Abstract
The in vitro activities of ceftaroline and comparators, using broth microdilution, were determined against 1,066 Staphylococcus aureus isolates from hospitalized patients. Seventeen medical centers from Latin American countries contributed isolates. Methicillin-resistant S. aureus (MRSA) percentages ranged from 46% (Brazil) to 62% (Argentina). All methicillin-susceptible S. aureus (MSSA) isolates were susceptible to ceftaroline. Ceftaroline activity against MRSA varied with MIC90s of 0.5 (Venezuela) to 2 (Brazil, Chile, and Colombia) μg/ml, which was the highest MIC value. ST-5 was the most common sequence type.
TEXT
Staphylococcus aureus is particularly adaptive to antimicrobial pressure and commonly isolated from acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) (1–3). Methicillin-resistant S. aureus (MRSA) has been problematic among hospitalized patients, although community-acquired MRSA (CA-MRSA) strains are becoming more prevalent and resistance to commonly used antimicrobial agents is increasing (4–6). A distinction between hospital-associated MRSA (HA-MRSA) infections and CA-MRSA has been based upon genetic characteristics. Clones are migrating globally and disseminating between these environments in recent years. Physicians need to understand the prevalent strains in their area to guide therapy (7–11). Multidrug-resistant (MDR) S. aureus requires an alternative therapeutic approach due to lack of effective drugs (12, 13).
Ceftaroline has in vitro bactericidal activity against MDR-MRSA, has a good safety profile, and has been approved by the Food and Drug Administration for treating adults with ABSSSI and CABP (14–28). This report from Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) summarizes the in vitro activity of ceftaroline against S. aureus isolates collected in Latin America during 2012, including molecular characterization of isolates with reduced susceptibility to ceftaroline.
Clinical isolates of S. aureus were collected from 17 medical centers in Latin America during 2012. Countries (number of medical centers) included Argentina (3), Brazil (2), Chile (3), Colombia (2), Mexico (5), and Venezuela (2). Single patient isolates were collected prospectively with a targeted number of methicillin-susceptible S. aureus (MSSA) and MRSA isolates. The majority of isolates were from skin and skin structure (696 isolates) and respiratory (285) specimens. Isolate identification was confirmed and antimicrobial susceptibility testing was performed by a central laboratory (International Health Management Associates [IHMA], Schaumburg, IL, USA). Susceptibility testing was performed by broth microdilution, and results were interpreted and quality controlled according to the Clinical and Laboratory Standards Institute (CLSI) performance standards (29, 30).
A random sample of 27 of the 130 isolates with ceftaroline MIC values of 2 μg/ml (intermediate MIC) based upon the current CLSI breakpoint was selected for molecular characterization. Whole-genome sequencing was performed to enable sequence-based analyses as previously described (31).
Overall MIC50 and MIC90 values for ceftaroline were 0.5 and 2 μg/ml against S. aureus, respectively, with 87.8% of isolates susceptible to ceftaroline (Table 1). Ceftaroline exhibited MIC90 values of 0.25 and 2 μg/ml against MSSA and MRSA, respectively. All of the MSSA isolates and 78.2% of MRSA isolates were susceptible to ceftaroline. No ceftaroline-resistant (MIC, >2 μg/ml) isolates were encountered. MRSA isolates exhibited high resistance to erythromycin, clindamycin, and levofloxacin (56.7%). All isolates were susceptible to linezolid, daptomycin, and vancomycin.
TABLE 1.
