Drugs that weaken the bacterial cell wall II: cephalosporins, carbapenems, vancomycin, telavancin, aztreonam, teicoplanin, and fosfomycin

CHAPTER 85


Drugs that weaken the bacterial cell wall II: cephalosporins, carbapenems, vancomycin, telavancin, aztreonam, teicoplanin, and fosfomycin


Like the penicillins, the drugs discussed in this chapter 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 four exceptions—vancomycin, telavancin, teicoplanin, and fosfomycin—the agents addressed here are beta-lactam drugs.




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.


image
Figure 85–1  Structural formulas of representative cephalosporins.
The unique structure and pharmacologic properties of individual cephalosporins are determined by additions made to the cephalosporin nucleus at the positions labeled R1 and R2.



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.











Third generation.


Third-generation cephalosporins (eg, 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 (eg, ceftazidime) have important activity against P. aeruginosa. Others (eg, cefixime) lack such activity. A new drug—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 methicillin-resistant Staphylococcus aureus (MRSA). In contrast to first- and second-generation cephalosporins, the third-generation agents reach clinically effective concentrations in the CSF.





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.






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.




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 cause of pseudomembranous colitis due to colonic overgrowth with Clostridium difficile. If this suprainfection 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



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.




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:




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.








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. Why? Because they are as effective as the newer drugs, are less expensive, and have a more narrow antimicrobial spectrum.




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. One agent—ceftaroline—is the only cephalosporin approved for MRSA infections.


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.




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.








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 below.




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).





Dosage and administration



Routes.


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.



Dosage.


Dosages are summarized in Table 85–3. For most cephalosporins (ceftriaxone excepted), dosage should be reduced in patients with significant renal impairment.

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Jul 24, 2016 | Posted by in NURSING | Comments Off on Drugs that weaken the bacterial cell wall II: cephalosporins, carbapenems, vancomycin, telavancin, aztreonam, teicoplanin, and fosfomycin

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