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Antimicrobial Agents and Chemotherapy, August 1999, p. 1914-1918, Vol. 43, No. 8
The Anti-Infective Research Laboratory,
Received 20 November 1998/Returned for modification 15 April
1999/Accepted 27 May 1999
Methicillin-resistant Staphylococcus aureus strains
with decreased vancomycin susceptibility have been isolated from
patients in the United States and Japan. The impact of decreased
vancomycin susceptibility on the drug's pharmacodynamic parameters has
not been addressed. We studied the activity of vancomycin against three
clinical strains of vancomycin intermediate-susceptible Staphylococcus aureus (VISA) under high- and low-inoculum
conditions, with stationary- and logarithmic-growth-phase kill curves,
and in postantibiotic effect (PAE) experiments. We also investigated the stability of the decreased vancomycin susceptibility by using population susceptibility profiles. The respective vancomycin microdilution MICs and MBCs for VISA strains HIP5836, 14379, and Mu50
were 8 and 8, 8 and 8, and 8 and 16 µg/ml. HIP5836 had the most
homogeneous elevation of vancomycin MICs, because the MIC for nearly
all bacteria in the inoculum was 8 µg/ml. The population MICs
(defined as the lowest vancomycin concentration inhibiting 99.9% of
growth) for the first serial passages of HIP5836, Mu50, and 14379 were
8, 4, and 2 µg/ml, respectively. After 10 passages, they decreased to
4, 2, and 1 µg/ml, respectively. The Mu50 population MIC increased to
12 µg/ml after five serial passages on vancomycin agar. In the low-
and high-inoculum kill curves, time to 99.9% killing was significantly
(P < 0.05) longer for both Mu50 and HIP5836 than that
for 14379 and a control strain. However, colony counts at 24 h
were similar to those of the vancomycin-sensitive strain for all VISA
strains. The PAE (at 4× MIC) ranged from 1.3 h for 14379 to
2.0 h for HIP5836 and was similar to or greater than the PAE
against the vancomycin-sensitive strain. In conclusion, we found that
the decreased vancomycin susceptibility increased during persistent
exposures to the drug and decreased upon removal of the selective
pressure. The decreased vancomycin susceptibility decreased the rate of
vancomycin killing, but did not affect the extent of killing or the PAE.
Staphylococcus aureus
continues to be a significant pathogen and has demonstrated an
impressive ability to become resistant to nearly all antistaphylococcal
antimicrobial agents used in clinical practice. Resistance to
penicillin (due to the production of The mechanism of decreased susceptibility to vancomycin in these
S. aureus strains is not yet fully understood. Expression of
reduced vancomycin susceptibility appears to be heterogeneous, and gene
probe hybridization studies indicate no presence of vanA or
vanB genes (2, 10-12, 16). These clinical VISA
strains appear to share common characteristics with laboratory-derived staphylococcal mutants with decreased vancomycin susceptibility, including thickened cell walls, increased production of cell wall precursors, decreased autolysis, increased penicillin-binding proteins
(PBPs), and slower growth than vancomycin-sensitive MRSA (7, 11,
16-18, 21, 22).
The recent isolation of these clinical strains of VISA highlights the
need for other effective antimicrobials for MRSA infections. However,
the impact of decreased vancomycin susceptibility on its
pharmacodynamic parameters and its clinical efficacy have not been
fully addressed. We studied the effect of reduced vancomycin susceptibility on its killing activity against high inocula, low inocula, and stationary- and logarithmic-growth-phase VISA, as well as
its impact on postantibiotic effect (PAE). Additionally, we studied the
stability of decreased vancomycin susceptibility and the effects of
persistent suboptimal vancomycin exposure on the population
susceptibility profiles of VISA.
Bacterial strains.
The VISA strains tested in this
investigation were 14379 (William Beaumont Hospital, Royal Oak, Mich.
[16]), Mu50 (Juntendo Hospital, Tokyo, Japan
[11]), and HIP5836 (Centers for Disease Control and
Prevention, Atlanta, Ga. [3]). A clinical strain of
vancomycin-susceptible MRSA, 494, was used for comparisons of
vancomycin activity.
