Pediatric Annals

A Strategy for Evaluating Which of the New Cephalosporins to Use

Ram Yogev, MD

Abstract

A recent letter from a pediatrician to the editor of the New England journal of Medicine1 expresses the confusion and frustration that most of us experience when we have to deal with the avalanche of the new cephalosporins. It is impossible for the practicing physician to become familiar with all the subtle differences among the various cephalosporins; thus, he depends more on somewhat biased advertising and pharmaceutical company representatives to provide him with the necessary information.

Do we really have to know all the details about the new cephalosporins, or, by making simple manipulations of the available data, can we familiarize ourselves with very few of these agents without denying the patient the best antibiotic? The purpose of this review is to formulate a strategy with which any physician will be able to evaluate the new cephalosporins and to choose the best one for him/her. Table 1 summarizes the cephalosporins which will be discussed in this review.

As can be seen in the Table, the cephalosporins are divided into three "generations." A practical way to define "generation" is by its in vitro activity against gram-negative bacteria. First-generation agents are usually active against E. coli, P. mirabilis and K. pneumoniae. The second-generation are in addition usually active against H. infiuenzae, Neisseria sp. and Enterobacter sp. The third-generation agents have a more expanded spectrum which covers most of the enteric bacteria. It is important to note that in general as activity against gram-negative organisms increases, activity against gram-positives decreases. Therefore, the first-generation cephalosporins are the cephalosporins of choice for treatment of gram-positive infections, while the second- and third-generation agents should be reserved for treatment of gram-negative infections. None of the cephalosporins are active against the bacteria shown in Table 2, and any infection in which these bacteria are suspected as the etiologic agent(s) should not be treated with cephalosporins. The only exception to this rule is Pseudomonas because ceftazidime is active against this genus. Thus, the only indication for using ceftazidime as a first-line agent in pediatrics is in management of Pseudomonas oeruginosa infections.

To make this discussion clearer, let us consider the activity of the cephalosporins against common pathogens encountered in pediatrie practice. Table 3 summarizes the in vitro activity (expressed as the amount needed to inhibit 90% of the strains tested = MIC90) of the various cephalosporins against six common aerobic and one anaerobic bacteria. Several important conclusions can be drawn from this table. First, cefoperazone is the least active drug against many of these bacteria, and thus it seems highly unlikely that this drug will have any first line indication in pediatrics. Therefore, we shall omit cefoperazone from further discussions. Second, moxalactam is the least active of the third-generation cephalosporins against gram-positive bacteria (eg, S. pneumoniae and group B streptococci). Thus, for many pediatrie infections such as meningitis, neonatal sepsis, or pneumonia, moxalactam should not be used as a single drug before the pathogen is identified. Third, the newer cephalosporins do not have much activity against B. /ragi/is, so that other antibiotics such as metronidazole or ciindamycin should be used instead for infections with this organism. Fourth, when considering the gram-negative bacteria shown in Table 3 (eg, Neisseria, Haemophilus and E. coli), there is not much difference in activity among the various third-generation cephalosporins. In contrast, cefuroxime (a second-generation cephalosporin) is not active against E. coli and therefore should not be used to treat neonatal infections when the pathogen is unknown. Fifth, as stated previously, first-generation cephalosporins are more active against gram-positive bacteria. From these conclusions, we can see that other characteristics of the various cephalosporins must be taken…

A recent letter from a pediatrician to the editor of the New England journal of Medicine1 expresses the confusion and frustration that most of us experience when we have to deal with the avalanche of the new cephalosporins. It is impossible for the practicing physician to become familiar with all the subtle differences among the various cephalosporins; thus, he depends more on somewhat biased advertising and pharmaceutical company representatives to provide him with the necessary information.

Do we really have to know all the details about the new cephalosporins, or, by making simple manipulations of the available data, can we familiarize ourselves with very few of these agents without denying the patient the best antibiotic? The purpose of this review is to formulate a strategy with which any physician will be able to evaluate the new cephalosporins and to choose the best one for him/her. Table 1 summarizes the cephalosporins which will be discussed in this review.

