Abstract
We evaluated the evolution of vancomycin MICs for Staphylococcus aureus and their relationship with vancomycin use among hospitalized children. S. aureus isolates recovered from sterile sites were prospectively tested for vancomycin susceptibility using the Etest between 1 April 2000 and 31 March 2008. Vancomycin MICs were grouped into three categories: ≤1, 1.5, and 2 μg/ml. The association between vancomycin MICs and aggregate vancomycin use and individual patient vancomycin exposure 6 months prior to the documented infection was assessed. The geometric mean values for vancomycin MICs for S. aureus fluctuated over time without a significant trend (P = 0.146). Of the 436 patients included in the study, 363 (83%) had methicillin-susceptible S. aureus (MSSA) and 73 (17%) had methicillin-resistant S. aureus (MRSA) infections. The rate of isolates with a vancomycin MIC of 2 μg/ml increased from 4% (2 of 46) in 2000 to 2001 to 24% (11 of 46) in 2007 to 2008, despite a decrease in vancomycin use (r = −0.11; P = 0.825). The percentage of isolates with a vancomycin MIC of 2 μg/ml was higher for MRSA (15%; 11 of 73) than for MSSA strains (5.2%; 19 of 363) (χ2 = 9.2; P = 0.01). Individual patient vancomycin exposure was not associated with a higher vancomycin MIC. In the unadjusted model, in which we compared patients with S. aureus infections with MICs of ≤1 μg/ml, the odds ratios of exposure rates for patients with isolates with MICs of 1.5 μg/ml and 2 μg/ml were 1.02 (P = 0.929) and 1.13 (P = 0.767), respectively. In our experience, the geometric means of vancomycin MICs from S. aureus isolates recovered from hospitalized children oscillated over time and were not associated with previous individual patient vancomycin exposure or aggregate vancomycin use.
INTRODUCTION
Over the past two decades, methicillin-resistant Staphylococcus aureus (MRSA) has become a major etiology of both community-acquired and health care associated infections in children (1–4). Since its introduction to the market in 1958, vancomycin has remained the first-line agent for management of hospitalized pediatric patients with these severe infections. Vancomycin MICs creeping above 1.5 μg/ml for MRSA strains and associated reduced vancomycin efficacy reported in adults have challenged clinicians' choices of effective antibiotic therapies in critically ill patients (5–14). Moreover, pharmacokinetic-pharmacodynamic (PK-PD) simulation studies in children promote the use of more aggressive vancomycin dosing despite limited available data regarding safety in this patient population (15, 16).
We evaluated the trend in vancomycin MICs for S. aureus over an 8-year period, its correlation with aggregate and individual-patient vancomycin exposure, and clinical outcomes associated with infections when the MIC of the isolate was 2 μg/ml.
(This study was presented in part as an abstract and a poster at the 47th Annual Meeting of the Infectious Diseases Society of America, Philadelphia, PA, October 2009 [17].)
MATERIALS AND METHODS
Settings.
The study was conducted at the Alfred I. DuPont Hospital for Children, a 180-bed tertiary-care academic pediatric hospital affiliated with Thomas Jefferson University (Philadelphia, PA). Overall, the inpatient units averaged 9,000 admissions per year, with 78 pediatric/medicine residents and 31 pediatric fellows providing rotating care (18).
Definition of antimicrobial susceptibility.
The Clinical and Laboratory Standards Institute (CLSI) defines S. aureus isolates with oxacillin MICs of ≤2 μg/ml and ≥4 μg/ml as methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains, respectively (19). Vancomycin-susceptible S. aureus (VSSA) isolates are considered susceptible if the MIC for vancomycin is ≤2 μg/ml. Vancomycin-intermediate S. aureus (VISA) strains require concentrations between 4 and 8 μg/ml for growth inhibition, and isolates requiring ≥16 μg/ml are considered resistant (19).
