotetan—can induce a state of alcohol intolerance. If a patient taking these drugs were to ingest alcohol, a disulfiram-like reaction could occur. (As discussed in Chapter 38, the disulfiram effect, which can be very dangerous, is brought on by accumulation of acetaldehyde secondary to inhibition of aldehyde dehydroge- nase.) Patients using these cephalosporins must not consume alcohol in any form.
Drugs That Promote Bleeding. As noted, cefotetan and ceftriaxone can promote bleeding. Caution is needed if these drugs are combined with other agents that promote bleeding (anticoagulants, thrombolytics, NSAIDs, and other antiplatelet agents).
Calcium and Ceftriaxone. Combining calcium with ceftriaxone can form potentially fatal precipitates. In neonates, but not in older patients, the combination of IV calcium and IV ceftriaxone has caused death from the deposit of precipitates in the lungs and kidneys. To minimize risk, the following rules apply:
• Don’t reconstitute powdered ceftriaxone with calcium- containing diluents (e.g., Ringer’s solution).
• Don’t mix reconstituted ceftriaxone with calcium- containing solutions.
• For patients other than neonates, IV ceftriaxone and IV calcium may be administered sequentially (not concur- rently) through the same line, provided the line is flushed between the infusions.
• For neonates, don’t give IV ceftriaxone and IV calcium through the same line or different lines within 48 hours of each other. If the patient must receive ceftriaxone and calcium, use oral calcium or IM ceftriaxone.
Therapeutic Uses
The therapeutic role of the cephalosporins is continually evolving as new agents are introduced and more experience is gained with older ones. Only general recommendations are considered here.
The cephalosporins are broad-spectrum bactericidal drugs with a high therapeutic index. They have been employed widely and successfully against a variety of infections. Cephalosporins can be useful alternatives for patients with mild penicillin allergy.
The five generations of cephalosporins differ significantly in their applications. With one important exception—the use of first-generation agents for infections caused by sensitive staphylococci—the first- and second-generation cephalosporins Elimination. Practically all cephalosporins are eliminated
by the kidneys; excretion is by a combination of glomerular filtration and active tubular secretion. Probenecid can decrease tubular secretion of some cephalosporins, thereby prolonging their effects. In patients with renal insufficiency, dosages of most cephalosporins must be reduced (to prevent accumulation to toxic levels).
One cephalosporin—ceftriaxone—is eliminated largely by the liver. Consequently, dosage reduction is unnecessary in patients with renal impairment.
Adverse Effects
Cephalosporins are generally well tolerated and constitute one of our safest groups of antimicrobial drugs. Serious adverse effects are rare.
Allergic Reactions. Hypersensitivity reactions are the most frequent adverse events. Maculopapular rash that develops several days after the onset of treatment is most common.
Severe, immediate reactions (e.g., bronchospasm, anaphylaxis) are rare. If, during the course of treatment, signs of allergy appear (e.g., urticaria, rash, hypotension, difficulty in breathing), the cephalosporin should be discontinued immediately. Ana- phylaxis is treated with respiratory support and parenteral epinephrine. Patients with a history of cephalosporin allergy should not be given these drugs.
Because of structural similarities between penicillins and cephalosporins, a few patients allergic to one type of drug may experience cross-reactivity with the other. In clinical practice, the incidence of cross-reactivity has been low: Only 1% of penicillin-allergic patients experience an allergic reaction if given a cephalosporin. For patients with mild penicillin allergy, cephalosporins can be used with minimal concern.
However, because of the potential for fatal anaphylaxis, cephalosporins should not be given to patients with a history of severe reactions to penicillins.
Bleeding. Two cephalosporins—cefotetan and ceftriaxone—
can cause bleeding tendencies. The mechanism is reduction of prothrombin levels through interference with vitamin K metabolism.
Several measures can reduce the risk of hemorrhage. During prolonged treatment, patients should be monitored for pro- thrombin time, bleeding time, or both. Parenteral vitamin K can correct an abnormal prothrombin time. Patients should be observed for signs of bleeding; if bleeding develops, the cephalosporin should be withdrawn. Caution should be exercised during concurrent use of anticoagulants or thrombolytic agents.
