Antibiotic resistance in staphylococci
Introduction
Staphylococci are inherently susceptible to most antibiotics except those with purely anti-Gram-negative spectra. Nevertheless, staphylococci remain frequent causes of morbidity and mortality, having proved extremely adept at developing resistance, both by mutation and by DNA transfer. Staphylococcus aureus is a classical pathogen, causing infections at many sites [1], [2]. Skin and soft tissue infections are frequent and range from minor eruptions through infected ulcers and cellulitis to severe impetigo. S. aureus is also a frequent invader of surgical and other wounds, sometimes leading to sepsis. In England and Wales, it is the second most common cause of bacteraemias after Escherichia coli, accounting for circa 20% of cases [3]. Staphylococcal bone and joint infections can arise through contamination in orthopaedic surgery, and S. aureus is the most common pathogen in this setting. Other surgical sites can be invaded too: S. aureus is one of the more common causes of prosthetic valve endocarditis and an occasional agent of post-neurosurgical meningitis; native valve endocarditis also can arise, mostly among intravenous narcotic abusers. S. aureus is an infrequent but serious cause of pneumonia, mostly in debilitated patients on ventilators, or following influenza [1], [2]. Some strains produce one or more enterotoxin, which cause severe diarrhoea if contaminated food is eaten. Despite its pathogenicity, S. aureus is also carried innocuously by ca. 30% of the population, usually on the moist skin in the nose, axillae and perineum [4]. It survives well on drier skin and inanimate surfaces facilitating cross-colonisation and -infection.
Coagulase-negative staphylococci (CNS) include Staphylococcus epidermidis, S. haemolyticus, S. saprophyticus, and a number of other species. Most are normal skin commensals, and all are much less pathogenic than S. aureus. They have gained a role as pathogens only as advances in other fields of medicine have provided an increasing supply of debilitated patients, highly prone to infection. CNS are important as causes of line-associated infections in the immunosuppressed and account for many of the bacteraemic episodes in neutropenic patients [5]. Overall, CNS account for about 7–9% of bacteraemias reported to the Public Health Laboratory Service [3] and are important also as causes of prosthetic valve endocarditis, being more frequent than S. aureus in this setting. They are also a frequent cause of peritonitis in continuous ambulatory peritoneal dialysis, and S. saprophyticus is a frequent cause of urinary tract infections [6].
Section snippets
Early use of antibiotics, and the emergence of resistance in S. aureus
In 1940 a policeman was admitted to the John Radcliffe Infirmary at Oxford with an aggressive cellulitis spreading from a lesion on the corner of his mouth [7]. S. aureus was isolated together with Streptococcus pyogenes. Because the S. aureus strain was already sulphonamide resistant, the first experimental preparations of penicillin were used as treatment. The patient began to respond, but penicillin could not be produced rapidly enough, and he died. This experience nevertheless revealed the
Penicillinase-stable β-lactams
The early 1960s saw a new burst of antibiotic development, much of it initially directed against S. aureus. The first cephalosporins — cephalothin and cephaloridine — were developed primarily for their stability to staphylococcal penicillinase, but were overtaken by the discovery of how to replace the 6′ phenylacetyl group benzylpenicillin with other acyl substituents. This discovery provided the synthetic route for methicillin, nafcillin and the oxacillins. These compounds all have bulky 6′
The emergence of MRSA
Despite these successes, the first methicillin-resistant S. aureus (MRSA) were discovered in the year (1961) when methicillin reached the market [17]. Whereas normal S. aureus employ three penicillin-binding proteins, PBPs 1, 2, and 3, to catalyse cross-linking of peptidoglycan, MRSA have an additional component, PBP 2′ or 2a, which has low affinity for β-lactams [18] (Fig. 2). MRSA consequently are resistant to all β-lactams. The mecA gene is carried by large (32–60 kb) sections of
Current therapy for MRSA infections
The mainstays of therapy for MRSA infections are the glycopeptides, vancomycin and teicoplanin. Alternatives include fusidic acid and rifampicin, although these carry the risk of selecting resistant mutants and should only be used in combination, usually with each other or with a glycopeptide [31]. In the United Kingdom, the EMRSA 15 and 16 strains often retain susceptibility to gentamicin and tetracyclines (Table 1), but this is not the case for the MRSA strains prevalent in Japan or in many
The coming of glycopeptide-intermediate S. aureus
Since the first vancomycin-resistant enterococci were recorded in 1986, it has been feared that their plasmid– and transposon-mediated VanA and VanB determinants would cross into S. aureus. Many other mobile resistances are prevalent in both genera, notably including the bifunctional aminoglycoside-modifying enzyme AAC(6′)-APH(2″); nevertheless others, including penicillinase, have remained almost exclusive to one or other genus [42]. Noble and his colleagues obtained transfer of VanA-coding
Resistance in coagulase-negative staphylococci
Coagulase-negative staphylococci (CNS) are much less virulent pathogens than S. aureus. As outlined earlier, their clinical role is largely restricted to immunosuppressed, prosthetic device infections, peritonitis in continuous ambulatory peritoneal dialysis and, in the case of S. saprophyticus, to urinary tract infections. CNS bacteraemias are much less rapidly fatal than those caused by most other pathogens, meaning that a delayed start to appropriate therapy is acceptable [5]. This is
Answers to resistant staphylococci: infection control and new antibiotics
It should be emphasised that the MRSA problem is essentially clonal, whereas most CNS infections involve sporadic strains. These factors have a major bearing on the potential for control. Many guidelines for MRSA control have been written, including recent joint recommendations in the United Kingdom by the British Society for Antimicrobial Chemotherapy, Hospital Infection Society Infection Control Nurses Association [31]. This guidance covers situations where MRSA are newly introduced to a
Acknowledgements
I am grateful to Hazel Aucken, Dot James, Alan Johnson, Stephen Murchan and Gail O'Neil for helpful comments on the draft of this manuscript.
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