Occurrence and expression of imipemide (N-formimidoyl thienamycin) resistance in clinical isolates of coagulase-negative staphylococci

Blumenthal, Robert; Raeder, Roberta; Takemoto, Carol; Freimer, Earl H.

doi:10.1128/aac.24.1.61

Cited by 29 publications

(8 citation statements)

References 43 publications

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“…The data obtained in this study ap peared to confirm and to expand the origi nal observation of Blumenthal et al [4], These investigators noted that certain iso lates of S. epidermidis and of S. simulans produced double zones of inhibition (Imidz) around imipenem disks. Their iso lates were multiple drug-resistant as well [1,7,8].…”

Section: Discussionsupporting

confidence: 72%

“…These isolates yielded double zones of inhibition (cocarde growths) around imipenem disks, a phenomenon noted already by Blumenthal et al [4], We were interested to determine whether this unusual phenomenon was a property of Staphylococcus epidermidis [4], Staphylo coccus simulans [4], or possibly of another staphylococcal species, because several of our isolates were resistant against novo biocin.…”

Section: Introductionmentioning

confidence: 99%

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<i>Staphylococcus haemolyticus</i>: Cocarde Growth around Imipenem Disks

Traub

Kohl²,

Spohr³

1988

Chemotherapy

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

<i>Staphylococcus haemolyticus</i>: Cocarde Growth around Imipenem Disks

Traub

Kohl²,

Spohr³

1988

Chemotherapy

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“…Even if the above results are accepted as evidence, the double-zone phenomenon with P-lactams observed in some strains of MRS recently isolated from clinical materials (4,24) cannot be explained by the alteration of PBPs. This double-zone phenomenon and the growth curve of cells when low concentrations of P-lactams were added to the culture medium of MRS suggest that contact of the organism with P-lactams might induce a more active mechanism of resistance.…”

Section: Discussionmentioning

confidence: 93%

Occurrence of a beta-lactam-inducible penicillin-binding protein in methicillin-resistant staphylococci

Ubukata¹,

Yamashita²,

Konno³

1985

Antimicrob Agents Chemother

218

166

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The mechanism of methicillin resistance was investigated in methicillin-resistant staphylococci (MRS) and in variants which had lost methicillin resistance. Phase-contrast microscopy showed that cells swelled at low concentrations of 13-lactam antibiotics in both MRS and variants which had lost methicillin resistance. Cells of variants which had lost methicillin resistance were lysed easily when higher concentrations of antibiotic were used. In contrast, MRS cells remained swollen at even higher concentrations of antibiotics. Furthermore, bacterial growth was inhibited at antibiotic concentrations much lower than MICs for MRS. Examination of the penicillin-binding proteins (PBPs) in MRS revealed that a new PBP-2' (molecular weight, 74,000) was induced in large quantity by exposure to P-lactams. PBP-2' was produced constitutively in variants of MRS which had lost a penicillinase plasmid. The induction of PBP-2' by (-lactams was not detected in variants which had lost methicillin resistance. High concentrations of ,l-lactam were required for saturation of PBP-2'. The optimum antibiotic concentration for the induction of PBP-2' varied with the 3-lactam used as the inducer, and PBP-2' was produced in a larger amount at 32°C than at 370C. From these results, we suggest that the mechanism of methicillin resistance depends on the induction of PBP-2', which may function as a detour enzyme for PBP-2 or PBP-3 or may be a particular enzyme involved in peptidoglycan synthesis.Methicillin-resistant strains of Staphylococcus aureus were first reported in 1961 (19), soon after the introduction of methicillin into clinical use. Subsequently, it has been shown that these strains also are resistant to many penicillins and cephems other than methicillin (2,11,15). In addition, methicillin resistance (MR) has been found to be temperature dependent (1, 7, 12) and affected by pH (27), NaCl concentration (3,12), and inoculum size (12, 23). Although methicillip-resistant staphylococci (MRS) produce penicillinase (PCase), curing of the PCase plasmid does not reduce the level of MR (28).Four main penicillin binding proteins (PBPs) have been identified in S. aureus (20), and either one or both PBP-2 and PBP-3 have been suggested to be the lethal target(s) for P-lactam action (13). In MRS, production of altered PBPs with extremely low affinity for ,3-lactams (14,16,17) or an increase of an altered PBP-3 (6) has been described. However, the double-zone phenomenon occasionally detected on a disk diffusion susceptibility test of P-lactams, such as methicillin, nafcillin (24), or imipenem (4), for MRS cannot be explained by the decreased affinities of PBPs for ,-lactams. This phenomenon suggests the existence of another mechanism for MR.Although MRS had not been a major clinical problem in Japan, after the introduction of third-generation cephems in 1982 isolates of MRS increased. We isolated two variant types from our clinical isolates of MRS. One type retained MR, whereas PCase activity became negative, and the other type lost MR along with ...

