Genetics of oxacillin resistance in clinical isolates of Streptococcus pneumoniae that are oxacillin resistant and penicillin susceptible

Dowson, Christopher G.; Johnson, Alan P.; Cercenado, Emilia; George, Robert C.

doi:10.1128/aac.38.1.49

Cited by 48 publications

(46 citation statements)

References 23 publications

(25 reference statements)

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“…These data, in conjunction with recent DNA sequence data (5), provide strong evidence for the development in pneumococci of resistance to ␤-lactams by horizontal transfer of mosaic pbp genes into susceptible isolates and by secondary modifications involving nucleotide substitutions. The concurrent occurrence of high-level resistance to extended-spectrum cephalosporins in several pneumococcal clones in the United States suggests that cephalosporin-resistant pneumococci are likely to be isolated with increasing frequency because of the strong selective pressure resulting from the high utilization of ␤-lactams for the treatment of pneumococcal infections in the United States (12,34,41).…”

Section: Discussionmentioning

confidence: 99%

“…At least three of the five high-molecular-weight PBPs are consecutively altered, with increasing levels of resistance to penicillin (9). An altered pbp2x appears to be a prerequisite for higher resistance levels involving the acquisition of modified, low-affinity variants of pbp2b and pbp1a in clinical isolates (10,12,27,28,38). High-level resistance to penicillin can be achieved by successive alterations of the genes encoding PBPs 2x, 2b, and 1a (11).…”

Section: Discussionmentioning

confidence: 99%

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Identification of multiple clones of extended-spectrum cephalosporin-resistant Streptococcus pneumoniae isolates in the United States

McDougal

Rasheed

Biddle

et al. 1995

Antimicrob Agents Chemother

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We characterized 12 isolates of Streptococcus pneumoniae with various levels of susceptibility to penicillin and extended-spectrum cephalosporins by antimicrobial susceptibility patterns, serotypes, ribotypes, chromosomal DNA restriction patterns by pulsed-field gel electrophoresis, multilocus enzyme electrophoresis patterns, penicillin-binding protein (PBP) profiles, and DNA restriction endonuclease cleavage profiles of pbp1a, pbp2x, and pbp2b. Seven cefotaxime-resistant (MIC, >2 g/ml) serotype 23F isolates were related on the basis of ribotyping, pulsed-field gel electrophoresis, and multilocus enzyme electrophoresis, but they had two slightly different PBP patterns: one unique to strains for which the MIC of penicillin is high (4.0 g/ml) and one unique to strains for which the MIC of penicillin is low (0.12 to 1.0 g/ml). The pbp1a and pbp2x fingerprints were identical for the seven isolates; however, the pbp2b fingerprints were different. An eighth serotype 23F isolate with high-level resistance to cephalosporins was not related to the other seven isolates by typing data but was a variant of the widespread, multiresistant serotype 23F Spanish clone. The PBP profiles and fingerprints of pbp1a, pbp2x, and pbp2b were identical to those of the Spanish clone isolate. An additional serotype 6B isolate with high-level resistance to cephalosporins had unique typing profiles and was unrelated to the serotype 23F cephalosporin-resistant isolates but was related on the basis of genetic typing methods to a second serotype 6B isolate that was cephalosporin susceptible. The serotype 6B isolates had different PBP profiles and fingerprints for pbp1a, but the fingerprints for pbp2x and pbp2b were the same.Penicillin-resistant strains of Streptococcus pneumoniae, first isolated in the late 1960s in Australia, are now prevalent throughout the world and are often associated with resistance to other antimicrobial agents (1, 25). In the United States, previous surveys revealed only sporadic occurrences of penicillin-resistant pneumococcal isolates (prevalence, Յ5% [23,46]); however, more recent surveys show much higher rates of infection caused by resistant pneumococci (14,16,47). Although the optimal therapy for infections caused by penicillinintermediate or -resistant strains of pneumococci has not been established, several reports indicate that cefotaxime or ceftriaxone is the drug of choice for initial empiric therapy for meningitis and sepsis caused by this pathogen (7,14,31).Most pneumococcal isolates that are resistant to penicillin also have increased resistance to extended-spectrum cephalosporins, including cefotaxime and ceftriaxone. The MICs of penicillin are generally equal to or two to four times higher than the MICs of the cephalosporins. Recently, we (45) and others (3, 14, 22) reported on infections caused by pneumococcal isolates that have not responded to cephalosporin therapy and for which the MICs of cefotaxime and ceftriaxone are 2 to 32 g/ml. These MICs are in excess of the MICs of penicillin for these isolat...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of multiple clones of extended-spectrum cephalosporin-resistant Streptococcus pneumoniae isolates in the United States

McDougal

Rasheed

Biddle

et al. 1995

Antimicrob Agents Chemother

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“…Much work has been done on laboratory mutants with defined point mutations in PBPs, but these relationships are more difficult to determine in clinical isolates. Laboratory transformation experiments have shown that lowaffinity forms of PBP2b and -2x confer low-level penicillin resistance and are prerequisites for high-level resistance (12,14,17,22). High-level penicillin resistance requires the presence of a low-affinity form of PBP1a as well as either lowaffinity PBP2x or low-affinity PBP2x and -2b (17,33).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, decreased affinity of PBP1a, -2x, and -2b for ␤-lactams has been reported to play an important part in resistance (4-6, 18, 23, 32). Alterations in the conserved motifs in PBP2b are associated with resistance to penicillin (14), and alterations in PBP2x mediate low-level resistance to cephalosporins (4,8,12,14). Additional alterations in PBP1a raise penicillin G MICs to Ն1 g/ml and cefotaxime MICs to Ն0.5 g/ml (4,26,33,37).…”