S. aureus clinical isolates.
S. aureus isolates recovered from sterile sites from pediatric patients admitted to the Alfred I. DuPont Hospital for Children from 1 April 2000 to 31 March 2008 were included in the study. Only one S. aureus isolate per patient per year was included in the analysis. Sterile sites included bloodstream (peripheral and catheter related), musculoskeletal (bone, joint, and muscle), cerebrospinal fluid, and pleural fluid. S. aureus isolates were identified according to standard procedures (e.g., growth conditions, morphological criteria, Gram staining, catalase test, Staphaurex test [Remel, Lenexa, KS], or tube coagulase test) and by Vitek (bioMérieux, Durham, NC) at the Alfred I. DuPont Hospital microbiology laboratory. The percentages of susceptibility for oxacillin and vancomycin were calculated according to the 2006 CLSI recommendations (20).
MIC determination.
Clinical isolates were tested prospectively for vancomycin susceptibility using an Etest (AB Biodisk, bioMérieux, S.A., Marcy l'Etoile, France) at the Alfred I. DuPont Hospital microbiology laboratory according to the manufacturer's instructions. Etest susceptibilities were read at the point of care by a single observer. Vancomycin MICs were grouped into three categories, MICs ≤1 μg/ml, 1.5 μg/ml, and 2 μg/ml. Oxacillin susceptibility analyses were routinely performed using a Vitek (bioMérieux, Durham, NC).
Data collection and definitions.
Patient demographic information was retrieved from medical records and recorded into the database. Clinical and outcome data of patients with MICs of 2 μg/ml were recorded into a separate database. Clinical data collected included underlying medical condition and diagnosis at admission as well as presence of a central venous catheter (CVC). Empirical antibiotic therapy refers to the antibiotic agents given pending culture reports. Definitive antibiotic therapy refers to antibiotics given based on isolate identification and susceptibility data. Outcome data collected included duration of bacteremia, the presence of sepsis, and death during hospitalization. Duration of bacteremia refers to the number of days from the first positive blood culture to the first negative blood culture. Attributable mortality was defined as death during bacteremia or sepsis in the absence of another cause.
Measures of vancomycin use.
Medication administration record (MAR) data were stored in the Cerner database and in the Nemours data warehouse. Tables containing selected critical data elements were downloaded daily from CareNet and PharmNet to the Nemours data warehouse by using an Oracle database (Oracle Corporation, Redwood Shores, CA) established to integrate business, operational risk, and clinical data with patient encounters (18). Numbers of vancomycin doses administered were retrieved by querying the Cerner medication administration record tables linked to vancomycin in the data warehouse (21). Data from 1 April 2000 to 31 March 2008 were captured by the number of doses administered to each unique patient. Doses administered were normalized per 1,000 patient-days to control for differences in the annual hospital census (18, 21).
Individual-patient vancomycin exposure.
Vancomycin therapy, expressed as doses administered and days of therapy, was recorded for each individual patient during the 6 months preceding the S. aureus infection.
The Nemours Institutional Review Board approved this study.
Statistics.
A chi-square test was used to determine the statistical significance between patient characteristics and groups of S. aureus MICs. Continuous variables were compared by use of the Student t test. Geometric means of vancomycin MICs were calculated and a simple linear regression of the log(MIC) of time was performed to determine the trend of the natural logarithm-transformed MIC over time. Temporal trends of aggregate vancomycin use per 1,000 patient-days were analyzed using a χ2 test trend for proportions (21). Spearman's correlation coefficient was used to evaluate the association between aggregate vancomycin use and rates of S. aureus infection with higher MICs. A multivariable logistic regression analysis was used to determine the association between individual-patient vancomycin exposure and the vancomycin MIC for S. aureus, while controlling for methicillin resistance. All tests were two tailed, with a P value of 0.05 as the set level of significance. Analyses were performed using IBM SPSS software version 20 (IBM Corp.) and statistical software R version 2.10.2.