Because of their antiplatelet effects, aspirin and other nonste- roidal anti-inflammatory drugs (NSAIDs) should be used with care. Caution is needed in patients with a history of bleeding disorders.
Thrombophlebitis. Thrombophlebitis may develop during IV infusion. This reaction can be minimized by rotating the infusion site and by administering cephalosporins slowly and in dilute solution. Patients should be observed for phlebitis.
If it develops, the infusion site should be changed.
Hemolytic Anemia. Rarely, cephalosporins have induced immune-mediated hemolytic anemia, a condition in which antibodies mediate destruction of red blood cells. If hemolytic anemia develops, the cephalosporin should be discontinued.
Blood transfusions may be given as needed.
Other Adverse Effects. Cephalosporins may cause pain at sites of IM injection; patients should be forewarned. Rarely, cephalosporins may be the
there is frequently no rational basis for choosing one drug over another in the outpatient setting. However, there are some differences between cephalosporins, and these differences may render one agent preferable to another for treating a specific infection in a specific host. The differences that do exist can be grouped into two main categories: antimicrobial spectrum and pharmacokinetics (e.g., route of administration, penetration to the CSF, time course, mode of elimination). Drug selection based on these differences is discussed next.
Antimicrobial Spectrum. A prime rule of antimicrobial therapy is to match the drug with the bug: The drug should be active against known or suspected pathogens, but its spectrum should be no broader than required.
When a cephalosporin is appropriate, we should select from among those drugs known to have good activity against the causative pathogen. The third- and fourth-generation agents, with their very broad antimicrobial spectra, should be avoided in situations where a narrower spectrum, first- or second-generation drug would suffice.
For some infections, one cephalosporin may be decidedly more effective than all others and should be selected on this basis. For example, ceftazidime (a third-generation drug) is the most effective of all cephalosporins against P. aeruginosa and is clearly the preferred cephalosporin for treating infections caused by this microbe. Similarly, ceftaroline is the only cephalosporin with activity against MRSA, and hence is preferred to all other cephalosporins for treating these infections.
Pharmacokinetics. Four pharmacokinetic properties are of interest: (1) route of administration, (2) duration of action, (3) distribution to the CSF, and (4) route of elimination. The relationship of these properties to drug selection is discussed here.
Route of Administration. Ten cephalosporins can be administered orally. These drugs may be preferred for mild to moderate infections in patients who can’t tolerate parenteral agents.
Duration of Action. In patients with normal renal function, the half-lives of the cephalosporins range from about 30 minutes to 9 hours (see Table 85.2). Because they require fewer doses per day, drugs with a long half-life are frequently preferred. Cephalosporins with the longest half-lives in each generation are as follows: first generation, cefazolin (1.5 to 2 hours); second generation, cefotetan (3 to 4.5 hours); and third generation, ceftriaxone (6 to 9 hours).
Distribution to CSF. Only the third- and fourth-generation agents achieve CSF concentrations sufficient for bactericidal effects. Hence, for meningitis caused by susceptible organisms, these drugs are preferred over first- and second-generation agents. It is suspected that the fifth-generation drug, cef- taroline, would be successful in treating infections of the CSF. A trial is currently recruiting participants to evaluate the use of ceftaroline in this capacity.
Route of Elimination. Most cephalosporins are eliminated by the kidneys; if dosage is not carefully adjusted, these drugs may accumulate to toxic levels in patients with renal impairment. Only one agent—ceftriaxone—is eliminated primarily by nonrenal routes, and hence can be used with relative safety in patients with kidney dysfunction.
Dosage and Administration
Routes. Many cephalosporins cannot be absorbed from the GI tract and must therefore be administered parenterally (IM or IV). Only 10 cephalosporins can be given orally. One drug—cefuroxime—can be administered both orally and by injection.
Dosage. Dosages are shown in Table 85.3. For most cephalosporins (ceftriaxone excepted), dosage should be reduced in patients with significant renal impairment.