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Effects of Amino Acid Alterations in Penicillin-Binding Proteins (PBPs) 1a, 2b, and 2x on PBP Affinities of Penicillin, Ampicillin, Amoxicillin, Cefditoren, Cefuroxime, Cefprozil, and Cefaclor in 18 Clinical Isolates of Penicillin-Susceptible, -Intermediate, and -Resistant Pneumococci

Nagai

Davies

Jacobs

et al. 2002

Antimicrob Agents Chemother

133

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Amino acid alterations in or flanking conserved motifs making up the active binding sites of penicillinbinding proteins (PBPs) 1a, 2b, and 2x of pneumococci were correlated with changes in affinities of penicillin, ampicillin, amoxicillin, cefditoren, cefuroxime, cefprozil, and cefaclor for these PBPs. Four penicillin-susceptible (PSSP), eight penicillin-intermediate (PISP), and six penicillin-resistant (PRSP) pneumococci were studied by DNA sequencing of the penicillin-binding sites of the pbp1a, -2x, and -2b genes of strains and by determining 50% inhibitory concentrations of the seven agents for PBP1a, -2x, and -2b. Two PSSP strains had alterations in PBP2x (L 546 3V) (one strain) or PBP2b (T 445 3A) (one strain). All eight PISP strains had at least two alterations--T 338 3P or A or H 394 3Y in PBP2X and T 445 3A in BPB2b. All PRSP strains had the same changes seen in PISP strains, as well as T 371 3A or S substitutions in PBP1a. The two most resistant PRSP strains had a second change in PBP2x (M 339 3F) in a conserved motif. The affinities of penicillin and ampicillin for all three PBPs were decreased for PRSP and most PISP strains. The affinity of amoxicillin for PBP1a and -2x was decreased only for PRSP. Cefaclor and cefprozil showed decreased affinity of PRSP but not PISP for all three PBPs. Cefuroxime showed decreased affinity of PISP and PRSP for PBP1a and -2x but no change for PBP2b. Cefditoren showed no difference in PBP affinity based on penicillin or cefditoren MICs, indicating a different PBP target for this agent. Overall, the MICs for and PBP affinities of the strains correlated with the changes found in the PBP active binding sites.The worldwide incidence of infections caused by Streptococcus pneumoniae isolates resistant to penicillin and other antimicrobial agents has increased at an alarming rate during the past 2 decades (2). In a recent U.S. study, penicillin-nonsusceptible pneumococci were found in 50.4% of 1,476 strains, and the prevalence of macrolide-resistant strains was 65.6% in penicillin-resistant strains (20). The higher the penicillin MIC, the more likely it is that the strain will be multidrug resistant. Multidrug-resistant (including resistance to fluoroquinolones) pneumococci have been reported in Hong Kong (19), Canada (7), and Spain (24), and the clonal spread of these strains from country to country and continent to continent is of concern. There is an urgent need for oral ␤-lactams that can be used for outpatient treatment of infections, such as pneumonia, bronchitis, sinusitis, and otitis media, caused by penicillin-and macrolide-nonsusceptible pneumococci. Amoxicillin has excellent in vitro antipneumococcal activity (1, 3, 18) and has been shown to select for resistant laboratory mutants less frequently than other compounds (27,29). Previous studies have documented the potent in vitro antipneumococcal activity of cefditoren, with MICs at which 50 and 90% of isolates are inhibited of 0.5 and 1.0 g/ml, respectively, against penicillin-resistant strains (35,36). Cefditoren a...

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Drug-Resistant Pneumococcal Infections in the United States

Simberkoff¹

1994

JAMA

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Drug-resistant Streptococcus pneumoniae (DRSP) strains were once considered to be laboratory curiosities1,2 or problems for far-off areas of the world.3-5 In the United States, however, pneumococci that were relatively resistant to penicillin (minimum inhibitory concentration, 0.12 to 1.0 \g=m\g/mL) were found among the isolates from Navajo Indians living in New Mexico in 1974,6 and a serotype 14 S pneumoniae isolate with high-level resistance to penicillin (minimum inhibitory concentration, \m=ge\2.0 \g=m\g/mL) was recovered from the blood of an immunocompromised child from Minnesota in 1977.7 Since these initial reports, foci of DRSP have been identified in various parts of this country.8-12 The reports from the Centers for Disease Control and Prevention from Kentucky and Tennessee,13 from Connecticut,14 and by Breiman et al15 in this issue of The JOURNAL are alarming because they prove that DRSP isolates can now be found in unselected, diverse sites in the United States. The findings present major problems for microbiology laboratories, public health, and clinicians.See also 1831.

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Genetics of oxacillin resistance in clinical isolates of Streptococcus pneumoniae that are oxacillin resistant and penicillin susceptible

Cited by 48 publications

References 23 publications

Identification of multiple clones of extended-spectrum cephalosporin-resistant Streptococcus pneumoniae isolates in the United States

Identification of multiple clones of extended-spectrum cephalosporin-resistant Streptococcus pneumoniae isolates in the United States

Effects of Amino Acid Alterations in Penicillin-Binding Proteins (PBPs) 1a, 2b, and 2x on PBP Affinities of Penicillin, Ampicillin, Amoxicillin, Cefditoren, Cefuroxime, Cefprozil, and Cefaclor in 18 Clinical Isolates of Penicillin-Susceptible, -Intermediate, and -Resistant Pneumococci

Drug-Resistant Pneumococcal Infections in the United States

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