RESULTS
During the study period, S. aureus geometric means of vancomycin MIC values fluctuated as depicted in Table 1. Over time, we did not find a statistically significant trend in the geometric mean change in the log(MIC) (slope [SE], 2.012 [0.008]; P = 0.146). A total of 436 children, with a median age of 4 years (range 0 to 20 years), developed invasive S. aureus infection. All documented infections were susceptible to vancomycin. Males represented 60% of individuals with infections. Of these, 363 (83%) developed infections with MSSA strains and 73 (17%) developed infections with MRSA. The geometric means of vancomycin MICs for MSSA and MRSA isolates were 1.1 μg/ml and 1.2 μg/ml, respectively (Table 1). Trends for the vancomycin MIC geometric means for MSSA and MRSA isolates were not statistically significant when evaluated separately (Table 1). Patient characteristics and rates of invasive staphylococcal infections based on S. aureus susceptibility to methicillin and vancomycin MICs are shown in Table 2. The rates of S. aureus isolates with vancomycin MICs of 2 μg/ml increased from 4% (2 of 46) during the first year of the study to 24% in 2007 to 2008 (11 of 46). From 2000 to 2001 to 2007 to 2008, a higher percentage of MRSA (15%; 11 of 73) isolates expressed a vancomycin MIC of 2 μg/ml than MSSA isolates (5.2%; 19 of 363) (χ2 = 9.2; P = 0.01). Rates of MSSA isolates with MICs of 2 μg/ml fluctuated between 2% (1 of 50) and 6% (2 of 35) in 2001 to 2002 and 2006 to 2007, respectively, and sharply increased to 21% (7 of 34) during the last year of the study. MRSA strains with MICs of 2 μg/ml were not recovered until 2001 to 2002 (20%; 1 of 5), and peaked in 2007 to 2008 at 33% (4 of 12).
Table 1.
Vancomycin MICs for Staphylococcus aureus by Etest at Alfred I. DuPont Hospital for Children, 1 April 2000 to 31 March 2008
| Years | Values for: |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| All isolates |
MSSA |
MRSA |
|||||||
| n | Geometric mean MIC (μg/ml) (±SD) (P = 0.146a) | Mode (μg/ml) | n (%) | Geometric mean MIC (μg/ml) (±SD) (P = 0.364b) | Mode (μg/ml) | n (%) | Geometric mean MIC (μg/ml) (±SD) (P = .425c) | Mode (μg/ml) | |
| 2000–2001 | 46 | 1.04 (±0.36) | 1 | 43 (94) | 1.05 (±0.36) | 1 | 3 (6) | 1.4 (±0.38) | 0.75 |
| 2001–2002 | 55 | 1.04 (±0.37) | 1 | 50 (91) | 1.02 (±0.35) | 1 | 5 (9) | 1.35 (±0.41) | 1 |
| 2002–2003 | 73 | 1.17 (±0.32) | 1 | 68 (93) | 1.2 (±0.31) | 1 | 5 (7) | 1.35 (±0.41) | 1 |
| 2003–2004 | 50 | 0.98 (±0.29) | 1 | 40 (80) | 1 (±0.29) | 1 | 10 (20) | 0.86 (±0.26) | 0.75 |
| 2004–2005 | 59 | 1.32 (±0.3) | 1.5 | 51 (86) | 1.3 (±0.29) | 1.5 | 8 (24) | 1.45 (±0.37) | 1.5 |
| 2005–2006 | 56 | 0.78 (±0.37) | 1 | 42 (75) | 0.74 (±0.32) | 0.5 | 14 (25) | 0.9 (±0.46) | 1 |
| 2006–2007 | 51 | 1.04 (±0.42) | 1 | 35 (69) | 0.98 (±0.42) | 1.5 | 16 (31) | 1.19 (±0.39) | 1 |
| 2007–2008 | 46 | 1.44 (±0.37) | 1.5 | 34 (74) | 1.45 (±0.34) | 1.5 | 12 (26) | 1.4 (±0.46) | 1.5 |
| Total | 436 | 1.08 (±0.39) | 1 | 363 (93) | 1.1 (±0.38) | 1 | 73 (17) | 1.2 (±0.44) | 1 |
Slope (SE) = 2.012 (0.008).
Slope (SE) = 2.008 (0.009).
