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A 52-year old woman sought medical care following worsening of respiratory illness that had persisted for several days. She had a temperature of 103ºF, shaking, chills, significant congestion, and difficulty in breathing despite self-treatment with ibuprofen and over-the-counter cough medicine and decongestant. An expectorated sputum specimen was obtained and sent to the laboratory for Gram stain, culture, and susceptibility testing; two sets of blood cultures were also obtained. A chest X-ray revealed a left lateral lobe infiltrate. The physician admitted the patient and prescribed ceftriaxone 1 gm every 24 hours. The patient responded to the antimicrobial therapy and was discharged after 48 hours. The sputum culture and both blood cultures grew Streptococcus pneumoniae; the blood culture was reported as follows (the report for the sputum culture was identical): Specimen: Blood Results: Streptococcus pneumoniae | MIC (ug/ml) | Interpretation | | cefotaxime | | | | | meningitis | 1 | I | | non-meningitis | 1 | S | | ceftriaxone | | | | meningitis | 1 | I | | non-meningitis | 1 | S | | erythromycin | >1 | R | | levofloxacin | <0.5 | S | | penicillin | 2 | R | | trimethoprim/sulfamethoxazole | >4/76 | R | | vancomycin | <0.5 | S | Report comments: - For cefotaxime, use of interpretive criteria for non-meningitis requires doses appropriate for serious pneumococcal infections (e.g., at least 1 g [adults] or 50 mg/kg [children] every 8 hours or more frequently).
- Patients with meningitis require therapy with maximum doses of cefotaxime or ceftriaxone.
- Erythromycin-resistant S. pneumoniae are also resistant to azithromycin and clarithromycin
The following excerpt from the latest NCCLS tables (M100-S12, published January 2002) shows updated information on pneumococcal breakpoints for extended-spectrum cephalosporins in bold-face type. | Test/ Report Group | Antimicrobial
Agent | MIC (ug/ml) Interpretive Standard | Comments | | | | S | I | R | | | | | | | | | | A | Penicillin | <0.06 | 0.12-1 | >2 | Rx: High doses of intravenous penicillins (e.g. at least 2 million units every 4 hours in adults with normal renal function) or similarly ampicillin (e.g., 2 g at every 6 hours) are effective in treating pneumococcal pneumonia due to strains in the intermediate category | | | | | | | | | B | Cefepime (non-meningitis) | <1 | 2 | >4 | Only report interpretations for non-meningitis and include the non-meningitis notation on the report. Cefepime does not have a U.S. Food and Drug Administration-approved indication for meningitis. | | B | Cefepime (meningitis) | <0.5 | 1 | >2 | | | | | | | | | B
B
| Cefotaxime (meningitis)
or
ceftriaxone (meningitis) | <0.5
<0.5
| 1
1
| >2
>2
| For cerebrospinal fluid (CSF) isolates, report only meningitis interpretations.
Rx: Patients with meningitis require therapy with maximum doses of cefotaxime or ceftriaxone. | | | | | | | | | B
B
| Cefotaxime (non-meningitis)
or
ceftriaxone (non-meningitis) | 1
<1
| 2
2
| >4
>4
| For all isolates other than those from CSF, report interpretations for both meningitis and non-meningitis.
Rx: For cefotaxime, use of interpretive criteria for non-meningitis requires doses appropriate for serious pneumococcal infections (e.g., at least 1 g [adults] or 50 mg/kg [children] every 8 hours or more frequently.) | Question 1:
Why are cefotaxime and ceftriaxone listed twice on the blood culture report? Answer: NCCLS has two sets of breakpoints for cefotaxime and ceftriaxone for pneumococci; one set pertains to strains causing meningitis and the other to strains causing infections other than meningitis. Originally published in 1993, the breakpoints for cefotaxime and ceftriaxone were developed primarily for the treatment of pneumococcal meningitis. However, several recent publications and the clinical experience of a number of investigators around the world suggest that non-meningeal S. pneumoniae infections (such as pneumonia) caused by strains for which the cefotaxime or ceftriaxone MICs are <1 ug/ml, can be effectively treated with adequate doses of extended-spectrum cephalosporins (i.e., cefotaxime and ceftriaxone). Thus, a second set of breakpoints was developed for these drugs for non-meningeal infections, based on both clinical outcome data from a number of studies and pharmacokinetic and pharmacodynamic data. Question 2:
Why is it necessary to report meningitis interpretations for cefotaxime and ceftriaxone on an isolate from blood? Answer: Patients with pneumococcal meningitis may have S. pneumoniae isolated from body sites other than cerebrospinal fluid. By reporting both interpretations, clinicians will have the ability to apply the interpretive criteria that are appropriate for the site of infection. Question 3:
Should laboratories be testing and reporting results for both cefotaxime and ceftriaxone on all S. pneumoniae? In NCCLS Table 1A, they are positioned in the same box with an "or" which suggests that only one needs to be tested and reported. Answer: It is not necessary to test and report both cefotaxime and ceftriaxone for all S. pneumoniae isolates. The decision on which antimicrobial agent to test and report should be made in conjunction with your medical and pharmacy services. In some cases, it may be appropriate to test and report both agents, depending on the needs of the physicians (e.g., if your laboratory serves multiple hospitals, some of which have cefotaxime on their formulary and others of which have ceftriaxone). According to NCCLS guidelines, the "or" in the box containing these two agents indicates that a susceptible (S), intermediate (I), or resistant (R) result for one agent can be used to predict a similar interpretation (or result) for the other. Despite this, some physicians may request that the laboratory report the MIC result, rather than just the interpretation (S, I, or R), particularly for isolates associated with invasive infections. Question 4:
Why is there only one set of interpretive criteria for penicillin for pneumococci? Answer: Although a recent publication by Hefelfinger et al. proposed an additional set of penicillin breakpoints for pneumococci, particularly for cases of pneumonia, NCCLS has not yet adopted these additional breakpoints. Two important issues continue to be discussed by NCCLS. First, if two sets of breakpoints were adopted, the breakpoints for non-meningitis (i.e., pneumonia) would be very different from those for meningitis (e.g., the intermediate category would change from 0.1 ug/ml to 1 ug/ml), which could lead to very major errors when treating meningitis if the incorrect breakpoint was used. Second, the ability to predict the susceptibility of all beta-lactam drugs for pneumococcal isolates if penicillin was susceptible would be lost (since strains for which the penicillin MICs were 1 ug/ml wouldn't necessarily be susceptible to extended-spectrum cephalosporins). Until the issue is resolved, if penicillin therapy is commonly used in your institution, it would be appropriate to add the following comment as suggested in NCCLS Table 2G. "High doses of intravenous penicillin (e.g., at least 2 million units every 4 hours in adults with normal renal function) or of ampicillin (e.g., 2 g at every 6 hours) are effective in treating pneumococcal pneumonia due to strains in the intermediate category." Question 5:
Our physicians want us to report cefepime routinely on S. pneumoniae. Is it acceptable to report cefepime on blood and CSF isolates of S. pneumoniae? Answer: In the United States, cefepime results may be reported for blood and other non-CSF isolates of S. pneumoniae, but should not be reported on CSF isolates of this organism. Cefepime does not have a Food and Drug Administration-approved indication for treating meningitis. M100-S12 lists interpretive criteria for cefepime and meningitis because NCCLS documents are used outside of the United States where it may be acceptable to consider cefepime for meningitis. In the United States, only the non-meningitis interpretative criteria should be included on the laboratory report. Question 6:
Is it necessary to test a fluoroquinolone routinely against S. pneumoniae? Answer: Each laboratory must determine if it is necessary to test and report a fluoroquinolone routinely for their isolates of S. pneumoniae. Gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, and sparfloxacin are listed in NCCLS Test/Report Group B (test routinely and report selectively). Based on several surveillance studies, the overall rate of resistance to these fluoroquinolones in the U.S is <3%, although it is as high as 14% in other parts of the world. Thus, emerging resistance of S. pneumoniae to fluoroquinolones is a concern and we suggest that a fluoroquinolone be included on the pneumococcal test panel. Question 7:
We test levofloxacin on our panel. If a physician asks for results of gatifloxacin, moxifloxacin, or sparfloxacin must they be tested? Answer: No. In NCCLS Tables 1A and 2G, gatifloxacin, levofloxacin, moxifloxacin, and sparfloxacin are listed in the same box connected with an "or." This means that results for these agents are usually similar and clinical efficacy is comparable. The addition of the word "or" designates a group of related agents that has an almost identical spectrum of activity and interpretive results, and for which cross-resistance and susceptibility are nearly equal. Therefore, testing any one of the four agents can predict the activity of the other three. Question 8:
The new "Warning" comment in Tables 1 and 1A states that "Routine reporting of the following on any species of bacteria included in this document isolated from CSF could be dangerously misleading for patient care: agents administered by the oral route only, first- and second-generation cephalosporins (except cefuroxime sodium), clindamycin, macrolides, tetracyclines and fluoroquinolones." Does this mean that we should not report erythromycin, tetracycline, or fluoroquinolones on CSF isolates of S. pneumoniae? Answer: Correct. The drugs listed in the new comment should not be reported on isolates from CSF since they are not appropriate for the treatment of meningitis. Question 9:
Why can't we use the disk diffusion test for cefotaxime or ceftriaxone? Answer: Disk diffusion testing with cefotaxime and ceftriaxone is unreliable for testing S. pneumoniae. Following extensive studies, NCCLS was unable to define zone diameter interpretive criteria that would consistently agree with MIC interpretive criteria. Question 10:
Is the oxacillin disk diffusion screening test still acceptable for S. pneumoniae? Answer: Yes. The oxacillin screen test is still appropriate for testing non-invasive isolates of pneumococci. For isolates with an oxacillin (1 ug) disk zone diameter of >20 mm, further testing of beta-lactams, including penicillin, cefotaxime, ceftriaxone, and meropenem, is not necessary because susceptibility to these agents can be deduced from the oxacillin screen result. However, for isolates with zone diameters <19 mm, MICs to penicillin, cefotaxime, ceftriaxone, and meropenem are required, particularly in cases of meningitis and sepsis. Because the incidence of penicillin resistance in S. pneumoniae in the United States is between 15-30%, some laboratories have eliminated the oxacillin screen test and now go directly to MIC testing of penicillin, cefotaxime, ceftriaxone, and meropenem to avoid delays in reporting results. For CSF isolates of S. pneumoniae, the oxacillin disk diffusion screen should not be used because of the potential delay in obtaining critical results. MICs to penicillin, cefotaxime, ceftriaxone, and meropenem should be performed as soon as sufficient colonies are available for testing. Question 11:
Our hospital does not have meropenem on its formulary; however, NCCLS states that it should be reported routinely on CSF isolates of S. pneumoniae. In our case, is this necessary? Answer: No. Testing meropenem is suggested but not mandatory.
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