Ten to forty percent of bacteremic pneumococcal infections occur in hospitalized patients, with the respiratory tract being the main portal of entry (2, 3). Empirical therapy of hospital-acquired pneumonia should cover Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) as “core pathogens” (1).
This study explored the in vitro activity of ceftaroline, a parenteral anti-MRSA cephalosporin in phase 3 development, against S. pneumoniae isolates not susceptible to previous parenteral antimicrobials.
Among the S. pneumoniae isolates received in the Spanish Pneumococcal Reference Laboratory (January 2005 to September 2007), 655 strains were selected. 60 were nonsusceptible to penicillin, 250 to amoxicillin, and 170 to cefotaxime; 339 were resistant to erythromycin, and 152 were resistant to levofloxacin, according to current CLSI breakpoints (parenteral drugs/nonmeningitis) (5). Of these isolates, 337 (51.5%) were invasive (84.3% from bacteremia).
Antimicrobial susceptibility was determined by agar dilution (4) in Mueller-Hinton agar (Difco Laboratories, Detroit, MI) supplemented with 5% sheep blood (Biomedics, Madrid, Spain), with 105 CFU/ml final inocula, incubating under 5% CO2 (6, 7). S. pneumoniae ATCC 6303, S. pneumoniae ATCC 49619, and five clinical isolates were used as controls (6, 7). CLSI breakpoints (susceptibility/resistance [μg/ml]) for parenteral drugs/nonmeningitis (5) considered were as follows: penicillin (≤2/≥8); amoxicillin (≤2/≥8); cefuroxime-sodium (≤0.5/≥2); cefotaxime, ceftriaxone, and cefepime (≤1/≥4); erythromycin (≤0.25/≥1); and levofloxacin (≤2/≥8). No CLSI breakpoints are defined for ampicillin and ceftaroline.
Among the 595 penicillin-susceptible (MIC ≤ 2 μg/ml) strains, MIC50/MIC90 (μg/ml) and percent susceptibility were as follows: 4/8 and 31.6% for cefuroxime, 2/8 and no breakpoint for ampicillin, 2/8 and 66.7% for amoxicillin, 1/2 and 66.4% for cefepime, 1/2 and 80.7% for cefotaxime, 1/2 and 100% for penicillin, and 0.5/1 and 98.8% for ceftriaxone, respectively. MIC50/MIC90 of ceftaroline were 0.12/0.12.
Among the 60 penicillin-nonsusceptible strains, only three isolates were fully resistant to penicillin (MIC = 8 μg/ml). Table 1 shows MIC50, MIC90, and percent susceptibility for isolates distributed by penicillin, amoxicillin, or cefotaxime nonsusceptibility and erythromycin or levofloxacin resistance. In this study, the decrease in susceptibility to penicillin was associated with decreased susceptibility to other β-lactams, increasing MIC90s to 2 μg/ml for ceftriaxone, 4 μg/ml for cefotaxime and cefepime, and ≥16 μg/ml for amoxicillin, cefuroxime, and ampicillin. In comparison, the influence of penicillin nonsusceptibility on ceftaroline activity was lower, with a ceftaroline MIC90 of 0.25 μg/ml for penicillin-nonsusceptible strains and amoxicillin- or cefotaxime-resistant strains. Against amoxicillin- and cefotaxime-resistant strains, the ceftaroline MIC90 (0.25 μg/ml) was 4 and 16 times lower, respectively, than that of ceftriaxone (1 and 4 μg/ml, respectively). Table 2 shows MIC distributions of most active β-lactams for strains nonsusceptible to penicillin, amoxicillin-resistant strains, or cefotaxime-resistant strains. With respect to non-β-lactams, ceftaroline MIC90s against erythromycin- and levofloxacin-resistant strains were 0.25 μg/ml and 0.12 μg/ml, respectively.
TABLE 1.
MIC50, MIC90, and percent susceptibility to study drugs for penicillin-nonsusceptible, amoxicillin- and cefotaxime-intermediate and -resistant, and erythromycin- and levofloxacin-resistant strainsa
| Drug | PEN-nonS (n = 60)
|
AMX-I (n = 85)
|
AMX-R (n = 165)
|
CTX-I (n = 144)
|
CTX-R (n = 16)
|
ERY-R (n = 339)
|
LVX-R (n = 152)
|
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MIC50/ MIC90 | % S | MIC50/ MIC90 | % S | MIC50/ MIC90 | % S | MIC50/MIC90 | % S | MIC50/ MIC90 | % S | MIC50/ MIC90 | % S | MIC50/ MIC90 | % S | |
| PEN | 4/4 | 0.0 | 2/2 | 94.1 | 2/4 | 71.5 | 2/4 | 76.4 | 4/8 | 31.3 | 1/2 | 93.5 | 0.06/2 | 98.0 |