Slope (SE) = 2.018 (0.022).
Table 2.
Selected characteristics of children with invasive staphylococcal infections at Alfred I. DuPont Hospital for Children, 1 April 2000 to 32 March 2008
| Characteristica | No. (%) of MSSA isolates with vancomycin MICs (μg/ml) of:b |
Pd | No. (%) of MRSA isolates with vancomycin MICs (μg/ml) of:c |
Pd | ||||
|---|---|---|---|---|---|---|---|---|
| ≤1 (n = 226) | 1.5 (n = 118) | 2 (n = 19) | ≤1 (n = 40) | 1.5 (n = 22) | 2 (n = 11) | |||
| Age (yr) | ||||||||
| ≤2 | 71 (32) | 39 (33) | 7 (37) | 9 (22.5) | 6 (27) | 4 (36) | ||
| >2 to ≤12 | 100 (44) | 52 (44) | 9 (47) | 22 (55) | 6 (27) | 5 (46) | ||
| >12 | 55 (24) | 27 (23) | 3 (16) | 0.9 | 9 (22.5) | 10 (46) | 2 (18) | 0.2 |
| Gender | ||||||||
| Male | 133 (59) | 68 (58) | 11 (58) | 26 (65) | 18 (82) | 6 (54.5) | ||
| Female | 93 (41) | 50 (42) | 8 (42) | 0.9 | 14 (35) | 4 (18) | 5 (45.5) | 0.2 |
| Infection site | ||||||||
| Blood | 128 (57) | 76 (64) | 9 (47) | 23 (57.5) | 13 (59) | 7 (64) | ||
| MS | 87 (38.5) | 36 (31) | 7 (37) | 14 (35) | 7 (32) | 3 (27) | ||
| CSF | 8 (3.5) | 5 (4) | 2 (11) | 3 (7.5) | 2 (9) | 1 (9) | ||
| Pleural | 3 (1) | 1 (1) | 1 (5) | 0.3 | 0 | 0 | 0 | 0.9 |
| Previous vancomycin exposure | 60 (27) | 34 (29) | 5 (26) | 0.9 | 13 (45) | 5 (23) | 4 (36) | 0.6 |
MS, musculoskeletal; CSF, cerebrospinal fluid.
Total n = 363.
Total n = 73.
Pearson's chi-square.
Of the 30 patients who developed S. aureus infections with strains expressing MICs of 2 μg/ml, 16 (53%) developed bacteremia, more commonly associated with MSSA isolates. Over time, the rates of bacteremia caused by isolates with an MIC of 2 μg/ml increased (χ2 trend= 13; P = 0.0003) (Fig. 1). No significant differences were noted between age groups and S. aureus infections (Pearson's χ2 = 0.907; P = 0.9) and/or bacteremia (Pearson's χ2 = 4.9; P = 0.3) caused by isolates with vancomycin MICs of 2 μg/ml. Demographic and clinical characteristics of children with S. aureus bloodstream infections (BSI) and non-BSI due to strains with vancomycin MICs of 2 μg/ml are shown in Table 3 and Table 4, respectively. Among these 30 patients, 9 (30%) had a preceding exposure to vancomycin within the previous 6 months. Patients treated with vancomycin received daily dosages ranging from 20 to 40 mg/kg of body weight per day. In this cohort, one death (3.3%) was attributed to MSSA BSI in a 12-month-old infant while on hospice care for intractable bilineal leukemia.
Fig 1.
Vancomycin use and percentage of patients at the Alfred I. DuPont Hospital for Children with S. aureus infections with vancomycin MICs of 2 μg/ml. Vancomycin use is expressed as number of doses administered per 1,000 patient-days (shown with bars on the left axis) and percentage of hospitalized children with S. aureus (SA) infections with MICs of 2 μg/ml (represented as dotted and solid lines on the right axis).
Table 3.
