Development of Daptomycin Nonsusceptibility with Heterogeneous Vancomycin-Intermediate Resistance and Oxacillin Susceptibility in Methicillin-Resistant Staphylococcus aureus during High-Dose Daptomycin Treatment

The use of daptomycin has increased in recent years, especially in patients with persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia following vancomycin treatment failure (10). We report a case of persistent MRSA bacteremia in a patient who received a dosage of daptomycin (12 mg/kg body weight/day) that was higher than that of the recommended standard therapy (6 mg/kg/day) (2, 10). The patient received 4 weeks of teicoplanin followed by 5 months of oral linezolid prior to daptomycin. In addition to daptomycin nonsusceptibility, the causative strain also developed heterogeneous and intermediate resistance to vancomycin, and an inverse or “seesaw” effect of daptomycin nonsusceptibility and oxacillin susceptibility was noted.

A 59-year-old man with stage IV non-Hodgkin's lymphoma was admitted for chemotherapy. Six days later, he developed catheter-associated septic phlebitis. Two sets of blood cultures (BCs) yielded MRSA (CGK1). Transesophageal ultrasound revealed no vegetation. Teicoplanin (800 mg/day) was initiated, and the patient's fever subsided. However, the hip magnetic resonance image (MRI) indicated left sacroiliac joint septic arthritis, and repeat BCs yielded MRSA (CGK2) after 4 weeks of teicoplanin. The patient chose to receive therapy at home. After 3 months of oral linezolid (1,200 mg/day), fever and MRSA bacteremia (CGK3) reoccurred on the second day after linezolid was discontinued, but the fever subsided immediately after restarting linezolid. MRSA bacteremia (CGK4) reoccurred after another 2 months. After the patient was readmitted, linezolid was replaced by parenteral daptomycin (700 mg/day; 12 mg/kg), but fever developed 12 days later. Peripheral vein and Port-A-Cath BCs both yielded MRSA (CGK5). The Port-A-Cath was removed, but fever and MRSA bacteremia persisted (CGK6). Transesophageal echocardiography performed on hospital day 26 revealed no vegetation, but MRI indicated infective spondylitis of the thoracic spine that was associated with a progressive infectious process on the left hip joint. On hospital day 35, daptomycin was replaced by parenteral linezolid (1,200 mg/day) and cefpirome (2 g every 12 h) because of persistent fever and refractory MRSA bacteremia (CGK7). BCs obtained 3 days after linezolid and cefpirome were started still grew MRSA (CGK8). Profound septic shock occurred thereafter, and the patient died on hospital day 45.

All 8 isolates had indistinguishable pulsed-field gel electrophoresis patterns (data not shown) and shared the same genetic profile (sequence type 59 [ST59], staphylococcal cassette chromosome mec type IV [SCCmec IV], pvl negative, agr group I), indicating that the persistent bacteremia was due to the same strain of MRSA or its progeny. The MICs of daptomycin increased from ≤0.75 μg/ml in CGK1 through CGK5 to 4 μg/ml in CGK6 through CGK8. Concurrent with the increase in daptomycin MICs, oxacillin MICs decreased from 32 to >256 μg/ml to 1 to 3 μg/ml (Table 1). Vancomycin nonsusceptibility also developed in CGK7, with a MIC of 3 μg/ml, which fit the vancomycin-intermediate S. aureus (VISA) category (4). Population analysis profiles showed a distinct increased population of CGK6 through CGK8 able to grow at daptomycin concentrations of ≥2 μg/ml (Fig. 1 A), and only CGK7 met the heterogeneous VISA (hVISA) criteria (Fig. 1B) (17). Sequencing of the mprF gene for all 8 isolates revealed an L431F amino acid substitution in CGK6 through CGK8, but no mutation was found in the sites (S295, P314, T345, I420) previously reported in other daptomycin-nonsusceptible strains (6-9, 11, 18).

TABLE 1.

MICs of daptomycin, linezolid, oxacillin, teicoplanin, and vancomycin for 8 MRSA isolates from a fatal, persistent bacteremia case prior to, during, and after high-dose daptomycin therapy

Isolate	Isolation date (mo/day/yr)	Day of daptomycin therapya	MIC (μg/ml)b
			Daptomycin	Linezolid	Oxacillin	Teicoplanin	Vancomycin
CGK1	12/1/08		0.5	2	32	1	1.5
CGK2	1/16/09		0.75	2	>256	1.5	1.5
CGK3	4/16/09		0.75	2	>256	1.5	2
CGK4	6/22/09		0.38	2	16	1	1.5
CGK5	7/6/09	11	0.75	2	>256	2	2
CGK6	7/12/09	17	4	1	1.5	2	2
CGK7	7/21/09	26	4	2	3	3	3
CGK8	7/27/09		4	1.5	1	2	2

^aThe patient was on teicoplanin (12/2/08 to 1/5/09), oral linezolid (1/17/09 to 4/14/09 and 4/16/09 to 6/22/09), daptomycin (6/25/09 to 7/21/09), and linezolid plus cefpirome (7/24/09 to 7/28/09).

^bMIC results are from the Etest (AB Biodisk, Solna, Sweden).

FIG. 1.

Population analysis profiles (PAP) of daptomycin (A) and vancomycin (B) on 6 of 8 sequential methicillin-resistant Staphylococcus aureus (MRSA) isolates from a fatal, persistent bacteremia case. CGK1, CGK3, and CGK5 isolates were daptomycin susceptible, and CGK6, CGK7, and CGK8 isolates were daptomycin nonsusceptible. The PAP of vancomycin was performed to look for heterogeneous vancomycin-intermediate strains (hVISA). If the ratio of the area under the curve (AUC) of the test isolate to that of Mu3 was ≥0.9, the isolate was considered positive for hVISA (17). N315, hVISA-negative control; Mu3, hVISA-positive control.

Much remains to be elucidated on the mechanisms involved in daptomycin and associated vancomycin nonsusceptibility (1-3, 5-9, 12, 14, 18) and the inversed oxacillin susceptibility (13, 15, 16). Previous reports have emphasized the importance of draining infection foci for successful treatment outcomes (2, 10), but surgical intervention was not possible in our patient due to coagulopathy secondary to his non-Hodgkin's lymphoma. The causative strain, with initial vancomycin MICs (2 μg/ml) at the upper susceptible limit, and priming by glycopeptide exposure (in this case, teicoplanin) likely contributed to the development of daptomycin and vancomycin nonsusceptibility (2, 10). Until practical laboratory methods for timely detection of strains with heteroresistance or attenuated susceptibility are developed, close monitoring for the emergence of daptomycin nonsusceptibility during treatment is needed.