| AMP | 8/≥16 | 4/8 | 8/≥16 | 8/≥16 | 8/≥16 | 4/8 | 0.12/8 | |||||||
| AMX | 8/≥16 | 13.3 | 4/4 | 0.0 | 8/16 | 0.0 | 4/16 | 30.6 | 8/16 | 6.3 | 2/8 | 62.2 | ≤0.06/8 | 73.7 |
| CXM | 8/16 | 0.0 | 4/16 | 0.0 | 8/16 | 0.0 | 8/16 | 0.0 | 16/≥32 | 0.0 | 4/8 | 26.8 | 0.25/8 | 55.3 |
| CTX | 2/4 | 25.0 | 1/2 | 62.4 | 2/2 | 49.7 | 2/2 | 0.0 | 4/8 | 0.0 | 1/2 | 77.0 | 0.06/1 | 96.7 |
| CRO | 1/2 | 83.3 | 1/1 | 95.3 | 1/1 | 95.2 | 1/1 | 97.2 | 2/4 | 31.3 | 0.5/1 | 97.1 | 0.06/1 | 99.3 |
| FEP | 2/4 | 8.3 | 2/2 | 40.0 | 2/8 | 16.4 | 2/2 | 29.9 | 2/4 | 12.5 | 1/2 | 64.9 | 0.25/2 | 82.9 |
| CPT | 0.12/0.25 | 0.12/0.25 | 0.12/0.25 | 0.12/0.25 | 0.25/0.25 | 0.12/0.25 | 0.03/0.12 | |||||||
| ERY | ≤0.12/≥32 | 63.3 | ≥32/≥32 | 30.6 | ≤0.12/≥32 | 58.2 | 0.25/≥32 | 50.0 | ≤0.12/≥32 | 62.5 | ≥32/≥32 | 0.0 | ≥32/≥32 | 40.8 |
| LVX | ≤1/≤1 | 95.0 | ≤1/16 | 78.8 | ≤1/16 | 86.7 | ≤1/1 | 97.2 | ≤1/1 | 93.8 | ≤1/16 | 72.0 | 16/≥32 | 0.0 |
MICs are as follows: ≥4 μg/ml for penicillin-nonsusceptible strains (PEN-nonS), 4 μg/ml for amoxicillin-intermediate strains (AMX-I), ≥8 μg/ml for amoxicillin-resistant strains (AMX-R), 2 μg/ml for cefotaxime-intermediate strains (CTX-I), ≥4 μg/ml cefotaxime-resistant strains (CTX-R), ≥1 μg/ml for erythromycin-resistant strains (ERY-R), and ≥8 μg/ml for levofloxacin-resistant strains (LVX-R). PEN, penicillin; AMP; ampicillin; AMX, amoxicillin; CXM, cefuroxime; CTX, cefotaxime; CRO, ceftriaxone; FEP, cefepime; CPT, ceftaroline; ERY, erythromycin; LVX, levofloxacin; S, susceptibility.
TABLE 2.
MIC distribution according to penicillin nonsusceptibility and amoxicillin and cefotaxime resistancea
| Strain type (MIC [μg/ml]; no. of isolates) | Drug | No. (accumulated %) of strains inhibited at indicated MIC (μg/ml)
|
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | ≥16 | ||
| Pencillin nonsusceptible (≥4; 60) | PEN | 57 (95.0) | 3 (100) | |||||||||
| AMX | 1 (1.7) | 7 (13.3) | 5 (21.7) | 28 (68.3) | 19 (100) | |||||||
| CTX | 15 (25.0) | 34 (81.7) | 9 (96.7) | 2 (100) | ||||||||
| CRO | 1 (1.7) | 14 (25.0) | 35 (83.3) | 8 (96.7) | 1 (98.3) | 1 (100) | ||||||
| FEP | 4 (6.7) | 44 (80.0) | 11 (98.3) | 1 (100) | ||||||||
| CPT | 2 (3.3) | 29 (51.7) | 28 (98.3) | 1 (100) | ||||||||
| Amoxicillin resistant (≥8; 165) | PEN | 4 (2.4) | 114 (71.5) | 44 (98.2) | 3 (100) | |||||||
| AMX | 137 (83.0) | 28 (100) | ||||||||||
| CTX | 3 (1.8) | 79 (49.7) | 72 (93.3) | 9 (98.8) | 2 (100) | |||||||
| CRO | 4 (2.4) | 66 (42.4) | 87 (95.2) | 6 (98.8) | 1 (99.4) | 1 (100) | ||||||
| FEP | 1 (0.6) | 20 (12.7) | 123 (87.3) | 20 (99.4) | 1 (100) | |||||||
| CPT | 11 (6.7) | 114 (75.8) | 39 (99.4) | 1 (100) | ||||||||
| Cefotaxime resistant (≥4; 16) | PEN | 5 (31.3) | 8 (81.3) | 3 (100) | ||||||||
| AMX | 1 (6.3) | 4 (31.3) | 5 (62.5) | 6 (100) | ||||||||
| CTX | 14 (87.5) | 2 (100) | ||||||||||
| CRO | 2 (12.5) | 3 (31.3) | 9 (87.5) | 1 (93.8) | 1 (100) | |||||||
| FEP | 1 (6.3) | 11 (85.0) | 3 (93.8) | 1 (100) | ||||||||
| CPT | 4 (25.0) | 11 (93.8) | 1 (100) | |||||||||
Data for strains inhibited at MIC50s and MIC90s are in boldface type. PEN, penicillin; AMX, amoxicillin; CTX, cefotaxime; CRO, ceftriaxone; FEP, cefepime; CPT, ceftaroline.
The ceftaroline MIC90 in this study was equal to that obtained in three earlier studies using broth microdilution (8, 10) or agar dilution (9), despite the absence or limited number of nonsusceptible S. pneumoniae isolates in those studies according to the new penicillin CLSI breakpoint (5). The intrinsic activity of ceftaroline against strains resistant to previous parenteral antimicrobials, together with potent anti-MRSA activity (8, 10), may represent an advantage when broader-spectrum empirical therapy is needed.
Acknowledgments
This study was supported by an unrestricted grant from Forest Laboratories, Inc.
Footnotes
Published ahead of print on 25 August 2008.
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