Antimicrobial agents and media.
Vancomycin (lot no.
35H040425) was commercially purchased from Sigma Chemical Company (St.
Louis, Mo.). Mueller-Hinton broth (Difco, Detroit, Mich.) supplemented
with calcium (25 mg/liter) and magnesium (12.5 mg/liter) (SMHB) was
used for all microdilution susceptibility testing, logarithmic-phase
time-kill curves, and PAE experiments. Phosphate-buffered saline (PBS)
supplemented with 1.2 g of MHB (PBS-MHB [supplying 1 g of
Casamino Acids per liter]) was used for the stationary-growth-phase
analyses. All experimental samples were plated on tryptic soy agar (TSA
[Difco]) to determine colony counts. Mueller-Hinton medium (Difco)
was used to prepare vancomycin-containing agar plates for agar dilution MICs and for analysis of population susceptibility profiles.
Susceptibility testing.
Microdilution MICs and MBCs (in SMHB
and PBS-MHB) and agar dilution MICs for vancomycin were determined for
each drug by using a standard inoculum of 5 × 105
CFU/ml according to the guidelines of the National Committee for
Clinical Laboratory Standards (18).
Population susceptibility profiles.
Vancomycin population
susceptibility profiles were determined in duplicate by modifications
of previously described methods (8, 22). Fifty microliters
of an ~1 × 109 to 1 × 1010 CFU/ml
suspension of bacteria was placed on Mueller-Hinton medium containing
doubling dilutions of vancomycin (range, 0.25 to 64 µg/ml) by using
an autoplate spiral dispenser (model 3000; Spiral Bioscience,
Frederick, Md.). After incubation at 35°C for 24 to 48 hours, colony
counts were determined with a laser bacterial colony counter (model
500A; Spiral System Instruments, Inc.). The lowest vancomycin
concentration inhibiting 99.9% of growth was defined as the population
MIC (22). Cultures of all three VISA strains were repeatedly
grown on TSA, and population susceptibility profiles were reassessed
after 2, 5, and 10 serial passages to evaluate the stability of
decreased vancomycin susceptibility. Additionally, one VISA strain
(Mu50) was grown on agar containing vancomycin at 1/2× and 1× MIC,
with reevaluation of the population susceptibility profile and MICs
after five serial passes.
Time-kill curves.
Time-kill curves were determined in
duplicate with starting inocula of 105 CFU/ml (low
inoculum), 106 CFU/ml (stationary phase), or
107 CFU/ml (high inoculum). Fresh overnight growths of
bacteria in SMHB were diluted as necessary to produce the desired
starting inocula in 10 ml of medium (SMHB for exponentially growing
high- and low-inoculum experiments and PBS-MHB for stationary-phase experiments). Vancomycin was tested at a concentration of 15 µg/ml to
approximate typical mid-dose concentrations in serum. Samples (0.1 ml)
were removed from each well at 0, 4, 8, and 24 h and diluted
appropriately in cold 0.9% sodium chloride. Colony counts were
determined by spotting 20-µl samples in triplicate onto TSA and
incubation at 35°C for 24 h. We determined these methods to have
a lower limit of reliable detection of 2 log10 CFU/ml. For the stationary-phase experiments with HIP5836, Mu50, and 14379, inclusion of all data points resulted in linear kill curves with r values of PAE.
The PAE was determined by methods described by Craig
and Gudmundsson (6). Organisms were grown overnight in SMHB,
diluted with prewarmed SMHB, and incubated for 2 to 4 h to allow
for ~7 log10CFU of exponentially growing bacteria per ml.
