- Email: [email protected]
Antimicrobial action of atorvastatin and rosuvastatin
Pathology Downloaded from informahealthcare.com by Nyu Medical Center on 01/08/15 For personal use only.
CORRESPONDENCE
689
FIG. 1 Effect of spiked carbamazepine in serum on Abbott TDx and Abbott Axsym TCA assays.
carbamazepine solution and the corresponding blank control were plotted against carbamazepine concentration. A linear positive interference by carbamazepine was observed at concentration 4–42 mmol/L (Fig. 1). That covered its therapeutic interval of 17–51 mmol/L.2 In clinical practice, it is not infrequent to encounter patients on both carbamazepine and TCAs. Carbamazepine can cause in vivo reduction of many TCAs via stimulation of hepatic CYP3A4 activity.3 However, therapeutic monitoring for this drug interaction would be hampered by the analytical interference as observed above. Our finding is supported by a similar report describing carbamazepine causing false positive TCA results in children with epilepsy.4 That is contrary to both the Abbott TDx and Abbott Axsym package inserts claims of detectable interference at a much higher level, i.e., in the toxic range of 127 mmol/L (29 972 ng/mL). Clinically significant cross-reactivity by quetiapine on the Abbott TDx TCA assay has also been reported.5 The imprecision/inaccuracy of this assay for therapeutic monitoring of specific TCA should also be considered. Although the manufacturer claims their assay is designed for diagnosis and monitoring of TCA overdose, it has been used by some laboratories for therapeutic monitoring. This technique should be adopted with caution and guidelines must be offered to clinicians for sensible result interpretation. The limitations of the Abbott TDx TCA assay in therapeutic drug monitoring were highlighted by a study comparing high performance liquid chromatography (gold standard) versus Abbott TDx TCA assay. This study showed that the Abbott TDx TCA assay can produce satisfactory results for desipramine, imipramine, nortriptyline and trimipramine but not for other TCAs with significant over-estimation.6 David Song Weldon Chiu Department of Chemical Pathology, Labplus, Auckland City Hospital, Auckland, New Zealand
Contact Dr D. Song. E-mail: [email protected] 1. Tricyclic antidepressants—blood level measurements and clinical outcome: an APA Task Force report. Am J Psychiatry 1985; 142: 155–62. 2. Burtis C, Ashwood ER. Teitz Textbook of Clinical Chemistry. Philadelphia: WB Saunders, 1999. 3. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2005; 61: 246–55. 4. Saidinejad M, Law T, Ewald MB. Interference by carbamazepine and oxacarbazepine with serum and urine screening assays for tricyclic antidepressants. Pediatrics 2007; 120: 504–9. 5. Cerullo MA, Albertz AA, Bell JN, Anthenelli RM, Delbello MP. Tricyclic antidepressant immunoassay may reflect quetiapine adherence. Am J Psychiatry 2008; 165: 919–20. 6. Hackett LP, Dusci LJ, Ilett KF. A comparison of high-performance liquid chromatography and fluorescence polarization immunoassay for therapeutic drug monitoring of tricyclic antidepressants. Ther Drug Monit 1998; 20: 30–4.
DOI: 10.3109/00313020903305878
Antimicrobial action of atorvastatin and rosuvastatin Sir, Statins are potent lipid lowering agents, well established in the management of cardiovascular disease. Recent literature suggests these drugs may be the panacea for ill health, with reported benefits in such diverse conditions as cancer, stroke, dementia, multiple sclerosis, and sepsis.1 Plausible biological mechanisms exist for many of these potential clinical benefits and several reviews have evaluated possible mechanisms for any impact in sepsis.2,3 A recent report demonstrated a direct antimicrobial effect of simvastatin and to a lesser extent fluvastatin against methicillinsusceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA).4 If the apparent antimicrobial activity represents a class effect, we hypothesised that two other commonly used
Pathology Downloaded from informahealthcare.com by Nyu Medical Center on 01/08/15 For personal use only.