Selected characteristics of children with Staphylococcus aureus bloodstream infection and vancomycin MICs of 2 μg/ml, Alfred I. DuPont Hospital for Children, 1 April 2000 to 31 March 2008
| Characteristica | MSSA (n = 9) | MRSA (n = 7) | P value |
|---|---|---|---|
| Age, median (range) | 8 mo (0–11 yr) | 3 mo (0–12 yr) | 0.4 |
| Male sex (n [%]) | 5 (56) | 4 (57) | 0.5 |
| Underlying condition (n) | |||
| Prematurity | 4 | ||
| Endocarditis | 1 | ||
| Osteomyelitis | 2 | 2 | |
| Leukemia, HLH | 4 | ||
| TPN dependent | 2 | ||
| Tracheostomy | 1 | ||
| Previous vancomycin exposure (n [%])b | 3 (33) | 3 (43) | |
| Sepsis (n) | 2 | 2 | |
| Central venous access (n) | 8 | 7 | |
| Empirical antibiotic therapyc (n) | |||
| Vancomycin | 2 | ||
| Vancomycin + β-lactamd | 5 | 1 | |
| Vancomycin + aminoglycoside | 2 | ||
| Vancomycin + clindamycin | 1 | ||
| Vancomycin + rifampin | 1 | ||
| β-Lactam + clindamycin | 1 | ||
| Clindamycin | 1 | ||
| β-Lactam | 2 | ||
| Days of bacteremia, mean (range) | 2.67 (1–6) | 2.29 (1–3) | 0.4 |
| Definitive antibiotic therapye (n) | |||
| Vancomycin alone | 1 | 5 | |
| Vancomycin + β-lactam | 1 | ||
| Vancomycin + rifampin | 1 | ||
| β-Lactam | 5 | - | |
| β-Lactam + rifampin | 1 | ||
| β-Lactam + aminoglycoside | 1 | ||
| Linezolid | 1 | ||
| Duration of therapy (mean [range]) (days) | 26 (1–42) | 17 (4–42) | 0.3 |
| Mortalityf (n) | 1g | 0 | 0.5 |
HLH, hemophagocytic lymphohistiocytosis; TPN, total parenteral nutrition. n, number of children with characteristic.
Patients with previous vancomycin exposure, measured as doses of vancomycin administered, 6 months prior to the documented S. aureus infection.
Antibiotic agents given pending culture reports.
β-Lactam antibiotics included oxacillin, nafcillin, cefazolin, cefepime, cefotaxime, ceftriaxone, and piperacillin-tazobactam.
Antibiotic therapy given based on identification and susceptibility report.
Attributable mortality.
Patient on hospice care admitted with sepsis and orders to not resuscitate.
Table 4.
Selected characteristics of children with Staphylococcus aureus nonbloodstream infection and vancomycin MICs of 2 μg/ml, Alfred I. DuPont Hospital for Children, 1 April 2000 to 31 March 2008
| Characteristic | MSSA (n = 10) | MRSA (n = 4) | P value |
|---|---|---|---|
| Age, median (range) (yr) | 8 (0–16) | 15 (3–19) | 0.12 |
| Male sex (n [%]) | 5 (50) | 2 (50) | |
| Underlying condition (n) | |||
| Osteomyelitis | 3 | 1 | |
| Malignancya | 2 | ||
| Hydrocephalus | 1 | ||
| Congenital heart diseaseb | 1 | ||
| Spine malformationc | 2 | 2 | |
| Previous vancomycin exposure (n [%])d | 2 (20) | 1 (25) | |
| Sepsis (n) | 1 | 1 | |
| Central venous access (n) | 7 | 2 | 0.5 |
| Site of infection (n) | |||
| Skin and soft tissue | 1 | 1 | |
| Surgical site infection | 5 | 2 | |
| Bone | 3 | 1 | |
| Lung | 1 | ||
| Empirical antibiotic therapye (n) | |||
| Vancomycin | 1 | ||
| Vancomycin + β-Lactamf | 3 | 1 | |
| Vancomycin + clindamycin | 1 | 1 | |
| Vancomycin + rifampin | 1 | 1 | |
| β-Lactam | 5 | ||
| Definitive antibiotic therapyg (n) | |||
| Vancomycin alone | 1 | 2 | |
| Vancomycin + rifampin | 1 | ||
| β-Lactam | 10 | ||
| Linezolid | 1 | 1 | |
| Duration of therapy (mean [range]) (days) | 33 (7–42) | 36 (30–42) | 0.45 |
| Mortalityh (n) | 0 | 0 |
Leukemia, brain tumor.