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“…The selection in vivo of a population of methicillinresistant S. epidermidis that is more highly resistant to methicillin or cephalothin than the challenge isolate following therapy with either of these antibiotics has also been described by Lowy et al (11). Furthermore, Forbes et al (5) and Blumenthal et al (2) were able to induce resistance to imipenem among methicillin-resistant Staphylococcus aureus and S. epidermidis isolates, respectively, in vitro by first exposing growing cultures to low concentrations of the antibiotic. While the susceptibility of imipenem-resistant S. epidermidis to methicillin was not examined in the study by Blumenthal et al (2), the heterotypic nature of imipenem resistance and appearance of colonies in the zones around disks is typical of resistance seen among S. epidermidis isolates to methicillin and other beta-lactam antibiotics.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, Forbes et al (5) and Blumenthal et al (2) were able to induce resistance to imipenem among methicillin-resistant Staphylococcus aureus and S. epidermidis isolates, respectively, in vitro by first exposing growing cultures to low concentrations of the antibiotic. While the susceptibility of imipenem-resistant S. epidermidis to methicillin was not examined in the study by Blumenthal et al (2), the heterotypic nature of imipenem resistance and appearance of colonies in the zones around disks is typical of resistance seen among S. epidermidis isolates to methicillin and other beta-lactam antibiotics. The appearance of more highly imipenem-resistant subpopulations of methicillin-resistant S. epidermidis in our study after 6 but not 3 days of imipenem therapy may be the correlation in vivo of the induction or selection of imipenem resistance noted in vitro.…”

Section: Resultsmentioning

confidence: 99%

Imipenem therapy of experimental Staphylococcus epidermidis endocarditis

Berry¹,

Johnston²,

Archer³

1986

Antimicrob Agents Chemother

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Imipenem was evaluated for its activity against Staphylococcus epidermidis in vitro and in a rabbit model of endocarditis. The MBC for imipenem of 55 methicillin-resistant S. epidermidis isolates from patients with prosthetic valve endocarditis increased by eightfold or greater with increasing inoculum size; there was no inoculum-associated increase in the imipenem MBC for 20 methicillin-susceptible S. epidermidis isolates. Endocarditis was produced in rabbits with either a methicillin-susceptible or a methicillin-resistant S. epidermidis isolate to investigate the correlation in vivo of the in vitro inoculum effect for imipenem. Six days of imipenem treatment eradicated methicillin-susceptible S. epidermidis from vegetations of infected rabbits significantly better than no therapy but was less effective against methicillin-resistant S. epidermidis in this regard. Among methicillin-resistant S. epidermidis-infected rabbits, 6 days of imipenem therapy (i) was not significantly better than that of the control and was significantly worse than that of vancomycin in eradicating bacteria from infected vegetations and (ii) increased the frequency of imipenem-resistant subpopulations in infected vegetations. Resistant subpopulations were not seen in vegetations from untreated or imipenemtreated, methicillin-susceptible S. epidermidis-infected rabbits. Imipenem may not be effective therapy for serious human methicillin-resistant S. epidermidis infections.Prosthetic valve endocarditis (PVE) is a serious illness with mortality rates as high as 60%. Staphylococcus epidermidis is the cause of more episodes of PVE than any other organism, accounting for approximately 40% of cases (3). As many as 80o of S. epidermidis isolates causing prosthetic valve endocarditis are resistant to the semisynthetic penicillinase-resistant penicillins (methicillin-resistant S. epidermidis) and other beta-lactam antibiotics (7). Because of this high incidence of antibiotic resistance, new antibiotics are continuously being sought to which resistant S. epidermidis will be susceptible. Imipenem, a new beta-lactam antibiotic, was shown to be active against methicillin-resistant S. epidermidis when tested in vitro against a low bacterial inoculum (9). However, other beta-lactam antibiotics which appear to be active against methicillin-resistant S. epidermidis when they are tested against a low bacterial inoculum are markedly less active when a higher inoculum is used (7). These antibiotics also show poor efficacy when they are evaluated in vivo (7,11,16). Therefore, to evaluate the activity of imipenem against methicillin-resistant S. epidermidis, we looked at the antibiotic in two ways. First, we tested the antibiotic in vitro against 55 methicillin-resistant S. epidermidis isolates recovered from patients with PVE, using both high and low bacterial inocula. Second, we examined the ability of imipenem to sterilize vegetations from rabbits with experimental endocarditis caused by clinical isolates of either a methicillin-resistant or a methicillinsu...

show abstract

Occurrence and expression of imipemide (N-formimidoyl thienamycin) resistance in clinical isolates of coagulase-negative staphylococci

Cited by 29 publications

References 43 publications

<i>Staphylococcus haemolyticus</i>: Cocarde Growth around Imipenem Disks

<i>Staphylococcus haemolyticus</i>: Cocarde Growth around Imipenem Disks

Occurrence of a beta-lactam-inducible penicillin-binding protein in methicillin-resistant staphylococci

Imipenem therapy of experimental Staphylococcus epidermidis endocarditis

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