690
CORRESPONDENCE
statins, atorvastatin and rosuvastatin, may also have antimicrobial action in vitro against a variety of both Gram positive and Gram negative organisms. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of atorvastatin (pure drug obtained from Pfizer and crushed commercially available tablets) and rosuvastatin (pure drug obtained from Astra Zeneca) was determined using a microtitre plate broth dilution method, based on the method described in Wiegand et al.5 Into each well of a 96 well microtitre plate an equal volume (100 mL) of statin solution and bacterial inoculum was added to a final volume of 200 mL. The concentration of statin in adjacent wells varied using doubling dilutions. For atorvastatin the concentrations tested ranged from 0.06 mg/L to 500 mg/L. For rosuvastatin the concentrations tested were 0.024–800 mg/L. These concentrations were chosen as they included and exceeded the peak plasma concentrations in routine use. A stock solution of 2 g/L was prepared for both rosuvastatin and atorvastatin. Atorvastatin was dissolved in solvent (both methanol and ethanol stock solutions were prepared) whilst rosuvastatin was dissolved in sterile water. Stock solution was added to appropriate volumes of Mueller Hinton broth to obtain the desired final concentrations. Each statin was tested against six different American Type Culture Collection (ATCC) organisms. These were Pseudomonas aeruginosa ATCC 27853 (Pseudomonas); Escherichia coli ATCC 25922 (E. coli); Vancomycin sensitive Enterococcus faecalis ATCC 29212 (VSE); vancomycin resistant Enterococcus faecalis ATCC 51299 (VRE); methicillin susceptible Staphylococcus aureus ATCC 25923 (MSSA), methicillin resistant Staphylococcus aureus ATCC 49476 (MRSA). These organisms were stored at 7708C on Protect beads (Technical Services Consultants, UK) and reconstituted for use onto 7% horse blood agar (HBA). The organisms were incubated on HBA at 358C for 24 h to check for purity and viability before use. A final inoculum density of 5 6 105 colony-forming units (CFU)/mL was achieved using serial dilutions of a 0.5 McFarland standard (1.5 6 108 CFU/mL). Growth, broth sterility and matched solvent controls were included on every microtitre plate. Each plate was repeated in triplicate. After incubation overnight at 358C, the presence of visible turbidity or sediment in the wells indicated growth of the organism. The MIC was defined as the lowest concentration of statin that prevented visible growth. As each microtitre plate was repeated in triplicate, the lowest concentration of statin across all three plates was deemed to be the MIC. To determine the MBC, subcultures were obtained from each well and inoculated on to HBA plates. The plates were incubated overnight at 358C and the MBC was determined as the lowest concentration of statin that prevented growth on all three HBA plates. Our results demonstrate that both rosuvastatin and atorvastatin in vitro have some bacteriostatic activity (Fig. 1). The MIC of pure atorvastatin-ethanol was 250 mg/L against MSSA, MRSA, VSE, VRE, E. coli and Pseudomonas. Subcultures from these wells demonstrated growth of all six bacterial strains, suggesting that this was a bacteriostatic rather than bactericidal effect. The higher concentration of 500 mg/L pure atorvastatin in ethanol
Pathology (2009), 41(7), December
FIG. 1 The MIC for atorvastatin (pure drug) and rosuvastatin (pure drug) against all six organisms tested. These were Escherichia coli (Ecoli), Pseudomonas aeruginosa (Pseud), methicillin susceptible Staphylococcus aureus (MSSA), methicillin resistant Staphylococcus aureus (MRSA), vancomycin sensitive Enterococcus faecalis (VSE) and vancomycin resistant Enterococcus faecalis (VRE).