Congenital heart disease, tetralogy of Fallot.
Spine malformations, neuromuscular and idiopathic scoliosis, spina bifida.
Patients with previous vancomycin exposure, measured as doses of vancomycin administered, 6 months prior to the documented S. aureus infection.
Antibiotic agents given pending culture reports.
β-Lactam antibiotics included oxacillin, nafcillin, cefazolin, cefepime, cefotaxime, ceftriaxone, and piperacillin-tazobactam.
Antibiotic therapy given based on identification and susceptibility report.
All-cause and attributable mortality.
We noted a sharp decline in the rates of S. aureus isolates with vancomycin MICs of ≤1 μg/ml between 2006 to 2007 and 2007 to 2008 (P < 0.001). No vancomycin-intermediate or vancomycin-resistant strains were recovered.
We previously reported the trends of vancomycin use 3 years before and after implementation of our antimicrobial stewardship program (21). Prior to the implementation of the antimicrobial stewardship program, vancomycin use increased from 112 doses administered/1,000 patient-days during the first year of the study to 378 doses administered/1,000 patient-days in 2003 to 2004 (χ2 trend = 218.14; P < 0.001). After the implementation of the program, the use of vancomycin decreased to 255 doses administered/1,000 patient-days in 2007 to 2008 (χ2 trend = 41.16; P < 0.001). Figure 1 depicts trends of aggregate vancomycin use and percentages of S. aureus infections associated with isolates expressing vancomycin MICs of 2 μg/ml (r = −0.11; P = 0.825). Of the 436 patients included in the study, 121 (27.8%) received vancomycin within 6 months of the documented infection. In these children, individual-patient vancomycin exposure was not associated with a higher vancomycin MIC. In the unadjusted model, in which we compared patients with S. aureus infections with MICs of ≤1 μg/ml, the odds ratios of exposure rates for patients whose isolates had MICs of 1.5 μg/ml and 2 μg/ml were 1.02 (P = 0.929) and 1.13 (P = 0.767), respectively. After we controlled for isolate susceptibility to methicillin, these odds ratios were 1.02 (P = 0.932) and 1.10 (P = 0.821), respectively, showing no differences between groups.
DISCUSSION
During the 8 years of the study, S. aureus infections in children at our institution were mainly associated with MSSA isolates. Over time, we did not find a statistically significant trend for the geometric mean of vancomycin MIC or an association between aggregate and individual-patient vancomycin exposure and vancomycin MICs among the S. aureus isolates recovered. The most striking finding was the higher proportion of S. aureus infections associated with higher MICs (2 μg/ml) noted during the last year of the study, despite the steadily declining use of vancomycin after the implementation of antimicrobial stewardship strategies. Of these patients, only 30% had a prior exposure to vancomycin. In our cohort, patients with MRSA bloodstream infections due to isolates with higher MICs were treated with vancomycin doses ranging between 20 and 40 mg/kg/day, and these patients cleared their bacteremia within 72 h. None of these patients died. Furthermore, we found no differences between days of positive blood cultures among patients with MSSA and MRSA treated with appropriate β-lactam antibiotics or vancomycin. Among these, four children with osteomyelitis did not have a history of previous vancomycin exposure. Susceptibility testing by Etest has been shown to yield higher vancomycin MICs than automated testing methods (8, 22, 23). This could explain the favorable clinical outcome seen in patients with MRSA bacteremia treated with vancomycin despite the high vancomycin MICs noted in vitro. Nevertheless, several studies have demonstrated poor clinical outcomes in adults with MRSA bacteremia and vancomycin MICs of >1.5 μg/ml measured by Etest (10, 24–27). Different confounding factors in this patient population, including comorbidities and pharmacokinetics, could be responsible for the differences in clinical outcomes. Diversity in bacterial genotype and expression of heteroresistance could play a role in the inferior outcomes reported in these patients (28).
