The prevalence of methicillin resistant Staphylococcus aureus (MRSA) in German hospitals has continued to increase, but the range of antimicrobials to which they are resistant has decreased. The trend cannot be attributed to changes in antibiotic consumption. Isolation nursing of patients who carry MRSA needs to be implemented consistently.

By the 1960s methicillin resistant strains of Staphylococcus aureus (MRSA) from European countries also exhibited resistance to antibacterials of different classes such as b -lactams, tetracycline, chloramphenicol, and macrolides (1). Later they acquired resistance to gentamicin (2). Most MRSA from around the world sources exhibit multiresistant phenotypes and this was true for MRSA acquired in German hospitals until 1995 (3). While the prevalence of MRSA in hospitals has continued to increase (1990: 1.7 %, 1995: 8.7 %, 1999: 15.1 % (4, 5)) in all regions of Germany (6) the resistance phenotypes of MRSA have changed since 1995. Resistance to gentamicin, oxytetracycline, and erythromycin has become less common (table 1). This raises the question whether widely disseminated strains have lost resistance determinants or whether new MRSAs have emerged and spread (7,8). This communication reports on comparative molecular typing of MRSA from German hospitals exhibiting different resistance phenotypes and their relationships to particular clonal groups of epidemic strains.

Table 1. Percentage of MRSA strains with resistance to various antibiotics: hospital acquired infections in Germany

Antibiotic

1994

1995

1996

1997

1998

(n=1238)

(n=1325)

(n=157)

(n=197)

(n=1693)

Ciprofloxacin

80

88

89

94

84

Erythromycin

94

85

73

67

72

Clindamycin

85

74

68

46

54

Gentamicin

94

86

75

55

55

Oxytetracyclin

75

38

27

26

27

Trimethoprim

68

31

23

17

20

Rifampicin

23

16

12

8

10

Fusidic acid 

13

9

3

3

3

Mupirocin

0

0

0

0.4

0.5

Quinupristin/Dalfopristin

0

0

0

0

0.2

Vancomycin

0

0

0

0

0

Teicoplanin

0

0

0

0

0

MRSA from sporadic infections and from outbreaks in hospitals were sent for typing to the German national reference centre for staphylococci at the Robert Koch Institute. This centre cooperates with 112 diagnostic laboratories throughout Germany. Strains were defined as MRSA by minimum inhibitory concentration (MIC) ³ 2 mg/l for oxacillin and polymerase chain reaction (PCR) demonstration of the mecA gene (7). In this study, a single isolation of a given strain was taken to indicate its presence in a hospital. If several isolates were identified in a particular hospital at a given time during the study period, molecular typing was performed for each distinguishable resistance phenotype and phage pattern. Susceptibility testing for antibiotic on all isolates referred to the reference centre was performed by the broth microdilution method according to guidelines from the National Committee for Clinical Laboratory Standards (NCCLS) (9)

Each isolate chosen for molecular typing was subjected to SmaI-macrorestriction patterns using pulsed field gel electrophoresis (6), processed images were stored in a databank system, and cluster analysis for similarity was performed (10). Isolates that exhibited patterns of multiresistance not attributable to the clonal groups of known epidemic strains were further subjected to PCR typing (6).

PCR detection of mecA coding for oxacillin resistance and for tetM coding for tetracycline resistance on Tn916 were performed as described elsewhere (7,11).

Results

The frequency distribution of known epidemic MRSA as identified by SmaI macrorestriction patterns and PCR typing methods among isolates sent in for typing is shown in table 2. Several hospitals recorded different epidemic strains during the same study period. The increase in the number of hospitals from which MRSA had been collected in 1998 resulted from the expansion of the network in the second half of 1998 in the Rhine area of Germany.

