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Glycopeptide Resistance in Gram-positive Bacteria

1995; Elsevier BV; Volume: 1; Issue: 1 Linguagem: Inglês

10.1111/j.1469-0691.1995.tb00026.x

1469-0691

D. C. E. Speller, William Lynn, Thomas R. Rogers,

Bacterial Identification and Susceptibility Testing

Readers are invited to use this article as a self-assessment exercise and to update their knowledge. A 20-year-old female presented in 1992 with nephritis due to systemic lupus erythematosus. Despite plasma-pheresis and immunosuppression she became dialysis-dependent. Previous complications included failed renal transplantation, recurrent bacterial and viral infections and cyclophosphamide-related common variable immunodeficiency. In late 1994 she was admitted for placement of a femoral venous shunt for haemodialysis access. She was admitted to a renal unit, which had an ongoing outbreak of colonization and infection with glyco-peptide-resistant Enterococcus faecium. She had previously been admitted to this ward on numerous occasions, and multiple courses of antibiotics, including cephalo-sporins, ciprofloxacin, gentamicin and vancomycin, had been given. At the time of admission she was afebrile and generally well and screening swabs showed no colonization with E. faecium. A right femoral vein gortex graft was inserted; the operation was complicated by a small hematoma. Antibiotic prophylaxis was given, with intravenous cefuroxime and metronidazole for 48 hours. On post-operative day 5 she became febrile, but the surgical wound was clean and there was no obvious infective source. The peripheral leukocyte count was 6.4 × 109/l and the C-reactive protein 159 mg/l (normal: 3 months in hospital patientstrue/falsec. in the feces of hospital stafftrue/falsed. in operating theatre airtrue/falsee. to persist for >3 days in the hospital environment.true/false Open table in a new tab 5.Tabled 1a. Vancomycin-resistant enterococci — endocarditis on natural heart valvestrue/falseb. Vancomycin-resistant enterococci — persistent bacteria without endocarditis or extravascular focustrue/falsec. Vancomycin-resistant Leuconostoc species — bacteremia associated with colonization of intravascular cannulatrue/falsed. Vancomycin-resistant lactobacillus endocarditis — relapse after treatment with penicillin alonetrue/falsee. Teicoplanin-resistant staphylococci — results of treatment poorly correlated with in vitro susceptibility test results.true/false Open table in a new tab 6.Tabled 1a. High-level (MIC >2000 mg/l) resistance to gentamicin and streptomycin implies absence of synergism with all available aminoglycosidestrue/falseb. Ampicillin alone in high doses may succeed in endocarditistrue/falsec. Ampicillin resistance may occur by β-lactamase productiontrue/falsed. Addition of sulbactam restores sensitivity to all ampicillin-resistant strainstrue/falsee. Ampicillin and vancomycin may show synergism against ampicillin- and vancomycin-resistant strains.true/false Open table in a new tab 7.Tabled 1a. glycopeptidestrue/false.b. cephalosporinstrue/falsec. aminoglycosidestrue/falsed. pristinamycinstrue/falsee. quinolones.true/false Open table in a new tab Resistance to vancomycin, in the gram-positive species susceptible to it, first appeared among enterococci in the 1980s, when a nosocomial outbreak of infection by vancomycin-resistant enterococci was reported (5Uttley AHC George RC Naidoo J et al.High-level vancomycin-resistant enterococci causing hospital infection.Epid Infect. 1989; 103: 173-181Crossref PubMed Scopus (266) Google Scholar). Since that time sporadic cases and clusters have been reported from Europe and the US. High- and low-level resistance has been encountered in Enterococcus faecium and Enterococcus faecalis, while low-level constitutive resistance is a characteristic of Enterococcus gallinarum and other species that are less frequently encountered in human infection (6Leclercq R Dutka-Malen S Duval J Courvalin P Vancomycin resistance gene vanC is specific to Enterococcus gallinarum.Antimicrob Agents Chemother. 