Our findings are consistent with those reported by Mason and colleagues (8). Among their cohort of pediatric patients with MRSA bacteremia treated with vancomycin, these authors did not find a correlation between MIC and duration of positive blood cultures (8). Additional outcome studies in pediatric patients with invasive MRSA infections with higher vancomycin MICs have not been published. In a multicenter prospective study of adult patients with MSSA and MRSA bacteremia, those with higher MICs had poorer outcomes. However, the antibiotic choice, specifically the use of vancomycin, was not a contributing factor for mortality (24). More data correlating MICs, mortality, and antibiotic choice are necessary in the pediatric population.
In the absence of randomized studies assessing clinical outcomes associated with vancomycin MICs and vancomycin dosing, these retrospective reports support the Infectious Diseases Society of America (IDSA) recommendations for antibiotic management of children infected with MRSA isolates expressing MICs of 2 μg/ml (29). Clinical practice guidelines indicate that therapy should be guided by the clinical response independent of the MIC (IDSA-U.S. Public Health Service grading system: A-III) and challenge PK-PD studies suggesting the need to use higher doses or an alternative agent in the presence of MICs of >1 μg/ml to <2 μg/ml and 2 μg/ml (15, 29, 30). The optimal vancomycin PK-PD parameter was evaluated in a single human study of 108 adult patients with MRSA pneumonia. For vancomycin, a value of ≥400 for the area under the concentration-time curve for 24 h (AUC24) divided by the MIC (AUC24/MIC) was shown to be associated with optimal clinical outcomes (31). Applying this principle in a PK-PD simulation study, Frymoyer et al. (15) reported that current vancomycin dosing of 40 mg/kg/day in children with invasive infections due to MRSA strains with an MIC of 1 μg/ml would not achieve an AUC24/MIC of ≥400 and more aggressive doses (60 mg/kg/day) should be used in these patients. For MRSA strains with an MIC of 2 μg/ml, the optimal AUC24/MIC cannot be achieved safely, and an alternative agent should be strongly considered (15, 32). Differences in tissue penetration and pharmacokinetics in children argue against the assumption that an AUC/MIC target ratio of >400 should apply to infections other than pneumonia (16). Moreover, vancomycin is among the most commonly used antibiotics in children, and higher dosing regimens in the absence of clinical efficacy and safety data could promote increased rates of toxicity.
One limitation of our study was that isolates were not available for subsequent testing, including automated susceptibility and assessment of S. aureus heterogeneous vancomycin-intermediate rates over time. The higher rate of vancomycin MICs noted during the last year of the study could have been related to nosocomial transmission of these organisms. The majority of patients (19 of 32, 59%) with isolates expressing higher MICs had underlying conditions requiring multiple hospitalizations. In addition, discontinuation of Etest and MIC reporting by the microbiology laboratory limited our ability to follow vancomycin MIC trends beyond the study period. Nevertheless, in the two subsequent years, the microbiology laboratory did not recover S. aureus isolates expressing vancomycin MICs of >2 μg/ml.
Most studies demonstrating a vancomycin MIC creep were limited to short time intervals (6–9, 33). Similar to our study, studies for which longer time spans have been reported had vancomycin MICs that fluctuated over time without showing a statistically significant trend (26, 34). Emergence of resistance is multifactorial and an expected adaptation to antibiotic selective pressure. Long-term studies are needed to determine the impact of vancomycin dosing and the use of trends of vancomycin MICs to modify these regimens. Most importantly, in an era of personalized medicine, further pediatric studies are warranted to evaluate the use of applied pharmacodynamic principles to target therapy to individual patient-pathogen interactions to improve clinical outcomes and avoid toxicity and the emergence of resistance.
ACKNOWLEDGMENT
The authors report no conflicts of interest relevant to this article.
Footnotes
Published ahead of print 19 June 2013
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