One milliliter of this suspension was added to 9 ml of prewarmed SMHB
containing vancomycin at concentrations of 1× and 4× MIC (8 and 32 µg/ml, respectively) for the VISA strains and 1×, 4×, and 8× MIC
(1, 4, and 8 µg/ml, respectively) for MRSA 494. The 8× MIC (64 µg/ml) concentration was not tested against the VISA strains, because this concentration is not commonly achieved during usual dosing. Test
tubes were sampled prior to and 1 h after antibiotic addition. Samples were diluted 1:1,000 into prewarmed SMHB after 1 h of exposure to vancomycin, and aliquots (0.1 ml) were removed immediately after this dilution and every hour thereafter for up to 7 h.
Colony counts were determined as described in the time-kill curve
section. The PAE was calculated by the equation PAE = T Statistical analyses.
The colony counts at 24 h and
times to 99.9% killing were compared between groups by using analysis
of variance with Tukey's test for multiple comparisons, with a
P value of Susceptibilities.
The respective vancomycin microdilution MICs
and MBCs for VISA strains HIP5836, 14379, and Mu50 were 8 and 8, 8 and
8, and 8 and 16 µg/ml. The respective MIC and MBC for the
vancomycin-sensitive clinical strain were 0.5 and 1 µg/ml. MICs and
MBCs in PBS-MHB were 2 to 4 times lower than SMHB values when read at
18 to 24 h, but were similar to SMHB MICs and MBCs at 48 h.
Vancomycin agar dilution MICs were similar to microtiter MICs for all strains.
Population susceptibility profiles.
Population susceptibility
profiles for the three strains of VISA are shown in Fig.
1. The population MICs for the first
serial passes of HIP5836, Mu50, and 14379 were 8, 4, and 2 µg/ml;
after passes 2, 5, and 10, they were 8, 8, and 4; 4, 2, and 2; and 1, 1, and 1, respectively. HIP5836 had the most homogeneous baseline elevation of vancomycin MICs, because the MIC for nearly all bacteria in the inoculum was 8 µg/ml.
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Analysis of Vancomycin Population Susceptibility
Profiles, Killing Activity, and Postantibiotic Effect against
Vancomycin-Intermediate Staphylococcus aureus
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-lactamase) was reported in
strains of S. aureus soon after its introduction and became
commonplace by the 1950s (24). S. aureus isolates
resistant to -lactamase-stable agents (methicillin-resistant S. aureus [MRSA]) were first reported in 1961 (1) and had become a widespread problem in most hospitals in
the United States by the 1980s. Vancomycin, a glycopeptide antibiotic,
was introduced into clinical practice in 1956 but was not used widely
due to its poorer perceived tolerability (14). With the
increase in MRSA, its use rapidly escalated because it commonly was the
only antibiotic treatment to which MRSA was susceptible
(23). Although an alarming increase in the prevalence of
vancomycin-resistant enterococci has occurred in the 1990s, resistance
in clinical strains of staphylococci has remained rare. The isolation
of vancomycin-intermediate S. aureus (VISA), for which MICs
were 8 µg/ml, was reported from Japan in 1997 (5) and soon
thereafter from two sites in the United States (3, 4). Each
VISA strain was recovered from patients who had received extended
treatment courses of vancomycin (3, 11).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
0.95. Linear regression of the entire kill
curves for these experiments was used to compute the time to 99.9%
kill. Linear regression of kill-curve data from the 0-, 4-, and 8-h time points only was used to determine the time to 99.9% kill for the
VISA 14379 and MRSA 494 high-inoculum experiments, the MRSA 494 stationary-phase experiments, and all low-inoculum experiments, since
inclusion of the 24-h data points resulted in nonlinear kill curves
(see Fig. 2). Growth controls also were sampled every hour until the
media became cloudy, and doubling times were calculated by using linear
regression of the growth control curve.
C, where T was the time to achieve
1-log10CFU/ml growth for the antibiotic-exposed sample and
C was the time to achieve 1-log10CFU/ml growth
for the untreated control sample. For all PAE experiments, T
and C were determined either by linear regression (if
r 0.95) or by visual inspection of the regrowth
curve. Each PAE experiment was performed in duplicate.
0.05 indicating statistical significance.
All statistical analyses were performed with SPSS statistical software
(release 6.1.3; SPSS, Inc., Chicago, Ill.).
