Resistance to teicoplanin developing during treatment of methicillin-resistant Staphylococcus aureus infection

Ashraf A. F. Elsaghiera, Hazel M. Auckenb, Jeremy M. Hamilton-Millera, Stephen Shawa and Christopher C. Kibblera,*

a Royal Free and University College Medical School, University College London, Royal Free Campus, Department of Medical Microbiology, London NW3 2PF; b PHLS Central Public Health Laboratory, Laboratory of Hospital Infection, London NW9 5HT, UK

Sir,

The emergence of vancomycin resistance in Staphylococcus aureus1 has caused considerable concern in Japan and the USA, but there have been few reports from the UK. We have detected reduced susceptibility to teicoplanin and vancomycin during the treatment of two methicillin-resistant Staphylococcus aureus (MRSA) infections with teicoplanin. Both patients died. We present these two cases in order to draw attention to this emerging problem and to emphasize the clinical significance of this form of resistance.

The first patient, a 66-year-old man, was admitted for cystectomy and formation of ileal conduit and became pyrexial 3 weeks post-operatively [38.5°C, white blood cell count (WBC) 18 x 109/L]. Line-related bacteraemia was confirmed when MRSA was isolated from blood cultures taken through the central line and peripherally, and from the central line tip after removal. Intravenous teicoplanin (400 mg daily after loading doses) was started. After 7 days treatment there was another episode of pyrexia and MRSA was again isolated from blood culture. Chest X-ray and CT scan of the chest and abdomen were normal. Teicoplanin was continued and fusidic acid (500 mg 8 hourly) was added. The patient's condition deteriorated and he was transferred to the Intensive Therapy Unit (ITU). Fusidic acid-resistant MRSA was isolated from a blood culture 12 days after the first MRSA isolate. Fusidic acid was stopped, the teicoplanin dose was increased to 600 mg daily and blood levels were monitored to ensure that trough levels of at least 20 mg/L were attained. A transoesophageal echocardiogram was normal but multiple splenic lesions were seen on CT scan. Laparotomy was carried out and the spleen was removed because of multiple splenic abscesses, from which MRSA was isolated. The patient failed to recover from sepsis and died shortly afterwards.

The second patient, a 17-year-old man, was admitted following a road traffic accident, to the ITU bed next to the first patient. Two weeks later he became pyrexial (38.5°C). Line-related bacteraemia was confirmed by isolation of MRSA from blood cultures taken through the central line and peripherally, and from culture of the catheter tip. Intravenous teicoplanin (400 mg daily after loading doses) was started. After 11 days of this regimen there was another episode of MRSA bacteraemia. Despite the addition of fusidic acid (500 mg 8 hourly) and central line replacement, MRSA continued to be isolated from the blood cultures during the following week. The patient was clinically septic (temperature 38°C, WBC 26 x 109/L). Transthoracic echocardiogram showed tricuspid valve vegetations, confirming a diagnosis of infective endocarditis. The patient died 4 days later, despite treatment with vancomycin and gentamicin.

Raised glycopeptide MICs were detected in the breakthrough isolates by the Royal Free Microbiology Department. Identification was confirmed, the strains were typed and their antibiotic susceptibilities re-determined at the Central Public Health Laboratory, Colindale. All were found to be a variant of EMRSA-16, differing from classical EMRSA-16 by a single band on pulsed-field gel electrophoresis. All isolates were identical by PCR analysis for the toxin genes sea, seg, sej and tst. These findings support the likelihood of cross-infection and the development of resistance in a single strain.

Isolates from the first patient showed a steady decrease in susceptibility to teicoplanin and vancomycin (TableGo). Susceptibility to fusidic acid fell while this antibiotic was being administered but increased after the drug was discontinued. There were gradual decreases in the MICs of methicillin and benzylpenicillin.


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Table. MICs for MRSA isolates and antibiotic therapy for case 1 and case 2
 
Although the second patient was admitted to the ITU at a time when the isolates from the first patient were already teicoplanin resistant, the first MRSA isolated from the former was susceptible to teicoplanin. However, within 14 days it also had become resistant (TableGo).

There have been previous reports of MRSA with reduced susceptibility to vancomycin from clinical specimens,1,2 but here we found an increase in teicoplanin resistance whereas the MRSA remained susceptible to vancomycin (although the MIC of vancomycin increased). In this respect, the strains isolated here resemble those of the new epidemic strain EMRSA-17 reported recently.3

The standard disc diffusion technique frequently fails to detect strains of S. aureus with reduced glycopeptide susceptibility. We used the Etest (AB Biodisk, Solna, Sweden), a simple, reproducible method shown to have high sensitivity and suitable for use in routine laboratories. The decreased MIC of methicillin and benzylpenicillin in the glycopeptide-resistant strains may be a consequence of the mechanism of the latter resistance, namely increased expression of penicillin-binding protein 2 (one of the target sites for penicillin).4 Recently, in vitro combinations of vancomycin and a ß-lactam antibiotic have been found to act synergically against staphylococci with reduced susceptibility to vancomycin,5 but clinical trials are required to determine whether such a combination will be therapeutically effective.

Control of the spread of MRSA, especially in high risk areas such as the ITU, is still a major problem when there are insufficient isolation facilities. However, these cases illustrate the need to contain the organism, coupled with the application of suitable laboratory measures for the detection of glycopeptide resistance.

Notes

* Corresponding author. Tel: +44-20-7794-0500; Fax: +44-20-7830-2179; E-mail: kibbler{at}rfc.ucl.ac.uk Back

References

1 . Hiramatsu, K., Hanaki, H., Ino, T., Yabuta, K., Oguri, T. & Tenover, F. C. (1997). Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. Journal of Antimicrobial Chemotherapy 40, 135–6.[Free Full Text]

2 . Howe, R. A., Bowker, K. E., Walsh, T. R., Feest, T. G. & MacGowan, A. P. (1998). Vancomycin-resistant Staphylococcus aureus. Lancet 351, 601–2.

3 . CDR Weekly (2000).10, 99–102.

4 . Moreira, B., Boyle-Vavra, S., deJonge, B. L. & Daum, R. S. (1997). Increased production of penicillin-binding protein 2, increased detection of other penicillin-binding proteins, and decreased coagulase activity associated with glycopeptide resistance in Staphylococcus aureus.Antimicrobial Agents and Chemotherapy41, 1788–93.[Abstract]

5 . Climo, M. W., Patron, R. L. & Archer, G. L. (1999). Combinations of vancomycin and ß-lactams are synergistic against staphylococci with reduced susceptibilities to vancomycin. Antimicrobial Agents and Chemotherapy 43, 1747–53.[Abstract/Free Full Text]