Cephalosporin Cephalexin Carbapenem Imipenem Other 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, and Proteus, Salmonella, Klebsiella, and Serratia species; these drugs are also effective against meningitis caused by Streptococcus pneumoniae, a gram-positive bacterium.
The third-generation cephalosporins should not be used routinely. Rather, they should be given only when conditions demand so as to delay emergence of resistance.
Fourth-Generation Cephalosporins
There are only two drugs in this category: cefepime [Maxipime] and ceftolozane/tazobactam [Zerbaxa]. Cefepime is commonly used to treat health care− and hospital-associated pneumonias, including those caused by the resistant organism Pseudomonas. Zerbaxa was approved in 2014 for the treatment of complicated intraabdominal and urinary tract infections.
Fifth-Generation Cephalosporins
Ceftaroline [Teflaro] is the only cephalosporin adequate for the treatment of MRSA-associated infections.
Drug Selection
Nineteen 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 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 three main categories: (1) antimicrobial spectrum, (2) adverse effects, and (3) pharmacokinetics (e.g., route of administration, penetration to the CSF, time course, mode of elimination). Drug selection based on these differences is discussed here.
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 in which 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.
Adverse Effects
Although most cephalosporins produce the same spectrum of adverse effects, a few can cause unique reactions. For example, cefotetan and ceftriaxone can cause bleeding tendencies. When an equally effective alternative is available, it would be prudent to avoid these drugs.
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 next.
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 70.2). 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 (1.5–2 hours); second generation, cefotetan (3–4.5 hours); and third generation, ceftriaxone (6–9 hours).
Distribution to Cerebrospinal Fluid
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.
Route of Elimination
Most cephalosporins are eliminated by the kidneys and, if dosage is not carefully adjusted, they 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 70.3. For most cephalosporins (ceftriaxone excepted), dosage should be reduced in patients with significant renal impairment.
TABLE 70.3
Cephalosporin Dosages
| Drug | Trade Name | Route | Dosing Interval (hr) | Total Daily Dosage* | |
| Adults (g) | 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 | Mefoxin | 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 |
| Ceftolozane/tazobactam | Zerbaxa | IV | 8 | 4.5 | — |
| FIFTH GENERATION | |||||
| Ceftaroline | Teflaro | IV | 12 | 1.2 | — |
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 induration, tenderness, and redness, and the prescriber informed if these occur.
Intravenous
For IV therapy, cephalosporins may be administered by three techniques: (1) bolus injection, (2) slow injection (over 3–5 minutes), and (3) continuous infusion over 30 to 60 minutes. Your prescriber order should state which method to use.
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. To delay emergence of resistance, these 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 other antimicrobial drugs. As a result, imipenem may be of special use for treating mixed infections in which anaerobes, S. 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 19). 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 with another antipseudomonal drug when used against this microbe. Dosing for the carbapenems is provided in Table 70.4.
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
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 because of risk for adverse developmental outcomes. All cephalosporins appear safe for use in pregnancy and are classified in FDA Pregnancy Risk Category B. |
| Breastfeeding women | Cephalosporins are generally not expected to cause adverse effects in breastfed infants. |
| Older adults | Doses should be adjusted in older adults with decreased renal function. |
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