Administration
Oral. If oral cephalosporins produce nausea, administration with food can reduce the response. Oral suspensions should be stored cold.
Intramuscular. Intramuscular injections should be made deep into a large muscle. Intramuscular injection of cephalosporins is frequently painful; the patient should be forewarned. The injection site should be checked for indura- tion, tenderness, and redness, and the prescriber should be informed if these occur.
Intravenous. For IV therapy, cephalosporins may be administered by three techniques: (1) bolus injection, (2) slow injection (over 3 to 5 minutes), and (3) continuous infusion over 30 to 60 minutes. The prescriber’s order should state which method to use. If there is uncertainty as to method, request clarification. Prepare solutions for parenteral administration according to the manufacturer’s recommendations.
are rarely drugs of choice for active infections. In most cases, equally effective and less expensive alternatives are available.
In contrast, the third-generation agents have qualities that make them the preferred therapy for several infections. The fourth- and fifth-generation agents are effective against resistant organisms.
The fifth-generation agent is used to treat skin infections, including MRSA, and healthcare-associated pneumonias.
First-Generation Cephalosporins. When a cephalosporin is indicated for a gram-positive infection, a first-generation drug should be used; these agents are the most active of the cephalosporins against gram-positive organisms and are less expensive than other cephalosporins. First-generation agents are frequently employed as alternatives to penicillins to treat infections caused by staphylococci or streptococci (except enterococci) in patients with penicillin allergy. However, it is important to note that cephalosporins should be given only to patients with a history of mild penicillin allergy—not those who have experienced a severe, immediate hypersensitivity reaction.
The first-generation agents have been employed widely for prophylaxis against infection in surgical patients. First-generation agents are preferred to second- or third-generation cephalosporins for surgical prophylaxis because they are as effective as the newer drugs, are less expensive, and have a more narrow antimicrobial spectrum.
Second-Generation Cephalosporins. Specific indications for second-generation cephalosporins are limited. Cefuroxime has been used with success against pneumonia caused by Haemophilus influenzae, Klebsiella, pneumococci, and staphylococci. Oral cefuroxime is useful for otitis, sinusitis, and respiratory tract infections. Cefoxitin is useful for abdominal and pelvic infections.
Prototype Drugs
DRUGS THAT INHIBIT CELL WALL SYNTHESIS Cephalosporins
Cephalexin Carbapenems Imipenem Others Vancomycin
Third-Generation Cephalosporins. Because they are highly active against gram-negative organisms and because they penetrate to the CSF, third- generation cephalosporins are drugs of choice for meningitis caused by enteric, gram-negative bacilli. Ceftazidime is of special utility for treating meningitis caused by P. aeruginosa. Nosocomial infections caused by gram-negative bacilli, which are often resistant to first- and second-generation cephalosporins (and most other commonly used antibiotics), are appropriate indications for the third-generation drugs. Two third-generation agents—ceftriaxone and cefotaxime—are drugs of choice for infections caused by Neisseria gonorrhoeae (gonorrhea), H. influenzae, Proteus, Salmonella, Klebsiella, and Serratia;
these drugs are also effective against meningitis caused by Streptococcus pneumoniae, a gram-positive bacterium.
Fourth-Generation Cephalosporins. There is only one drug in this category: cefepime [Maxipime]. Cefepime is commonly used to treat healthcare- and hospital-associated pneumonias, including those caused by the resistant organism Pseudomonas.
Fifth-Generation Cephalosporins. Ceftaroline [Teflaro] is the only cephalosporin adequate for the treatment of MRSA-associated infections.
Drug Selection
Eighteen cephalosporins are currently employed in the United States, and selection among them can be a challenge. Within each generation, the similarities among cephalosporins are more pronounced than the differences. Hence, aside from cost,
drugs should be reserved for patients who cannot be treated with a more narrow-spectrum agent.