As can be seen in the Table, the cephalosporins are divided into three "generations." A practical way to define "generation" is by its in vitro activity against gram-negative bacteria. First-generation agents are usually active against E. coli, P. mirabilis and K. pneumoniae. The second-generation are in addition usually active against H. infiuenzae, Neisseria sp. and Enterobacter sp. The third-generation agents have a more expanded spectrum which covers most of the enteric bacteria. It is important to note that in general as activity against gram-negative organisms increases, activity against gram-positives decreases. Therefore, the first-generation cephalosporins are the cephalosporins of choice for treatment of gram-positive infections, while the second- and third-generation agents should be reserved for treatment of gram-negative infections. None of the cephalosporins are active against the bacteria shown in Table 2, and any infection in which these bacteria are suspected as the etiologic agent(s) should not be treated with cephalosporins. The only exception to this rule is Pseudomonas because ceftazidime is active against this genus. Thus, the only indication for using ceftazidime as a first-line agent in pediatrics is in management of Pseudomonas oeruginosa infections.

To make this discussion clearer, let us consider the activity of the cephalosporins against common pathogens encountered in pediatrie practice. Table 3 summarizes the in vitro activity (expressed as the amount needed to inhibit 90% of the strains tested = MIC90) of the various cephalosporins against six common aerobic and one anaerobic bacteria. Several important conclusions can be drawn from this table. First, cefoperazone is the least active drug against many of these bacteria, and thus it seems highly unlikely that this drug will have any first line indication in pediatrics. Therefore, we shall omit cefoperazone from further discussions. Second, moxalactam is the least active of the third-generation cephalosporins against gram-positive bacteria (eg, S. pneumoniae and group B streptococci). Thus, for many pediatrie infections such as meningitis, neonatal sepsis, or pneumonia, moxalactam should not be used as a single drug before the pathogen is identified. Third, the newer cephalosporins do not have much activity against B. /ragi/is, so that other antibiotics such as metronidazole or ciindamycin should be used instead for infections with this organism. Fourth, when considering the gram-negative bacteria shown in Table 3 (eg, Neisseria, Haemophilus and E. coli), there is not much difference in activity among the various third-generation cephalosporins. In contrast, cefuroxime (a second-generation cephalosporin) is not active against E. coli and therefore should not be used to treat neonatal infections when the pathogen is unknown. Fifth, as stated previously, first-generation cephalosporins are more active against gram-positive bacteria. From these conclusions, we can see that other characteristics of the various cephalosporins must be taken into account (eg, efficacy of current antibiotics, pharmacokinetics, side effects, and cost) before we can decide upon which cephalosporin to use.

When an antibiotic is needed, the first question should be: Is a cephalosporin the drug of choice for the infection in question or are currently available antibiotics as good or better? For example, is there justification for use of a cephalosporin for treatment of urinary tract infection when cheaper and highly effective antibiotics are available (eg, trimethoprim-sulfamethoxazole), or is there a reason to treat systemic S. pyogenes infections (pneumonia, osteomyelitis, etc.) with a cephalosporin as long as penicillin is such an excellent drug?

Table

TABLE 1THE CEPHALOSPORINS BY GENERATION

TABLE 1

THE CEPHALOSPORINS BY GENERATION

Table

TABLE 2BACTERIA AGAINST WHICH CEPHALOSPORINS ARE INEFFECTIVE

TABLE 2

BACTERIA AGAINST WHICH CEPHALOSPORINS ARE INEFFECTIVE

Table

TABLE 3MINIMAL CONCENTRATIONS (µg/ml) NEEDED TO INHIBIT 90% (MIC90) OF THE BACTERIA TESTED

TABLE 3

MINIMAL CONCENTRATIONS (µg/ml) NEEDED TO INHIBIT 90% (MIC90) OF THE BACTERIA TESTED

If the decision is made to use a cephalosporin, its penetration to the area of infection should be considered. Let us examine, for example, the levels achieved by various cephalosporins in the serum and the cerebrospinal fluid and how long it takes the serum levels to decrease by half (the half-life or T172), which is the determinant of how often the drug should be administered. Again, several conclusions can be drawn from Table 4- First, all of the newer cephalosporins penetrate the CSF in the presence of" inflammation. Note that the absolute concentrations are shown, rather than percentages of the serum concentrations. The absolute CSF concentration is the important figure rather than the percentage of the serum concentration, because the latter can be manipulated, for example, by the timing of obtaining CSF samples. Secondly, the reported CSF concentrations for the various newer cephalosporins are in the same general range. Thirdly, it is obvious that ceftriaxone has the longest serum half-life of all these drugs, and it can therefore be administered less frequently.

