Drugs that weaken the bacterial cell wall II: cephalosporins, carbapenems, vancomycin, telavancin, aztreonam, teicoplanin, and fosfomycin
Cephalosporins
The cephalosporins are beta-lactam antibiotics similar in structure 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. As shown in Figure 85–1, this nucleus contains a beta-lactam ring fused to a second ring. The beta-lactam ring is required for antibacterial activity. Unique properties of individual cephalosporins are determined by additions made to the nucleus at the sites labeled R1 and R2.
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 (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 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 cephalosporinases. Some of the beta-lactamases that act on cephalosporins 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– and fourth-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 cephalosporins as a result.
Classification and antimicrobial spectra
The cephalosporins can be grouped into four “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. In general, as we progress from first-generation agents to fourth-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). These differences are summarized in Table 85–1.
TABLE 85–1 
Major Differences Between Cephalosporin Generations
| Class | Activity Against Gram-Negative Bacteria | Resistance to Beta-Lactamases | Distribution to Cerebrospinal Fluid |
| First generation (eg, cephalexin) | Low | Low | Poor |
| Second generation (eg, cefoxitin) | Higher | Higher | Poor |
| Third generation (eg, cefotaxime) | Higher | Higher | Good |
| Fourth generation (cefepime) | Highest | Highest | Good |
Pharmacokinetics
Absorption.
Because of poor absorption from the GI tract, many cephalosporins must be administered parenterally (IM or IV). Of the 20 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.
TABLE 85–2 
Pharmacokinetic Properties of the Cephalosporins
| Half-Life (hr) | |||||
| Class | Drug | Routes of Administration | Major Route of Elimination | 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 | |
| Cefoperazone | IM, IV | Biliary | 1.7–2.6 | 2.2 | |
| Cefotaxime | IM, IV | Renal | 0.9–1.4 | 3–11 | |
| Cefpodoxime | PO | Renal | 2–3 | 9.8 | |
| Ceftaroline* | IV | Renal | 2.6 | Increased | |
| Ceftazidime | IM, IV | Renal | 1.9–2 | — | |
| Ceftibuten | PO | Renal | 2 | Increased | |
| Ceftizoxime | IM, IV | Renal | 1.1–2.3 | 30 | |
| Ceftriaxone | IM, IV | Hepatic | 5.8–8.7 | 15.7 | |
| Fourth Generation | Cefepime | IM, IV | Renal | 2 | Increased |
*Ceftaroline is classified here as a third-generation cephalosporin, because it has an antimicrobial spectrum much like that of ceftriaxone. However, ceftaroline is sometimes classified as a fifth-generation agent, because it is the only cephalosporin with activity against MRSA.
Distribution.
Cephalosporins distribute well to most body fluids and tissues. Therapeutic concentrations are achieved in pleural, pericardial, and peritoneal fluids. However, concentrations 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- and fourth-generation drugs are generally sufficient for bactericidal effects.
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 (eg, bronchospasm, anaphylaxis) are rare. If, during the course of treatment, signs of allergy appear (eg, urticaria, rash, hypotension, difficulty in breathing), the cephalosporin should be discontinued immediately. Anaphylaxis 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.
Three cephalosporins—cefoperazone, 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 prothrombin time, bleeding time, or both. Parenteral vitamin K can correct an abnormal prothrombin time. Patients should be observed for signs of bleeding, and, 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 nonsteroidal anti-inflammatory drugs should be used with care. Caution is needed in patients with a history of bleeding disorders.
Drug interactions
Alcohol.
Four cephalosporins—cefazolin, cefmetazole, cefoperazone, 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 dehydrogenase.) Patients using these cephalosporins must not consume alcohol in any form.
Drugs that promote bleeding.
As noted, cefmetazole, cefoperazone, cefotetan, and ceftriaxone can promote bleeding. Caution is needed if these drugs are combined with other agents that promote bleeding (anticoagulants, thrombolytics, nonsteroidal anti-inflammatory drugs 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 depositing precipitates in the lungs and kidneys. To minimize risk, the following rules apply:
• Don’t reconstitute powdered ceftriaxone with calcium-containing diluents (eg, 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 concurrently) 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 four 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 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 role of fourth-generation agents is yet to be established.
Drug selection
Twenty 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, there is frequently no rational basis for choosing one drug over another. 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 three main categories: (1) antimicrobial spectrum, (2) adverse effects, and (3) pharmacokinetics (eg, route of administration, penetration to the CSF, time course, mode of elimination). Drug selection based on these differences is discussed below.
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.
Although most cephalosporins produce the same spectrum of adverse effects, a few can cause unique reactions. For example, cefmetazole, cefoperazone, cefotetan, and ceftriaxone can cause bleeding tendencies. When an equally effective alternative is available, it would be prudent to avoid these drugs.
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 below.
Ten cephalosporins can be administered orally. These drugs may be preferred for mild to moderate infections in patients who can’t tolerate parenteral agents.
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).
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.
Most cephalosporins are eliminated by the kidneys and, if dosage is not carefully adjusted, 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.
Many cephalosporins cannot be absorbed from the GI tract and must therefore be administered parenterally (IM or IV). As shown in Table 85–2, only 10 cephalosporins can be given orally. One drug—cefuroxime—can be administered both orally and by injection.
Dosages are summarized in Table 85–3. For most cephalosporins (ceftriaxone excepted), dosage should be reduced in patients with significant renal impairment.
TABLE 85–3 
| Dosing Interval (hr) | Total Daily Dosage* | ||||
| Drug | Trade Name | Route | 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 | 25–50 |
| Second Generation | |||||
| Cefaclor | Ceclor, Raniclor | PO | 8 | 0.75–1.5 | 20–40 |
| Cefotetan | generic only | IM, IV | 12 | 2–6 | — |
| Cefoxitin | generic only | IM, IV | 4, 8 | 3–12 | 80–160 |
| Cefprozil | generic only | PO | 12, 24 | 0.5–1 | 30 |
| Cefuroxime | Ceftin | PO | 12 | 0.5–1 | 250–500 |
| Zinacef | IM, IV | 8 | 2.25–9 | 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 |
| Cefoperazone | Cefobid | IM, IV | 6, 8 | 2–12 | 100–150 |
| Cefotaxime | Claforan | IM, IV | 4, 8 | 2–12 | 100–200 |
| Cefpodoxime | Vantin | PO | 12 | 0.2–0.4 | 10 |
| Ceftaroline† | Teflaro | IV | 12 | 1.2 | — |
| Ceftazidime | Ceptaz, Fortaz, Tazidime, Tazicef | IM, IV | 8, 12 | 0.5–6 | 90–150 |
| Ceftibuten | Cedax | PO | 24 | 0.4 | 9 |
| Ceftizoxime | Cefizox | IM, IV | 6, 12 | 2–12 | 150–200 |
| Ceftriaxone | Rocephin | IM, IV | 12, 24 | 1–4 | 50–100 |
| Fourth Generation | |||||
| Cefepime | Maxipime | IM, IV | 12 | 1–2 | 100 |
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