1992; 36: 2005-2008Crossref PubMed Google Scholar). Answers to multiple choice questions Q1a. true; b. true; c. true; d. false; e. falseQ2a. false; b. true; c. false; d. true; e. trueQ3a. true; b. false; c. true; d. true; e. falseQ4a. true; b. true; c. true; d. false; e. trueQ5a. true; b. true; c. true; d. true; e. trueQ6a. true; b. true; c. true; d. false; e. trueQ7a. true; b. false; c. false; d. true; e. true Answers to multiple choice questions Q1a. true; b. true; c. true; d. false; e. falseQ2a. false; b. true; c. false; d. true; e. trueQ3a. true; b. false; c. true; d. true; e. falseQ4a. true; b. true; c. true; d. false; e. trueQ5a. true; b. true; c. true; d. true; e. trueQ6a. true; b. true; c. true; d. false; e. trueQ7a. true; b. false; c. false; d. true; e. true Resistance to glycopeptides is common in lactic acid bacteria, such as Pediococcus, Leuconostoc and Lactobacillus species (7Swenson JM Facklam RR Thornsberry C Antimicrobial susceptibility of vancomycin-resistant Leuconostoc, Pediococcus and Lactobacillus species.Antimicrob Agents Chemother. 1990; 34: 543-549Crossref PubMed Scopus (151) Google Scholar). These have been noted more frequently as opportunistic pathogens, particularly following glycopeptide administration. In the case of other gram-positive bacteria that are often resistant to glycopeptides, such as Nocardia spp. and Erysipelothrix rhusiopathiae, administration of glycopeptides does not usually arise, either as a predisposing factor or as a therapeutic option. A fear is that the genetic material mediating resistance to the glycopeptides may be transferred to species which are sensitive at present, such as Streptococcus pneumoniae. It is particularly worrying that vancomycin resistance can be transferred (in the laboratory) from an enterococcus to Staphylococcus aureus (8Noble WC Virani Z Cree RGA Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus.FEMS Microbiol Lett. 1992; 93: 195-198Crossref Google Scholar), but thus far no confirmed report of resistance in clinical S. aureus isolates has been published. Low-level resistance to teicoplanin, however, has been reported (9Vedel G Leruez M Lemann F Hraoui E Ratovahery D Prevalence of Staphylococcus aureus and coagulase-negative staphylococci with decreased sensitivity to glycopeptides as assessed by determination of MICs.Eur J Clin Microbiol Infect Dis. 1990; 9: 820-822Crossref PubMed Scopus (23) Google Scholar, 1Woodford N Johnson AP Morrison D Speller DCE. Current perspectives of glycopeptide resistance..Clin Microbiol Rev. 1995 in press; PubMed Google Scholar). In coagulase-negative staphylococci teicoplanin resistance dominates (10Goldstein FW Coutrot A Sieffer A Acar JF Percentages and distributions of teicoplanin? and vancomycin-resistant strains among coagulase-negative staphylococci.Antimicrob Agents Chemother. 1990; 34: 899-900Crossref PubMed Scopus (87) Google Scholar), although vancomycin resistance has been encountered (11Veach LA Pfaller MA Barrett M Koontz FP Wenzel RP Vancomycin resistance in Staphylococcus haemolyticus causing colonization and bloodstream infection.J Clin Microbiol. 1990; 28: 2064-2068PubMed Google Scholar). The earlier reports of high-level teicoplanin resistance concerned Staphylococcus haemolyticus, but this phenomenon is also seen in Staphylococcus epidermidis, Staphylococcus warneri, Staphylococcus hominis and Staphylococcus xylosus. Exercises comparing the performance of laboratories in the detection of glycopeptide resistance, in Europe and in the USA, have shown success in the detection of high-level vancomycin resistance in enterococci, but poor results with strains showing resistance at a lower level (12Snell JJS Brown DFJ Perry SF George R Antimicrobial susceptibility testing of enterococci: results of a survey conducted by the United Kingdom National External Quality Assessment Scheme for Microbiology.J Antimicrob Chemother. 1993; 32: 401-411Crossref PubMed Scopus (21) Google Scholar, 13Tenover FC Tokars J Swenson J Paul S Spitalny K Jarvis W Ability of clinical laboratories to detect antimicrobial agent-resistant enterococci.J Clin Microbiol. 