dalfopristin, a new addition to the antimicrobial arsenal

COMMENTARY

Quinupristin/dalfopristin, a new addition to the antimicrobial arsenal Antibiotic resistance, especially that in gram-positive bacteria, is a huge problem, not only in terms of human costs, but also in terms of the financial burden on healthcare systems. Every year in the USA alone, about two million patients develop nosocomial infections, with 50–60% involving antibiotic-resistant bacteria, and nosocomial infections add at least US$4·5 billion to the cost of health care.1 There is thus a clear need for new antibacterial drugs, particularly those active against multiresistant strains. One such new drug is quinupristin/dalfopristin (Synercid, Rhône Poulenc Rorer), a streptogramin recently licensed in the UK and the USA. Quinupristin/dalfopristin is active against gram-positive bacteria, including difficult organisms such as meticillinresistant strains of Staphylococcus aureus (MRSA) and of coagulase-negative staphylococci, S aureus with intermediate glycopeptide resistance, vancomycinresistant Enterococcus faecium, and penicillin-resistant and macrolide-resistant pneumococci.2-5 The indications for the use of quinupristin/dalfopristin in the UK are restricted to nosocomial pneumonia and skin and soft-tissue infections caused by gram-positive bacteria and clinically significant infections due to E faecium. The drug is specifically indicated when no other antibacterial agents are suitable. When mixed infections are confirmed or suspected, quinupristin/ dalfopristin should be used in combination with one or more agents active against nosocomial gram-negative bacteria, because its activity is exclusively against grampositive pathogens. Data from several clinical trials and a compassionateuse programme illustrate the efficacy of quinupristin/ dalfopristin. In two randomised, open-label trials involving 893 patients with complicated skin and skinstructure infections, due predominantly to S aureus, coagulase-negative staphylococci, and Streptococcus pyogenes, the clinical success rate for evaluable patients receiving quinupristin/dalfopristin (68·2%) was equivalent to that in patients receiving cephazolin, oxacillin, or vancomycin (70·7%).6,7 Although the bacterial eradication rate (by pathogen rather than by patient) in evaluable patients receiving quinupristin/dalfopristin (66·6%) was lower than that in those receiving comparator agents (77·7%, p=0·004), this difference probably reflected the higher proportion of polymicrobial infections among the former group, and the early discontinuation of quinupristin/dalfopristin treatment by some patients because of local venous adverse events.6,7 2012

The efficacy of quinupristin/dalfopristin for infections due to vancomycin-resistant E faecium has been assessed in two studies involving a total of 396 patients. In the first, patients were enrolled at 44 American centres with high prevalence rates of vancomycin-resistant E faecium infection; the second reviewed patients who received quinupristin/dalfopristin as part of the worldwide emergency-use programme.8,9 The lack of other suitable treatment options meant that in both these studies the evaluation of quinupristin/dalfopristin was noncomparative. The disorders treated included intraabdominal infections (34%), bacteraemias, including those associated with central catheters (36%), urinarytract infections (9%), and skin and skin-structure infections (8%). Other sites of infection included bone, joints, the heart, the respiratory tract, and wounds. The clinical and bacteriological success rates for quinupristin/dalfopristin exceeded 70%, which was excellent, since the study population consisted of seriously ill patients with a high prevalence of bacteraemia and a range of underlying disorders, including diabetes mellitus, liver failure, cancer, malnutrition, and requirement for mechanical ventilation or dialysis. Quinupristin/dalfopristin thus seems to be an effective treatment for serious, lifethreatening infections due to vancomycin-resistant E faecium.8,9 Data from the clinical trials and compassionate-use programme also enable assessment of the safety and tolerability of quinupristin/dalfopristin.8–10 In the comparative trials, patients in the quinupristin/ dalfopristin and comparator study groups had similar rates of diarrhoea, vomiting, or skin rashes, whereas nausea was less prevalent among patients receiving quinupristin/dalfopristin. In the non-comparative trials, arthralgia and myalgia were the commonest systemic adverse events, occurring in about 10% of patients.9,10 Peripheral venous infusion was commonly associated with local adverse effects, such as inflammation, pain, oedema, and thrombophlebitis, hence the recommendation that quinupristin/dalfopristin should be given through a central venous catheter over a period of 60 min.8–10 Despite these promising results, quinupristin/ dalfopristin is unlikely to prove a panacea against multiresistant gram-positive bacteria. One drawback is its lack of activity against Enterococcus faecalis, which makes up 80–90% of clinical isolates of enterococci.2,3 Although E faecalis generally remains sensitive to ampicillin and is much less frequently vancomycin resistant than E

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faecium, appropriate use of quinupristin/dalfopristin will require identification of enterococci to the species level, which is not routinely done in many microbiology laboratories. A further problem may be the reduced bactericidal activity of quinupristin/dalfopristin against strains of S aureus that have acquired the erm gene and express it constitutively (MLSB/C strains). These strains are resistant to both erythromycin and clindamycin, and their resistance to chemically diverse drugs reflects the overlapping ribosomal target sites of macrolides, lincosamides, and group B streptogramins (including quinupristin).11 This pattern of multiresistance has implications for dosing regimens, in that although the manufacturer’s product summary states that quinupristin/dalfopristin may be used twice daily for most skin or soft-tissue infections, it should be given three times a day for those due to MRSA resistant to erythromycin and clindamycin, and thus inferred to be MLSB/C strains. An additional concern is that resistance to quinupristin/dalfopristin has already been reported, both in E faecium and in staphylococci. Several mechanisms of resistance have been identified, including acetylation or efflux of dalfopristin and hydrolysis of quinupristin.12 Although streptogramin resistance is currently rare, reservoirs may have been preselected through use of the related drug virginiamycin as a growth promoter in farm animals, and the resistance may become more prevalent under the selective pressure of increasing quinupristin/ dalfopristin use. Despite these caveats, the effectiveness of quinupristin/dalfopristin against multiresistant grampositive pathogens, including MRSA and vancomycinresistant E faecium, is good news giving clinicians an additional agent against serious gram-positive infections. The availability of quinupristin/dalfopristin, and the likely licensing, within 1–5 years, of other agents active against gram-positive organisms give grounds for cautious optimism. Agents in the pipeline include oxazolidinones (linezolid), everninomicins (Ziracin), ketolides, anti-MRSA cephalosporins, daptomycin, and glycylcyclines. *Alan P Johnson, David M Liver more Antibiotic Resistance Monitoring and Reference Laboratory, Public Health Laboratory, Colindale, London NW9 5HT, UK 1