Imipenem
Imipenem [Primaxin], a beta-lactam antibiotic, has an extremely broad antimicrobial spectrum—broader, in fact, than nearly all
CARBAPENEMS
Carbapenems are beta-lactam antibiotics that have very broad antimicrobial spectra—although none is active against MRSA.
Four carbapenems are available: imipenem, meropenem, ertapenem, and doripenem. With all four, administration is parenteral (Table 85.4). To delay emergence of resistance, these
Drug Brand Name Route
Dosing Interval (hr)
Total Daily Dosagea
Adults (gm) Children (mg/kg) FIRST GENERATION
Cefadroxil Generic only PO 12, 24 1–2 30
Cefazolin Generic only IM, IV 6, 8 2–12 80–160
Cephalexin Keflex PO 6 1–4 25–100
SECOND GENERATION
Cefaclor Raniclor PO 8 0.75–1.5 20–40
Cefotetan Generic only IM, IV 12 1–6 —
Cefoxitin Generic only IM, IV 4, 8 3–12 80–160
Cefprozil Generic only PO 12, 24 0.5–1 15–30
Cefuroxime Ceftin PO 12 0.5–1 250–500
Zinacef IM, IV 8 1.5–6 50–100
THIRD GENERATION
Cefdinir Omnicef PO 12, 24 0.6 14
Cefditoren Spectracef PO 12 0.4–0.8 —
Cefixime Suprax PO 24 0.4 8
Cefotaxime Claforan IM, IV 4, 8 2–12 100–200
Cefpodoxime Vantin PO 12 0.2–0.4 10
Ceftazidime Fortaz,
Tazicef IM, IV 8, 12 0.5–6 60–150
Ceftibuten Cedax PO 24 0.4 9
Ceftriaxone Rocephin IM, IV 12, 24 1–4 50–100
FOURTH GENERATION
Cefepime Maxipime IM, IV 12 1–6 100–150
FIFTH GENERATION
Ceftaroline Teflaro IV 12 1.2 —
TABLE 85.3 ■ Cephalosporin Dosages
aWith the exception of ceftriaxone, cephalosporins require a dosage reduction in patients with severe renal impairment.
Drug Uses Pharmacokinetics Adverse Effects Preparations and
Adult Dosage Imipenem Most gram-positive and gram-
negative aerobes and anaerobes Half-life: 1 hr
Excretion: urine Nausea, vomiting, diarrhea
Rarely causes seizure activity IV; 500 mg every 6 hr Meropenem Gram-positive and gram-negative
aerobes and anaerobes Half-life: 1 hr
Excretion: urine Rash, nausea, vomiting
Rarely causes seizure activity IV; 1 gm every 8 hr Ertapenem Most gram-positive bacteria and
anaerobes Half-life: 4 hr
Excretion: urine, feces Diarrhea, nausea, headache IM/IV; 1 gm every 24 hr Doripenem Gram-positive, gram-negative, and
anaerobic bacteria, including P.
aeruginosa
Half-life: 1 hr
Excretion: urine Headache, nausea, rash,
phlebitis at injection site IV; 500 mg every 8 hr TABLE 85.4 ■ Carbapenems
with another antipseudomonal drug when used against this microbe.
Preparations, Dosage, and Administration
Imipenem is formulated in 1 : 1 fixed-dose combinations with cilastatin. This combination product is marketed under the brand name Primaxin. This product is supplied in powdered form and must be reconstituted in accord with the manufacturer’s instructions. The usual adult dosage is 500 mg every 6 hours.
Dosage should be reduced in patients with renal impairment.
other antimicrobial drugs. As a result, imipenem may be of special use for treating mixed infections in which anaerobes, Staph. aureus, and gram-negative bacilli may all be involved.
Imipenem is supplied in fixed-dose combinations with cilastatin, a compound that inhibits destruction of imipenem by renal enzymes.
Mechanism of Action
Imipenem binds to two PBPs (PBP1 and PBP2), causing weakening of the bacterial cell wall with subsequent cell lysis and death. Antimicrobial effects are enhanced by the drug’s resistance to practically all beta-lactamases and by its ability to penetrate the gram-negative cell envelope.