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
View larger version (49K):
[in a new window]
FIG. 1.
Vancomycin population susceptibility profiles for
HIP5836 (A), Mu50 (B), and 14379 (C). 
, first pass; 
, second
pass; 
, fifth pass; 
, tenth pass; ×, fifth pass on vancomycin
agar for Mu50. mcg, micrograms.
2 µg/ml by the fifth pass.
The population susceptibility profile for the tenth pass of VISA strain
14379 was not determined due to the absence of any subpopulations with
decreased vancomycin susceptibility.
Growth characteristics and time-kill curves. The doubling times for Mu50, HIP5836, 14379, and 494 were 34, 39, 75, and 29 min, respectively. VISA 14379 was the only strain that grew substantially slower than 494. Results from the time-kill curves are shown in Fig. 2 and Table 1. Colony counts at 24 h were similar for all of the strains tested. In the low- and high-inoculum kill curves, time to 99.9% killing was significantly longer (P < 0.05) for both Mu50 and HIP5836 than those for 14379 and 494. The times to 99.9% killing were similar for all strains in the stationary-phase kill curves.
|
, high inoculum; 
, growth control in PBS-MHB.
|
PAE.
Vancomycin PAEs are summarized in Table
2. Mean PAEs at 1× MIC ranged from
0.5 h for 14379 to 1.2 for HIP5836. PAEs at 4× MIC approximately
doubled for each VISA isolate and ranged from 1.3 h for 14379 to
2.0 h for HIP5836. PAEs were not appreciably different against the
VISA strains versus those for the vancomycin-sensitive strain.
|
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
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Therapeutic failures or slow responses with vancomycin therapy
versus staphylococci have been previously attributed to such factors as
a slower killing rate versus -lactam antibiotics, decreased
penetration to infected tissue sites, the presence of foreign bodies,
or the underlying compromised health status of the patient (13,
14, 22). However, the recent reports of MRSA with decreased
vancomycin susceptibility indicate that therapeutic failures against
MRSA soon will be related to vancomycin resistance.
We evaluated this decreased vancomycin susceptibility and its potential
to impact the pharmacodynamic parameters of vancomycin. We found that
all three VISA strains expressed heterogeneous resistance to vancomycin
("hetero-VISA" or "hetero-VRSA" [vancomycin-resistant S. aureus]) (12). Each strain had different percentages
of subpopulations expressing decreased vancomycin susceptibility, with
HIP5836 being the strain closest to achieving homogeneous expression of
resistance, followed by Mu50 and 14379. It is notable that our Mu50
population susceptibility profile differed appreciably from that
previously described (12). In that investigation, nearly
100% of Mu50 cells grew on 4 µg of vancomycin agar per ml, and
0.001% of the total cells grew on 10 µg/ml. In contrast, we found
that only 1% of the total Mu50 cell population grew on 4 µg of
vancomycin agar per ml, while no colonies grew on concentrations 8
µg/ml. This discrepancy probably is explained best by our finding of
diminished subpopulations with decreased vancomycin susceptibility for
Mu50 (as well as for the other two VISA strains) with serial passages. We do not know the exact number of serial passages of Mu50 on antibiotic-free media prior to our acquisition of this isolate, but at
least two passages occurred prior to the generation of the frozen
bacterial stock used for all subsequent experiments. These observations
are important and need to be considered during future study of VISA strains.
The potential for the development of glycopeptide resistance in staphylococci has been studied for well over a decade. During this time, it has been reported that sequential in vitro exposures select for teicoplanin resistance more readily than for vancomycin resistance (20, 25). As well, decreased vancomycin susceptibility in staphylococci has been reported to be both stable (7, 10, 12, 22) and unstable (9, 25). These discrepancies in resistance stability could be related to different selection methods used (broth versus agar, continuous passes in the presence of drug versus alternating passes in drug-containing and drug-free media, etc.), different resistance assessment methods (broth dilution MICs versus population susceptibility profiles), or differences in resistance mechanisms between strains. Our findings of increased vancomycin susceptibility after repeated serial passages under antibiotic-free conditions and the emergence of further vancomycin-resistant subpopulations after repeated passages on vancomycin agar both suggest that decreased susceptibility may result from the selection of cells which have adapted to survive in the presence of the drug.