Activities of ceftaroline and comparator agents against S. aureus isolates from Latin America
| S. aureus type (n) | Drug | MIC50 (μg/ml) | MIC90 (μg/ml) | % susceptiblea | % resistant |
|---|---|---|---|---|---|
| All (1,066) | Ceftaroline | 0.5 | 2 | 87.8 | 0.0 |
| Ceftriaxoneb | >32 | >32 | 44.1 | 55.9 | |
| Erythromycin | 1 | >4 | 45.3 | 44.2 | |
| Clindamycin | 0.12 | >2 | 70.5 | 29.3 | |
| Levofloxacin | 0.25 | >2 | 66.8 | 32.5 | |
| Daptomycin | 0.5 | 1 | 100 | 0.0 | |
| Linezolid | 2 | 2 | 100 | 0.0 | |
| Vancomycin | 1 | 1 | 100 | 0.0 | |
| MSSA (470) | Ceftaroline | 0.25 | 0.25 | 100 | 0.0 |
| Ceftriaxoneb | 4 | 4 | 100 | 0.0 | |
| Erythromycin | 0.5 | >4 | 68.7 | 15.7 | |
| Clindamycin | 0.12 | 0.12 | 99.2 | 0.6 | |
| Levofloxacin | 0.25 | 0.25 | 97.7 | 1.7 | |
| Daptomycin | 0.5 | 1 | 100 | 0.0 | |
| Linezolid | 2 | 2 | 100 | 0.0 | |
| Vancomycin | 1 | 1 | 100 | 0.0 | |
| MRSA (596) | Ceftaroline | 0.5 | 2 | 78.2 | 0.0 |
| Ceftriaxoneb | >32 | >32 | 0.0 | 100 | |
| Erythromycin | >4 | >4 | 26.9 | 66.6 | |
| Clindamycin | >2 | >2 | 48.0 | 51.9 | |
| Levofloxacin | >2 | >2 | 42.5 | 56.7 | |
| Daptomycin | 1 | 1 | 100 | 0.0 | |
| Linezolid | 2 | 2 | 100 | 0.0 | |
| Vancomycin | 1 | 1 | 100 | 0.0 |
According to CLSI breakpoint criteria.
Susceptibility based upon methicillin (oxacillin) susceptibility.
The highest ceftaroline MIC value among MRSA isolates was 2 μg/ml with MIC90 values of 0.5 μg/ml in Venezuela, 1 μg/ml in Mexico, and 2 μg/ml in Argentina, Brazil, Chile, and Colombia (Table 2). MRSA isolates with a ceftaroline MIC of 2 μg/ml occurred in Argentina (10.6%), Brazil (25%), Chile (73.2%), Colombia (30.8%), and Venezuela (5.1%), but all MRSA isolates in Mexico were ceftaroline susceptible.
TABLE 2.
Ceftaroline MIC distributions (cumulative percentages) against S. aureus isolates from Latin American countries
| Country (no. of sites) | Organism (n) | No. of isolates (cumulative %) with MIC (μg/ml)a: |
|||||
|---|---|---|---|---|---|---|---|
| 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | ||
| All (17) | MSSA (470) | 4 (0.9) | 107 (23.6) | 351 (98.3) | 8 (100) | ||
| MRSA (596) | 0 (0) | 0 (0) | 15 (2.5) | 289 (51.0) | 162 (78.2) | 130 (100) | |
| Argentina (3) | MSSA (93) | 0 (0) | 15 (16.1) | 78 (100) | |||
| MRSA (151) | 0 (0) | 0 (0) | 5 (3.3) | 118 (81.5) | 12 (89.4) | 16 (100) | |
| Brazil (2) | MSSA (33) | 1 (3.0) | 10 (33.3) | 22 (100) | |||
| MRSA (28) | 0 (0) | 0 (0) | 1 (3.6) | 11 (42.9) | 9 (75.0) | 7 (100) | |
| Chile (3) | MSSA (93) | 1 (1.1) | 29 (32.3) | 60 (96.8) | 3 (100) | ||
| MRSA (123) | 0 (0) | 0 (0) | 3 (2.4) | 20 (18.7) | 10 (26.8) | 90 (100) | |
| Colombia (2) | MSSA (37) | 0 (0) | 10 (27.0) | 27 (100) | |||
| MRSA (39) | 0 (0) | 0 (0) | 2 (5.1) | 22 (61.5) | 3 (69.2) | 12 (100) | |
| Mexico (5) | MSSA (141) | 1 (0.7) | 34 (24.8) | 102 (97.2) | 4 (100) | ||
| MRSA (156) | 0 (0) | 0 (0) | 2 (1.3) | 29 (19.9) | 125 (100) | ||
| Venezuela (2) | MSSA (73) | 1 (1.4) | 9 (13.7) | 62 (98.6) | 1 (100) | ||
| MRSA (99) | 0 (0) | 0 (0) | 2 (2.0) | 89 (91.9) | 3 (94.9) | 5 (100) | |
Boldface values represent MIC90 values.
Similar percentages of MRSA were observed among isolates from ABSSI (56%) and respiratory tract infections (RTI) (55%). Ceftaroline susceptibility was higher among the isolates from ABSSI (83.3%) than among those from RTI (69.4%) (Table 3). This trend was also observed when analyzed by country, with the exception of Brazil.
TABLE 3.