To understand how a decision can be made regarding the choice of the most effective cephalosporin one should become familiar with the concept of the inhibitory quotient (IQ). The IQ is the ratio between the concentration of the drug at the site of infection (Table 4) divided by the minimal inhibitory concentration (MIC) of the suspected bacteria (Table 3). In theory, the IQ should exceed 10 or 20 before cultures will be consistently sterile.3 For example, the IQ of ceftriaxone for H. influenzar in the CSF will be between 555 (2.20/0-004) and 3,375 (13.50/0.004). From Table 4, it is obvious that all of the new cephalosporins should be effective in H. influenzas meningitis, with cefuroxime expected to be somewhat less effective. Because cefuroxime has demonstrated a success rate greater than 90% in this disease,4 more than 1,000 patients would have to be studied in order to show that it might be significantly less effective than ceftriaxone, for example. Such a large study will never be done.

Previously we saw that for gram-negative bacteria the third-generation cephalosporins are approximately equally effective (Table 3). Similarly, the IQs in the CSF for H. influenzae in the CSF did not distinguish these agents (Table 4). However, if we calculate the IQs for S. pneumontae, group B streptococci or E. coli2 (all important causes of meningitis in newborns or young infants) it is apparent that only ceftriaxone and cefotaxime should be used for treatment of meningitis before the pathogen has been identified. Prior to making a decision regarding which one of these two drugs is preferable, their side effects should be compared. Both antibiotics, like all other cephalosporins, have relatively few side effects.5 For these drugs, skin rash has been reported in 1% to 2%, pain or phlebitis at the site of injection in 1. 5% to 5% highest with cefotaxime), pseudomembranous colitis in 0.15%, eosinophilia in 1.3% to 7-4% highest for ceftazidime), leukopenia in 0.3% to 1.1%, positive Coombs' test in 0.4% to 6.4% (highest for ceftazidime), and prolonged prothrombin time and clinical bleeding in 0. 5%. The higher rate of the latter effects with moxalactam is well-documented in adults. In pediatrie patients such an association has not been found, probably because fewer pediatrie patients bave the renal and/or hepatic diseases which predispose patients to these side effects. Diarrhea was reported in 0.3% to 6% and is more common with drugs excreted by the liver, ie, moxalactam and ceftriaxone. Superinfection with resistant bacteria ranges between 1% and 3%. In summary, the safety profile of the various newer cephalosporins compares favorably with other agents, and none of them seems to be safer than the others.

Table

TABLE 4PHARMACOKINETIC CHARACTERISTICS OF THE NEW CEPHALLOSPORINS

TABLE 4

PHARMACOKINETIC CHARACTERISTICS OF THE NEW CEPHALLOSPORINS

The last step before deciding which drug to use for our example of meningitis due to an unknown pathogen is to consider cost factors. Because the cost includes not only the actual cost of the drug but also the considerable cost of its administration (which is influenced by dosing frequency), it is obvious that drugs with a longer half-life can be given less frequently. Thus, in our example, ceftriaxone with its TI/Z 0^ 4-4 hours) would appear to be the drug of choice for meningitis. This agent has been shown to be effective not only with using twice daily dosing6,7 but also with once daily administration.8,9 Furthermore, a shorter overall duration of therapy with ceftriaxone has been suggested to be effective for bacterial meningitis.10

Obviously, my final conclusion that ceftriaxone is the drug of choice for bacterial meningitis in pediatrics (except for areas of the VJS where Listeria mono* cytogenes is prevalent and ampicillin must be added for neonatal meningitis) to some degree reflects a bias related to my greater experience with this drug as compared to the other cephalosporins. With a few variations in logic, one could reach the conclusion that cefuroxime is most appropriate for treatment of meningitis in infants over 3 months of age, or cefotaxime with ampicillin for meningitis in neonates and infants up to 3 months of age.