The exact mechanisms involved in the production and regulation of decreased vancomycin susceptibility in staphylococci are not completely determined. Studies of vancomycin resistance in enterococci have shown that a family of van genes allow the bacteria to replace the peptidoglycan D-alanyl-D-alanine terminus (the active binding site for vancomycin) with a D-alanyl-D-lactate terminus which has a 1,000-fold-decreased affinity for vancomycin (15). The presence of van genes has not been documented in VISA (11, 16), but increased production of cell wall precursors, thickened and irregular cell walls, decreased autolysis, increased quantities of PBPs, and slower growth have been described in both in vivo (10-12) and in vitro (7, 16, 17, 19, 21) resistant staphylococcal mutants. Although all of our VISA isolates grew more slowly than the vancomycin-sensitive strain, only one (14379) had substantially reduced growth. This VISA strain (which grows as small nonpigmented colonies) appears to be one of the small-colony variants, which usually are less susceptible to cell wall-active agents. Because vancomycin activity was appreciably decreased against all VISA strains and against all slow-growing bacteria (regardless of the vancomycin susceptibility), it appears that the decreased growth rates were not a primary factor decreasing vancomycin susceptibility.
Decreased vancomycin susceptibility significantly reduced the rate but not the extent of vancomycin killing for both HIP5836 and Mu50 compared to the vancomycin-sensitive MRSA. These decreases were noted without regard to inoculum. In contrast, 14379 was killed at a rate similar to that of the vancomycin-sensitive strain. These findings likely were explained by the population susceptibility profiles for each VISA strain. Because 14379 possessed much fewer cells with decreased susceptibility compared to HIP5836 and Mu50, the vast majority of cells in the test inoculum probably were killed similar to a vancomycin-susceptible strain. For all of these VISA strains, it appears that maintaining vancomycin concentrations at least 2× greater than the MIC could result in adequate killing activity.
Vancomycin PAEs against VISA were similar to or greater than the PAEs against the vancomycin-sensitive strain and also were within ranges previously reported for vancomycin-sensitive staphylococci (6). Interestingly, the PAEs for all three strains doubled upon increasing the concentration from 1 to 4× the MIC. This finding could be related to the "trapping" of vancomycin by the excess cell wall material which previously has been reported for vancomycin- and teicoplanin-resistant strains of S. aureus (21) and coagulase-negative staphylococci (22). These bacteria had the ability to quantitatively remove glycopeptide from the test media, which then was recovered from purified cell wall fractions in a biologically active form (21). Thus, the higher vancomycin concentrations could increase the PAEs against VISA in our experiments through better delivery of vancomycin to the site of active cell wall synthesis.
In conclusion, we found that decreased susceptibility to vancomycin appears to be a selective or inducible process that increased during persistent suboptimal exposure to the drug and decreased upon removal of the selective pressure. The decreased susceptibility to vancomycin decreased the rate but not the extent of vancomycin killing during exposure to concentrations approximately 2× greater than the MIC. The vancomycin PAE was more dependent on the concentration relative to the MIC against these strains. Because of the time-dependent killing activity for vancomycin, more frequent doses or continuous infusions of the drug might improve its activity against VISA until newer antibiotics become available.
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FOOTNOTES |
|---|
* Corresponding author. Mailing address: The Anti-Infective Research Laboratory, Department of Pharmacy Services (1B), Detroit Receiving Hospital and University Health Center, 4201 St. Antoine Blvd., Detroit, MI 48201. Phone: (313) 745-4554. Fax: (313) 993-2522. E-mail: mrybak{at}dmc.org.
Present address: The University of Connecticut, School of Pharmacy,
Storrs, CT 06269.
| |
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Discussion
References
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Antimicrobial Agents and Chemotherapy, August 1999, p. 1914-1918, Vol. 43, No. 8
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