Activities of ceftaroline against S. aureus isolates from skin and skin structure and respiratory tract specimens in Latin American countries
| Source/country (no. of sites)/phenotype (n) | MIC (μg/ml) |
% |
||||
|---|---|---|---|---|---|---|
| MIC50 | MIC90 | Range | Susceptiblea | Intermediate | Resistant | |
| Skin and skin structure | ||||||
| All MSSA (306) | 0.25 | 0.25 | 0.06–0.5 | 100 | 0.0 | 0.0 |
| All MRSA (390) | 0.5 | 2 | 0.25–2 | 83.3 | 16.7 | 0.0 |
| Argentina (3) | ||||||
| MSSA (58) | 0.25 | 0.25 | 0.12–0.25 | 100 | 0.0 | 0.0 |
| MRSA (116) | 0.5 | 1 | 0.25–2 | 90.5 | 9.5 | 0.0 |
| Brazil (2) | ||||||
| MSSA (14) | 0.25 | 0.25 | 0.12–0.25 | 100 | 0.0 | 0.0 |
| MRSA (6) | 0.5 | —b | 0.5–2 | 66.7 | 33.3 | 0.0 |
| Chile (3) | ||||||
| MSSA (63) | 0.25 | 0.25 | 0.06–0.5 | 100 | 0.0 | 0.0 |
| MRSA (63) | 2 | 2 | 0.25–2 | 28.6 | 71.4 | 0.0 |
| Colombia (2) | ||||||
| MSSA (23) | 0.25 | 0.25 | 0.12–0.25 | 100 | 0.0 | 0.0 |
| MRSA (24) | 0.5 | 2 | 0.25–2 | 87.5 | 12.5 | 0.0 |
| Mexico (5) | ||||||
| MSSA (89) | 0.25 | 0.25 | 0.06–0.5 | 100 | 0.0 | 0.0 |
| MRSA (100) | 1 | 1 | 0.25–1 | 100 | 0.0 | 0.0 |
| Venezuela (2) | ||||||
| MSSA (59) | 0.25 | 0.25 | 0.06–0.5 | 100 | 0.0 | 0.0 |
| MRSA (81) | 0.5 | 0.5 | 0.25–2 | 95.1 | 4.9 | 0.0 |
| Respiratory tract | ||||||
| All MSSA (128) | 0.25 | 0.25 | 0.06–0.5 | 100.0 | 0.0 | 0.0 |
| All MRSA (157) | 1 | 2 | 0.25–2 | 69.4 | 30.6 | 0.0 |
| Argentina (3) | ||||||
| MSSA (25) | 0.25 | 0.25 | 0.12–0.25 | 100.0 | 0.0 | 0.0 |
| MRSA (22) | 0.5 | 2 | 0.25–2 | 86.4 | 13.6 | 0.0 |
| Brazil (2) | ||||||
| MSSA (15) | 0.25 | 0.25 | 0.06–0.25 | 100.0 | 0.0 | 0.0 |
| MRSA (15) | 1 | 2 | 0.25–2 | 86.7 | 13.3 | 0.0 |
| Chile (3) | ||||||
| MSSA (24) | 0.25 | 0.25 | 0.12–0.25 | 100.0 | 0.0 | 0.0 |
| MRSA (57) | 2 | 2 | 0.25–2 | 26.3 | 73.7 | 0.0 |
| Colombia (2) | ||||||
| MSSA (10) | 0.25 | 0.25 | 0.12–0.25 | 100.0 | 0.0 | 0.0 |
| MRSA (4) | 0.5 | —b | 0.5–2 | 75.0 | 25.0 | 0.0 |
| Mexico (5) | ||||||
| MSSA (44) | 0.25 | 0.25 | 0.12–0.5 | 100.0 | 0.0 | 0.0 |
| MRSA (46) | 1 | 1 | 0.5–1 | 100.0 | 0.0 | 0.0 |
| Venezuela (2) | ||||||
| MSSA (10) | 0.25 | 0.25 | 0.12–0.25 | 100.0 | 0.0 | 0.0 |
| MRSA (13) | 0.5 | 0.5 | 0.5 | 100.0 | 0.0 | 0.0 |
According to CLSI breakpoint criteria.
—, number insufficient to calculate MIC90 value.