The important point is that one can utilize this scheme to evaluate whether a new cephalosportn is superior to the cephalosporin he/she currently uses. Let us assume that a new cephalosporin, called cephalo-X, reaches the market and we want to compare it with cefuroxime for treatment of septic arthritis in an 18 month'old infant. From the Figure, we see that we first have to know the MlCs of cefuroxime and cefoX against the most common causes of septic arthritis in this age group eg S. aureus and H. influenzae). If the MIC of cefo- X is more than tenfold higher than that of cefuroxime for either of these bacteria ( ie, that it is less active in vitro), there would be no reason to change to the new drug. If the MICs are equivalent or cefo-X's MICs are tenfold lower than cefuroxime's MICs, consider the penetration of the two drugs into the site of infection, the joint. If cefo-X penetrates less well than cefuroxime (comparing reported absolute drug concentrations in joint fluid rather than percentage of the serum concentrations), again one should not change to the cefo-X. However, if cefo-x is found to penetrate at least as well as cefuroxime, the IQs of the drugs should be calculated. If the IQs of the two drugs are comparable, one should not necessarily change drugs, because familiarity with a drug is valuable, especially with respect to its possible side effects. If the IQ of cefo-X is superior, one must consider the side effects of the two drugs. If they are much less for cefo-X, it should become the new drug of choice, while if they are comparable, cost should be considered and only if cefo-X is significantly cheaper should one start using it.

Figure. Suggested scheme for evaluating the potential efficacy of a new cephalosponn [N) compared to currently used cephalosporinfCJ.

Figure. Suggested scheme for evaluating the potential efficacy of a new cephalosponn [N) compared to currently used cephalosporinfCJ.

Following this kind of scheme should allow you to decide rationally whether or not to begin to use a new cephalosporin. In addition, applying the same logic will help you to devise your own regimens for other pediatrie infections and to evaluate published recommendations for usage of antibiotics in various bacterial infections.

REFERENCES

1. Trotter JF Jr: Influx of new cephalosporins. N Engl J Med 1985; 313:330-331.

2. Yogev R: Advances in diagnosis and treatment of childhood meningitis. Pediatr Infect Dis 1985; 4:121-125.

3. Sande MA; Antibiotic therapy of bacterial meningitis. Lessons we have learned. Am J Med 1981; 507-508.

4. Schaad UB. Kruckn J, Pfenninger J: An extended experience with cefuroxime therapy of childhood bacterial meningitis. Pediatr Infect Dis 1984; 3:410-416.

5. Meyers BR: Comparative toxicities of third -generation cephalosporins. Am J Med 1985; 79(supp) 2A)-96-103.

6. Del Rio M, Chame D, Sheiron S. et al;. Ceftriaxime versus ampcillin and chloramphenicol for treatment of bacterial mineningitis in children. Lancet 1983; 1:1241-1244.

7. Chadwick EG. Connor EM. ShulmanST, et al: Efficacy of ceftriaxsinf in trearment of serious childhood infections. J Pediatr 1983; 103:141-145.

8. Congeni BL, Bradley J, Haimnerachlag MR: Safety and efficacy of once daily cefrtiaxone for the treatment of bacterial meningitis. Pediatr Infect Dis. in press.

9. Yogev R. Shulman ST. Chalwick CG. et al: Once daily cefrnaixone few CNS and other senous Pediatric infections. Pediatr Infect Dis, in press.

10 Lin TY, Chame DF. Nrbcn JD, el al: Seven Jays of cettriamme Therapy is as effective as ten days' trealtment for bacterial meningitis. JAMA 1985: 253:559-3563.

TABLE 1

THE CEPHALOSPORINS BY GENERATION

TABLE 2

BACTERIA AGAINST WHICH CEPHALOSPORINS ARE INEFFECTIVE

TABLE 3

MINIMAL CONCENTRATIONS (µg/ml) NEEDED TO INHIBIT 90% (MIC90) OF THE BACTERIA TESTED

TABLE 4

PHARMACOKINETIC CHARACTERISTICS OF THE NEW CEPHALLOSPORINS

10.3928/0090-4481-19860601-11

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