1993; 31: 1695-1699PubMed Google Scholar. Several factors contribute to inconsistent laboratory reporting. There are discrepancies between the interpretive breakpoints recommended in different countries (14National Committee for Clinical Laboratory StandardsMethods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically — third edition.Approved Standard M7-A3. National Committee for Clinical Laboratory Standards, Villanova, Pa1993Google Scholar, 15Working Party of the British Society for Antimicrobial Chemotherapy.A guide to sensitivity testing.J Antimicrob Chemother. 1991; 27: 1-50Google Scholar. The diffusion characteristics of the large molecules make the zones of inhibition in disc tests very small and less easy to interpret. In addition, very different MIC values of teicoplanin may be obtained with various media, with and without the addition of blood, and with changes in inoculum (16Felmingham D Solomonides K O'Hare MD Wilson APR Grüneberg RN The effect of medium and inoculum on the activity of vancomycin and teicoplanin against coagulase-negative staphylococci.J Antimicrob Chemother. 1987; 20: 609-610Crossref PubMed Scopus (36) Google Scholar). There is no evidence of destruction of glycopeptides by resistant strains of E. faecium and E. faecalis (17Johnson AP Uttley AHC Woodford N George RC Resistance to vancomycin and teicoplanin: an emerging clinical problem.Clin Microbiol Rev. 1990; 3: 280-291PubMed Google Scholar). Such strains have been shown to synthesize novel membrane proteins, which in some cases have been shown to possess D-ala-D-ala ligase activity and to produce different peptide side-chains on the cell wall components. These will not bind glycopeptides and, even in their presence, can link up to give the strengthening cross-linking structure to the bacterial cell wall (18Woodford N Johnson A Glycopeptide resistance in gram-positive bacteria; from black and white to shades of grey.J Med Microbiol. 1994; 40: 375-378Crossref PubMed Scopus (15) Google Scholar). The resistant enterococci first described showed inducible high-level resistance to vancomycin and also resistance to teicoplanin: the “VanA phenotype”. Other strains were encountered, however, showing lower levels of inducible vancomycin resistance and sensitivity to teicoplanin: the “VanB phenotype” (“VanC” describes the low-level constitutive resistance to vancomycin with sensitivity to teicoplanin seen in E. gallinarum and some other species). The corresponding genes have been identified. More recently strains possessing the vanB gene, rather than the vanA gene, have been described with high-level vancomycin resistance and resistance to teicoplanin (19Hayden MK Trenholme GM Schultz JE Sahm DF In vivo development of teicoplanin resistance in a VanB Enterococcus faecium isolate.J Infect Dis. 1993; 167: 1224-1227Crossref PubMed Scopus (134) Google Scholar). VanA glycopeptide resistance was early demonstrated to be plasmid-borne and transferable. Mobility of this genetic material is enhanced by its occurrence as a transposon. The resistance transposon Tn1546 carries a complex of genes encoding glycopeptide resistance (including vanA) and its regulation (20Arthur M Molinas C Depardieu F Courvalin P Characterization of Tn1546, a Tn3-related transposon conferring glycopeptide resistance by synthesis of depsipeptide peptido-glycan precursors in Enterococcus faecium BM4147.J Bacteriol. 1993; 175: 117-127Crossref PubMed Scopus (459) Google Scholar). Glycopeptide-resistant enterococci were first encountered in hospitals, and it is believed that antibiotic pressure, first of cephalosporins (to which enterococci are intrinsically resistant) and subsequently of glycopeptides, is important in their emergence. Nevertheless, glycopeptide-resistant enterococci have been discovered in the gastro-intestinal tracts of patients in the community (21Jordens JZ Bates J Griffiths DT Faecal carriage and nosocomial spread of vancomycin-resistant Enterococcus faecium.J Antimicrob Chemother. 1994; 34: 515-528Crossref PubMed Scopus (180) Google Scholar), in farm animals and in poultry for sale (22Bates J Jordens JZ Griffiths DT Farm animals as a putative reservoir for vancomycin-resistant enterococcal infection in man.J Antimicrob Chemother. 