Part I: Antibiotic resistance - Local scenario
1.2 Methicillin-resistant Staphylococcus aureus (MRSA)
Due to the alteration of penicillin binding protein, MRSA are resistant to penicillins (including oxacillin, cloxacillin and flucloxacillin), ß-lactam/ß-lactamase inhibitor combinations, cephalosporins, and carbapenems. Only the new anti-MRSA ß-lactams (e.g. ceftaroline) retain activity against MRSA. However, in vitro and in vivo reduced susceptibility to ceftaroline has recently been reported (8–9).
MRSA has been categorised into healthcare-associated (HA-MRSA) and community-associated (CA-MRSA). The Centers for Disease Control and Prevention (CDC) classification, which is the most widely accepted, classified HA-MRSA and CA-MRSA epidemiologically (10). However the border between the two is becoming blurred and surveillance using epidemiological criteria alone has become insufficient.
1.2.1 Healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA)
- For S. aureus that are susceptible to methicillin, vancomycin is inferior to anti-staphylococcal ß-lactam (11). However, vancomycin remains the treatment of choice for infection caused by MRSA. The efficacy of vancomycin may be limited by inadequate potency of generic drug, suboptimal dosing, poor tissue penetration, slow bactericidal activity and strains with reduced susceptibility to the drug (11–12).
- In the recent years, a silent and gradual increase in the vancomycin minimal inhibitory concentration (MIC) has been observed. This phenomenon is known as ‘vancomycin creep’ (13–14). Since the increment is small and the MIC still falls within the ‘sensitive’ range, it usually goes unnoticed. This phenomenon has also been observed in HK (15). In HK, there has been a gradual increase in the number of strains with vancomycin MIC = 1 μg/mL from 1997 to 2008. The elevated MIC paralleled an increase in consumption of vancomycin (15).
- The vancomycin creep has been observed in some, but not all hospitals. This is probably due to difference in the susceptibility testing methods, clonal dissemination of more resistant strains and the intensity of vancomycin usage (15).
- Unfortunately, there is no international consensus on the appropriate breakpoint for interpretation of vancomycin MIC results for staphylococci (Table 1.5). Vancomycin MIC ≥ 2 μg/mL has been associated with vancomycin treatment failure (16–18). Therefore, guidelines have recommended isolates with vancomycin MIC ≥ 2 μg/mL be treated with an alternative antibiotic instead of vancomycin (11).
Table 1.5 Interpretation of vancomycin susceptibility for staphylococci
Vancomycin MIC (μg/mL) Susceptible Intermediate Resistant Staphylococcus aureus EUCAST 2017 ≤2 none >2 CLSI 2017 ≤2 4─8 ≥16 Coagulase-negative
EUCAST 2017 ≤4 none >4 CLSI 2017 ≤4 8─16 ≥32
- The susceptibility profile cannot be used as a differentiating feature of HA-MRSA and CA-MRSA. In a recent local report, it demonstrated an increase in prevalence of multi-susceptible MRSA (MS-MRSA) over the past few years in the hospital setting. The increase in multi-susceptible strains actually represents a rise in HA-MRSA, which was associated with the spread of the clone ST45/t1081 possessing SCCmec type IV or V. About 75% of these isolates were recovered from elderly living in residential care homes. This suggests that these strains may be more transmissible among the elderly in residential care home and convalescent care settings, serving as a reservoir (19).
- In 2011, a local study on MRSA carriage at admission to 15 acute medical units showed that the overall carriage rate was 14.3%. Risk factors include MRSA history within the past 12 months, old age home residence, bed-bound state. Molecular typing revealed that ST45/t1081 is a major clone circulating among the patients (20).
1.2.2 Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)
- CA-MRSA was first reported in HK in 2001, and is rapidly emerging over the past 10 years (21–22). Reporting to the Department of Health (DH) has been made mandatory since January 2007. It is responsible for 10.4% of purulent cellulitis and 5% of cutaneous abscess in the Accident & Emergency setting (23).
- In 2007, a total of 173 cases of CA-MRSA infection were notified to the Centre for Health Protection (CHP). The number increased by more than 6 times to 1,148 in 2016. Among the reported cases, about two-thirds of the cases required hospitalisation, while the remaining cases were managed in outpatient settings. The absolute increase in the total number of cases reflects the increasing burden of CA-MRSA in HK (24–25).
- A total of 3,650 cases of CA-MRSA were recorded between January 2012 and October 2015. Majority of the CA-MRSA presented with uncomplicated skin and soft tissue infections (98%) and 74% of these cases required surgical management. Fifty-three (2%) of the cases presented with invasive CA-MRSA infections, where 14 cases were admitted to the ICU for treatment. Four (0.1%) cases died from sepsis (n=2), pneumonia (n=1) and necrotising fasciitis (n=1) (24).
- Patients infected with CA-MRSA do not have the usual risk factors associated with HA-MRSA. Locally, case control studies revealed that ethnic minority and sharing of personal items with other persons were risk factors for CA-MRSA while frequent hand washing was protective against CA-MRSA infection (21,26).
- Panton-Valentine leukocidin (PVL) toxin is a pore forming cytotoxin that is capable of destroying human monocytes and neutrophils. PVL toxin has been associated with virulence and transmissibility of CA-MRSA. While presence of PVL toxin in MRSA is used as a criterion for reporting of CA-MRSA in HK, it has been showed that some of the CA-MRSA causing skin and soft tissue infection were PVL negative (21).
- Other than skin and soft tissue infections, PVL toxin is also associated with necrotising pneumonia, necrotising fasciitis and meningitis. CA-MRSA has also been reported to co-infect with influenza resulting in fulminant pneumonia (27–29).
Figure 1.1 Number of CA-MRSA reported to the CHP from 2007–2016.
* Notifiable since 5 January 2007