MRSA isolates with an intermediate susceptibility to ceftaroline (MIC, 2 μg/ml) were observed across the region (Table 2). Reports of ceftaroline MIC values in the nonsusceptible range (≥2 μg/ml) have been associated with modifications in the mecA-encoded penicillin-binding protein 2a (PBP2a) and substitutions in the non-penicillin-binding domain of PBP2a (31). This region has been proposed to be functionally important for interactions with other protein partners or ligands during cell wall biogenesis or in allosteric regulation by a second ceftaroline molecule and has been associated with intermediate ceftaroline MIC values (31, 32). Ceftaroline MIC values higher than 2 μg/ml require additional substitutions in key residues in the transpeptidase pocket of the penicillin-binding domain (31, 32). No ceftaroline-resistant isolates were collected from the region, and modifications in the transpeptidase pocket of the penicillin-binding domain were not observed. Of the random isolates selected for genetic characterization, a single isolate from Brazil carried three substitutions in the non-penicillin-binding domain (Asn146Lys, Asn204Lys, and Gly246Glu), while the remaining 26 isolates, irrespective of the country of isolation, carried the PBP2a substitutions Met122Ile and Glu150Lys (Table 4). Multilocus sequence typing demonstrated that the single isolate from Brazil that carried the three PBP2a substitutions belonged to the ST-239 lineage (Brazilian/Hungarian clone) and carried SCCmec type III. All remaining isolates that possessed the Met122Ile and Glu150Lys substitutions belonged to the UK-EMRSA-3 ST-5 lineage and carried SCCmec type I.
TABLE 4.
Molecular analysis of PBP2a from 27 ceftaroline-nonsusceptible (intermediate) S. aureus isolates from Latin America
| Country (n) | MecA mutations | ST type |
|---|---|---|
| Argentina (6) | Met122Ile, Glu150Lys | ST-5 |
| Brazil (4) | Met122Ile, Glu150Lys | ST-5 |
| Brazil (1) | Asn146Lys, Asn204Lys, Gly246Glu | ST-239 |
| Chile (7) | Met122Ile, Glu150Lys | ST-5 |
| Colombia (4) | Met122Ile, Glu150Lys | ST-5 |
| Venezuela (5) | Met122Ile, Glu150Lys | ST-5 |
Ceftaroline exhibited good in vitro activity, with no resistance observed against clinical isolates of S. aureus from Latin American countries isolated in 2012. Ceftaroline activity against MRSA was variable in the six countries participating in the Latin America AWARE surveillance program. A previous prospective surveillance study performed under the auspices of the AWARE program in seven Latin American countries reported lower ceftaroline susceptibility (83.6%) against S. aureus than did this 2012 study (87.8%), despite collecting a lower percentage of MRSA isolates (42.8% versus 55.9%, respectively) (34). The reasons for the lower susceptibility observed in Latin America remain uncertain but could be due to the inclusion of high numbers of S. aureus isolates sourced from respiratory infections (26.7% in this study and 30% in the 2011 AWARE study conducted in the region [34]).
None of the isolates investigated had changes in the penicillin-binding region of PBP2a, which are the types of substitutions observed in ceftaroline-resistant isolates (MIC of >2 μg/ml), and only substitutions in the non-penicillin-binding domain that confer low-level (intermediate) resistance to ceftaroline were detected (31, 32). A recent study has proposed a novel resistance mechanism to explain the observed non-penicillin-binding domain changes and their impact on ceftaroline susceptibility. The hypothesis claims a disruption of an allosteric trigger by the mutations in PBP2a, affecting the ability of ceftaroline to bind within the functional pocket (35). However, other studies have demonstrated no impact of ceftaroline inhibition in purified protein containing non-penicillin-binding domain changes (33).
All isolates, except for one with a ceftaroline MIC of 2 μg/ml, showed the sequence type ST-5. This sequence type, ST-5, was similar to that in a study among S. aureus isolates from Brazil that were resistant to tigecycline and daptomycin (36). A possible relationship with this sequence type and increased resistance to these drug classes would require more extensive typing and analysis. However, molecular studies of Latin American S. aureus, from Argentina in particular, have documented an epidemic spread of the MRSA ST-5-IV clone (37, 38).
Ceftaroline fosamil is a useful addition to the antimicrobial agents that can be used to treat S. aureus infections, especially with the capability of covering MRSA, including CA-MRSA.
ACKNOWLEDGMENTS
We gratefully acknowledge the contributions of the local investigators, laboratory personnel, and all members of the AWARE program.
This study at IHMA was supported by AstraZeneca Pharmaceuticals LP, which also included compensation fees for services in relation to preparing the manuscript. D.J.B., D.J.H., D.F.S., and S.K.B. are employees of International Health Management Associates, Inc. None of the IHMA authors have personal financial interests in the sponsor of this paper (AstraZeneca Pharmaceuticals). E.R. is an employee of AstraZeneca. R.A.A., S.D.L., and J.E.A. are former employees of AstraZeneca.
All authors provided analysis input and read and approved the final manuscript.
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