Table 2: Regional distribution of resistance phenotypes of MRSA in Germany

Grouping according to molecular typing

Resistance phenotype

Frequency (%) of occurence in different German hospitals¹ (outbreaks and sporadic infections)

1994

1995

1996

1997

1998

(n=121)

(n=142)

(n=140)

(n=191)

(n=337)

Northern German epidemic MRSA

PEN, OXA, GEN, ERY, CLI, OTE, SXT, RIF, CIP

22

23

17

16

13

Southern German epidemic MRSA 

PEN, OXA, ERY, CLI, CIP, (GEN)², (OTE)³

16

35

34

24

29

Hannover area epidemic MRSA 

PEN, OXA, GEN, ERY, CLI, OTE, SXT, CIP

32

17

16

16

15

South-eastern Germany and western Austria MRSA 

PEN, OXA, GEN, ERY, CLI, OTE, SXT, CIP

5

3

1

0.5

0.6

Vienna epidemic MRSA 

PEN, OXA, GEN, ERY, CLI, SXT, CIP, OTE, (FUS)

4

3

1

1

1

Berlin epidemic MRSA 

PEN, OXA, CIP, (GEN, ERY, ERY-CLI, SXT)

11

11

22

18

26

Barnim MRSA

PEN, OXA, ERY, CLI, CIP

8

9

Phage group I MRSA

PEN, OXA, (ERY, CLI)

1

10

2

Other

Various

10

9

8

6

5

Number of hospitals affected

98

128

130

130

241

Traditional multiresistant epidemic strains such as the northern German epidemic MRSA and the Hannover area epidemic MRSA became less common. At the same time the prevalence of newly emerging epidemic strains possessing fewer resistance determinants (such as the ‘Berlin’ epidemic MRSA and the ‘Barnim’ epidemic MRSA) increased.

Oxytetracycline resistance was lost in 87% of isolates of the clonal group ‘southern German’ epidemic strain in 1997 and 1998, which had possessed tetM on Tn916 as evidenced by PCR, but oxytetracycline resistance remained stable in the other clonal groups of multiresistant strains.

MRSA with narrower resistance phenotypes are not restricted to a particular geographical area. The Berlin epidemic MRSA and the Barnim epidemic MRSA have spread from Berlin and the territory to the north of the city to the northern half of Germany and also reached hospitals in the south (figure). Phage group I MRSA were restricted to a few hospitals until 1998.

The narrowing of resistance phenotypes of MRSA in German hospitals is due mainly to a decline in epidemic strains of MRSA that were prevalent until the mid 1990s and the emergence of ‘new’ epidemic strains in which resistance to gentamicin and to oxytetracycline are rare. In addition, the tetM gene that confers oxytetracycline resistance was lost by a considerable proportion of strains of the southern German epidemic MRSA. The basis for epidemicity of particular strains of MRSA is unknown, but multiresistance to antibiotics is clearly not the only factor.

The Berlin epidemic strain, the Barnim epidemic strain, and phage group I MRSA have originated from clonal groups of S. aureus that were sensitive to methicillin (5,6,12) and widespread outside hospitals. We may speculate (it remains to be demonstrated) that these strains have a better capacity for colonisation and are therefore replacing the older epidemic strains.

The prevalence of resistance to a particular antibiotic does not always reflect antibiotic consumption, as has been seen in American hospitals (13). The same applies in Germany. Consumption of gentamicin has remained stable (5 million counting units (one counting unit corresponds to one dosage unit such as a tablet or ampoule) per year). The volume of macrolides used in German hospitals rose from 7.2 million counting units in 1991 to 12.6 in 1998 and that of tetracyclines fell from 8.9 millions in 1991 of counting units to 3.6 in 1998 (data from German Institute for Medical Statistics) .

Although the range of antimicrobials to which MRSA in Germany carries resistance has become narrower, the prevalence of MRSA has increased (5). Detailed recommendations in Germany for the prevention of spread of MRSA within and between hospitals focus on nursing affected patients in isolation (14), reflecting, in this respect, the recommendations in the United States (15). The increasing prevalence of MRSA (5) and the increasing number of hospitals from which MRSA were sent for typing suggest that the recommendations are not being followed sufficiently (table 2). Hospitals themselves and local medical officers who carry the immediate responsibility for control of hospital acquired infections must give this topic more priority.

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