1994; 34: 507-514Crossref PubMed Scopus (367) Google Scholar). The carriage rate of patients in intensive care, renal and hematology units may be high, and the glycopeptide-resistant enterococci may persist for long periods (23Boyce JM Opal SM Chow JW et al.Outbreak of multidrug-resistant Enterococcus faecium with transferable vanB class vancomycin resistance.J Clin Microbiol. 1994; 32: 1148-1153PubMed Google Scholar). The factors affecting patient-to-patient spread during outbreaks are still obscure. Staff may become colonized (24Handwerger S Raucher B Altarac D et al.Nosocomial outbreak due to Enterococcus faecium highly resistant to vancomycin, penicillin and gentamicin.Clin Infect Dis. 1993; 16: 750-755Crossref PubMed Scopus (368) Google Scholar) but this is not a consistent finding. Likewise, contamination of the immediate environment of patients and transient contamination of staff hands have appeared to be significant factors in some outbreaks (25Karanfil LV Murphy M Josephson A et al.A cluster of vancomycin-resistant Enterococcus faecium in an intensive care unit.Infect Control Hosp Epidemiol. 1992; 13: 195-200Crossref PubMed Scopus (232) Google Scholar, 26Rhinehart E Smith N Wennersten C et al.Rapid dissemination of beta-lactamase-producing aminoglycoside-resistant Enterococcus faecium.N Engl J Med. 1990; 323: 1814-1818Crossref PubMed Scopus (155) Google Scholar) but not in others. Most of the species of glycopeptide-resistant gram-positive bacteria under discussion characteristically act as opportunistic pathogens in impaired hospital patients. Even when they are isolated from deep specimens their clinical significance may be difficult to assess. Bacteremia may persist without a defined focus and with seemingly little deleterious effect on the patient (27Gray J March PJ Stewart D Pedler SJ Enterococcal bacteraemia: a prospective study of 125 episodes.J Hosp Infect. 1994; 27: 179-186Abstract Full Text PDF PubMed Scopus (54) Google Scholar). Removal of an intravascular cannula may be sufficient to cure the bacteraemia (28Handwerger S Horowitz H Coburn K Kolokathis A Wormser GP Infection due to Leuconostoc species: six cases and review.Rev Infect Dis. 1990; 12: 602-610Crossref PubMed Scopus (87) Google Scholar). Assessment of clinical results assisted the National Committee for Clinical Laboratory Standards in establishing break-points for teicoplanin (14National Committee for Clinical Laboratory StandardsMethods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically — third edition.Approved Standard M7-A3. National Committee for Clinical Laboratory Standards, Villanova, Pa1993Google Scholar), but many investigators have commented on the poor correlation between in vitro results and clinical outcome (29O'Connell B Browne PV Cafferkey MT McCann SR Coagulase-negative staphylococcal bacteraemia treated with teicoplanin.J Antimicrob Chemother. 1993; 31: 438-439Crossref PubMed Scopus (10) Google Scholar). Endocarditis provides a clear test of the power of an antibiotic regimen. In the case of endocarditis caused by the lactic acid bacteria, definitive advice on treatment cannot be given, but it is clear that a bactericidal synergistic combination should be used (30Griffiths JK Daly JS Dodge RA Two cases of endocarditis due to Lactobacillus species: antimicrobial susceptibility, review and discussion of therapy.Clin Infect Dis. 1992; 15: 250-255Crossref PubMed Scopus (96) Google Scholar). Unfortunately, glycopeptide-resistant strains of E. faecium are often resistant to β-lactams and, at high-level, to aminoglycosides. Gentamicin is the amino-glycoside usually tested. If there is high-level resistance to this agent, it is worthwhile to test streptomycin. High-level resistance to both implies that no clinically available aminoglycoside will give satisfactory synergy (31Eliopoulos GM Aminoglycoside resistant enterococcal endocarditis.Infect Dis Clin N Amer. 1993; 7: 117-133PubMed Google Scholar). In these circumstances, apparent sensitivity to amikacin does not denote sufficient activity to