Antimicrobial Spectrum
Imipenem is active against most bacterial pathogens, including organisms resistant to other antibiotics. The drug is highly active against gram-positive cocci and most gram- negative cocci and bacilli. In addition, imipenem is the most effective beta-lactam antibiotic for use against anaerobic bacteria.
Pharmacokinetics
Imipenem is not absorbed from the GI tract and hence must be given intravenously. The drug is well distributed to body fluids and tissues. Imipenem penetrates the meninges to produce therapeutic concentrations in the CSF.
Elimination is primarily renal. When employed alone, imipenem is inactivated by dipeptidase, an enzyme present in the kidneys. As a result, drug levels in urine are low. To increase urinary concentrations, imipenem is administered in combination with cilastatin, a dipeptidase inhibitor. When the combination is used, about 70% of imipenem is excreted unchanged in the urine. The elimination half-life is about 1 hour.
Adverse Effects
Imipenem is generally well tolerated. Gastrointestinal effects (nausea, vomiting, diarrhea) are most common. Superinfections with bacteria or fungi develop in about 4% of patients. Rarely, seizures have occurred.
Hypersensitivity reactions (rashes, pruritus, drug fever) have occurred, and patients allergic to other beta-lactam antibiotics may be cross-allergic with imipenem. Fortunately, the incidence of cross-sensitivity with penicillins is low—only about 1%.
Interaction With Valproate
Imipenem can reduce blood levels of valproate, a drug used to control seizures (see Chapter 24). Breakthrough seizures have occurred. If possible, combined use of imipenem and valproate should be avoided. If no other antibiotic will suffice, supplemental antiseizure therapy should be considered.
Therapeutic Use
Because of its broad spectrum and low toxicity, imipenem is used widely. The drug is effective for serious infections caused by gram-positive cocci, gram-negative cocci, gram-negative bacilli, and anaerobic bacteria. This broad antimicrobial spectrum gives imipenem special utility for antimicrobial therapy of mixed infections (e.g., simultaneous infection with aerobic and anaerobic bacteria). When imipenem has been given alone to treat infection with P. aeruginosa, resistant organisms have emerged. Consequently, imipenem should be combined
Cephalosporins, Carbapenems, and Others
Life Stage Patient Care Concerns
Infants Third-generation cephalosporins are used to treat bacterial infections in neonates, as well as infants.
Children/
adolescents Cephalosporins are commonly used to treat bacterial infections in children, including otitis media and gonococcal and pneumococcal infections.
Pregnant women Administration of telavancin during pregnancy should be avoided due to a risk for adverse developmental outcomes. All cephalosporins appear safe for use in pregnancy and are classified in FDA Pregnancy Risk Category B.a
Breast-feeding
women Cephalosporins are generally not expected to cause adverse effects in breast-fed infants.
Older adults Doses should be adjusted in older adults with decreased renal function.
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
aAs of 2020, the FDA will no longer use Pregnancy Risk Categories.
Please refer to Chapter 9 for more information.
OTHER INHIBITORS OF CELL WALL SYNTHESIS
Vancomycin
Vancomycin [Vancocin] is the most widely used antibiotic in U.S. hospitals. Principal indications are C. difficile infection (CDI), MRSA infection, and the treatment of serious infections with susceptible organisms in patients allergic to penicillins.
The major toxicity is renal failure. Unlike most other drugs discussed here, vancomycin does not contain a beta-lactam ring.
Mechanism of Action
Like the beta-lactam antibiotics, vancomycin inhibits cell wall synthesis and thereby promotes bacterial lysis and death.
However, in contrast to the beta-lactams, vancomycin does not interact with PBPs. Instead, it disrupts the cell wall by binding to molecules that serve as precursors for cell wall biosynthesis.
Antimicrobial Spectrum
Vancomycin is active only against gram-positive bacteria. The drug is especially active against Staph. aureus and Staphylococcus epidermidis, including strains of both species that are methicillin resistant. Other susceptible organisms include streptococci, penicillin-resistant pneumococci, and C. difficile.