Central

Tomasz A. Multiple-antibiotic-resistant pathogenic bacteria: a report on the Rockefeller University Workshop. N Engl J Med 1994; 330: 1247–51. 2 Leclercq R, Courvalin P. Streptogramins: an answer to antibiotic resistance in gram-positive bacteria. Lancet 1998; 352: 591–92. 3 Nadler H, Dowzicky MJ, Feger C, Pease MR, Prokocimer P. Quinupristin/dalfopristin: a novel selective-spectrum antibiotic for the treatment of multi-resistant and other gram-positive pathogens. Clin Microbiol Newslett 1999; 13: 103–12. 4 Tenover FC, Lancaster MV, Hill BC, et al. Characterization of staphylococci with reduced susceptibilities to vancomycin and other glycopeptides. J Clin Microbiol 1998; 36: 1020–27. 5 Ploy MC, Grélaud C, Martin C, de Lumley L, Denis F. First clinical isolate of vancomycin-intermediate Staphylococcus aureus in a French hospital. Lancet 1998; 351: 1212. 6 Nichols RL, Graham DR, Barriere SL, et al. Treatment of hospitalised patients with complicated gram-positive skin and skin structure infections: two randomised, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin. J Antimicrob Chemother 1999; 44: 263–73. 7 Nichols RL. Optimal treatment of complicated skin and skin structure infections. J Antimicrob Chemother 1999; 44 (suppl A): 19–23. 8 Moellering RC, Linden PK, Reinhardt J, Blumberg EA, Bompart F, Talbot GH. The efficacy and safety of quinupristin/dalfopristin for

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the treatment of infections caused by vancomycin-resistant Enterococcus faecium. J Antimicrob Chemother 1999; 44: 251–61. 9 Moellering RC. Quinupristin/dalfopristin: therapeutic potential for vancomycin-resistant enterococcal infections. J Antimicrob Chemother 1999; 44 (suppl A): 25–30. 10 Rubinstein E, Prokocimer P, Talbot GH. Safety and tolerability of quinupristin/dalfopristin:administration guidelines. J Antimicrob Chemother 1999; 44 (suppl A): 37–46. 11 Low DE, Nadler HL. A review of in-vitro antibacterial activity of quinupristin/dalfopristin against methicillin-susceptible and resistant Staphylococcus aureus. J Antimicrob Chemother 1997; 39 (suppl A): 53–58. 12 Thal LA, Zervos MJ. Occurrence and epidemiology of resistance to virginiamycin and streptogramins. J Antimicrob Chemother 1997; 43: 171–76.

Vulvar melanoma, biologically different from other cutaneous melanomas Malignant melanoma may show a predisposition for vulvar skin. Although 3–7% of all melanomas in women affect the vulva, the skin in this area accounts for only 1–2% of the total surface area of the body.1 The unusual nature of vulvar melanoma and how it differs biologically from other cutaneous melanomas are highlighted in reports of a nationwide 25-year follow-up study of 219 Swedish women with primary melanoma of the vulva.2,3 The reports confirm previous data and add insight to the natural history of this rare tumour. In the Swedish cohort, there were 2·5 times as many vulvar melanomas as other cutaneous melanomas. During the period of the study, the incidence of cutaneous melanomas in women in Sweden increased by about 5% annually, whereas that of vulvar melanoma declined by about 3% annually. However, the prognosis of vulvar melanoma (47% 5-year survival) remained poorer than that for other cutaneous melanomas (80% 5year survival). Vulvar melanomas have been classified pathologically into superficial spreading melanomas, nodular melanomas, and mucosal lentiginous melanomas (MLM). MLM is histologically similar to acral lentiginous melanoma (ALM). In the Swedish series, MLM was the commonest type, followed by nodular melanoma. Superficial spreading melanoma was least common. This order is opposite to that for cutaneous melanoma in most series. The contrasting patterns of change in incidence of vulva melanomas and other cutaneous melanomas have been thought to indicate that MLM/ALM differ biologically from other cutaneous melanomas and that their pathogenesis is less dependent on DNA damage induced by ultraviolet light. Vulvar melanoma seems to have a stronger resemblance to primary anal melanoma disease; they are similar in clinical presentation and prognosis.4 Vulvar melanoma is generally a disease of older patients, with most studies recording a mean age of over 60 years at diagnosis.5 Likewise, in the Swedish study only 19 of the 219 patients were aged under 54 years. By contrast, the average age of female patients with cutaneous melanoma is younger.6 The Swedish study revealed several important clinical and histopathological findings. Malignant melanoma of the vulva presented as polypoid tumours in 35% of patients. Of special clinical note is that 27% of the tumours were macroscopically amelanotic. The commonest sites of disease were the clitoral area and the labia majora, which accounted for more than 60% of all lesions. Only 15% of tumours were located primarily in 2013