give synergy. If an aminoglycoside-resistant strain is ampicillin-sensitive this agent alone in high doses is the current recommendation in endocarditis (31Eliopoulos GM Aminoglycoside resistant enterococcal endocarditis.Infect Dis Clin N Amer. 1993; 7: 117-133PubMed Google Scholar). Sometimes it is possible to demonstrate, in strains resistant to both β-lactams and glycopeptides, a synergistic activity of a combination of these agents, but this is not a consistent finding (32Gutmann L Al-Obeid S Billot-Klein D Guerrier M-L Collatz E Synergy and resistance to synergy between β-lactam antibiotics and glycopeptides against glycopeptide-resistant strains of Enterococcus faecium.Antimicrob∗∗∗ Agents Chemother. 1994; 38: 824-829Crossref PubMed Scopus (30) Google Scholar). Resistance caused by β-lactamase production has been described, especially in the USA, and the β-lactamase is susceptible to clavulanate and to sul-bactam (33La∗∗∗voie SR Wong ES Coudron PE Williams DS Markowitz SM Comparison of ampicillin-s∗∗∗ulbactam with vancomycin for treatment of experimental endocarditis due to a β-lactamase-producing, highly gentamicin-resistant isolate of Enterococcus faecalis.Antimicrob Agents Chemother. 1993; 37: 1447-1451Crossref PubMed Scopus (16) Google Scholar), but most β-lactam-resistant strains are resistant by a different mechanism: modification of penicillin-binding proteins. Because of these increasing therapeutic problems, there is a need to search for new active compounds. Investigation of β-lactams and aminoglycosides has not been fruitful. The clinical activity of newer peptides, such as daptomycin, has been disappointing thus far, although further compounds with much greater activity are under development and appear promising (34Felmingham D Towards the ideal glycopeptide.J Antimicrob Chemother. 1993; 32: 663-666Crossref PubMed Scopus (19) Google Scholar, 35Nicas TI Activity of novel semi-synthetic glycopeptides against vancomycin-resistant enterococci.Program Abstr 7th Eur Cong Clin Microbiol Infect Dis. 1995; 560 (abstr)Google Scholar. New fluoroquinolones, with increased activity against gram-positive bacteria, are being developed (36Piddock LJV New quinolones and gram-positive bacteria.Antimicrob Agents Chemother. 1994; 38: 163-169Crossref PubMed Scopus (112) Google Scholar) and offer some promise although they require clinical trial in these infections. The injectable pristinamycin combination, quinupristin/dalfopristin has been used with success against some infections by multi-resistant enterococci (37Lynn WA Clutterbuck E Want S et al.Treatment of CAPD-peritonitis due to glycopeptide-resistant Enterococcus faecium with quinupristin/dalfopristin.Lancet. 1994; 344: 1025-1026Abstract PubMed Scopus (57) Google Scholar). This is more active against E. faecium than against E. faecalis and appears to have almost no bactericidal activity against enterococci. Bacteriostatic activity is also shown by the glycylcylines (tetracycline derivatives) (38Eliopoulos GM Wennersten CB Cole G Moellering RC In vitro activity of two glycylcyclines against gram-positive bacteria.Antimicrob Agents Chemother. 1994; 38: 534-541Crossref PubMed Scopus (44) Google Scholar). Despite the comparatively non-pathogenic character of many of the species that show glycopeptide resistance, the need to treat infections caused by them is becoming more frequent. The ready transmissibility of the underlying genetic material poses a serious threat to our future use of antibiotics. We thank Dr Elaine Clutterbuck for permission to report the case, and we are most grateful to our colleagues, Dr P. Johnson, Dr N. Woodford and Mr D. Morrison, for their assistance in the production of this article. We thank Rhône-Poulenc Rorer, Paris for providing Quinopristin/Dalfopristin for compassionate use. This article is intended to inaugurate a series of exercises for Continuing Education in the disciplines of Clinical Microbiology and Infectious Diseases. The Editors will be interested to receive comments on the relevance and usefulness of this article and on its format, and also suggestions for future topics.