12.5% was bactericidal against E. coli and Pseudomonas but growth was detected for all Gram positive organisms tested. The crushed atorvastatin-methanol showed no inhibition of growth for Pseudomonas or E. coli at any concentration tested. MSSA had an MIC of 250 mg/L (12.5% methanol) and VSE had an MIC of 500 mg/L (25% methanol). No bactericidal effect was detected for any Gram positive or Gram negative organisms at the concentrations tested. Pure rosuvastatin was dissolved in water and showed an MIC of 100 mg/L against all six organisms. Rosuvastatin showed no bactericidal activity in vitro against any of the organisms studied at all concentrations up to 800 mg/L. Both ethanol and methanol controls demonstrated some bacteriostatic and bactericidal effects on all organisms tested. Ten percent ethanol was bactericidal against E. coli and Pseudomonas whilst 15% ethanol was bactericidal for MSSA and VSE. Better growth was observed for all organisms in methanol controls with an MBC of 15% for Pseudomonas, 25% for E. coli, 35% for MSSA and 50% for VSE. For atorvastatin dissolved in ethanol, the solvent is not responsible for the bacteriostatic effect as the percentage of ethanol in atorvastatin 250 mg/L (6.25%) is lower than the solvent control MIC against all organisms tested. However, solvent controls showed significant bactericidal effects. The observed MBCs for atorvastatin in ethanol or methanol could be explained by solvent bactericidal effect. Our study demonstrates that methanol has less impact on bacterial growth than ethanol and therefore would be the solvent of choice for further studies evaluating antibacterial properties in lipid soluble statin agents. This study suggests the observed antimicrobial effect of both atorvastatin and rosuvastatin is bacteriostatic rather than bactericidal. The MICs obtained in this study are considerably higher than those previously described for simvastatin in methanol against MSSA and MRSA.4 Both atorvastatin and rosuvastatin are fully synthetic compounds and previous authors have suggested that because simvastatin is derived from fungi it may contain more inherent antibacterial activity.4 Our results suggest the synthetic compounds do possess some antimicrobial
Pathology Downloaded from informahealthcare.com by Nyu Medical Center on 01/08/15 For personal use only.
CORRESPONDENCE
properties although a molecular basis for the antibacterial action it not currently known. The MIC of crushed atorvastatin tablets yielded results different to those seen with pure drug. No inhibition of Gram negative organisms and a higher MIC (500 mg/L) against VSE was seen with crushed tablet preparation. This may reflect the potential for loss of drug in the mortar and pestle reflecting the difficulty in preparing accurate stock solution concentrations when compared to using pure drug in a fine powdered form, or an interaction or dilution effect of the filler used to stabilise the tablets. The MICs achieved in this study far exceed the typical peak plasma concentration of statins when used to lower cholesterol and would preclude systemic usage as antimicrobial agents. For pure atorvastatin the MIC of 250 mg/L is 25 000-fold higher than a typical peak plasma concentration of 0.01 mg/L. For pure rosuvastatin the MIC of 100 mg/L is 2700-fold higher than a typical peak plasma concentration of 0.037 mg/L. A recent report investigating topical simvastatin application in an animal model of infected skin wound healing demonstrated a reduced bacterial load and improved healing.6 It is interesting to speculate that a topical preparation at these higher concentrations may have antibacterial effects and warrants further investigation. This study demonstrates that statins have a reproducible bacteriostatic effect in vitro. This may be a class effect as antimicrobial activity has now been demonstrated for atorvastatin, rosuvastatin, simvastatin and fluvastatin, a combination of fully synthetic and fungal derived drugs. This effect is probably not relevant in current clinical practice as the high concentrations required to achieve a reliable antimicrobial effect are well above those achieved in routine use to lower cholesterol. Anne-Marie Welsh* Peter Kruger*{ Joan Faoagali{ Departments of *Intensive Care and {Microbiology, Princess Alexandra Hospital, Woolloongabba, Brisbane, and {University of Queenland, Brisbane, Queensland, Australia Contact Dr P. Kruger. E-mail: [email protected] ACKNOWLEDGEMENTS We would like to thank Mrs S. Kleinschmidt for her invaluable assistance in the laboratory. This work was supported in part by a grant from Princess Alexandra Hospital Foundation. Pure compound was kindly supplied by the manufacturers, Pfizer (atorvastatin) and Astra Zeneca (rosuvastatin). Neither company had any role in the experimental design, performance of the study or analysis of results.
1. Kruger PS, Kostner K, Venkatesh B. Statins in critical illness. In: Vincent JL, editor. Yearbook of Intensive Care and Emergency Medicine. Berlin: Springer Verlag, 2005; 477–87. 2. Kruger PS. Statins: the next anti-endotoxin. Crit Care Resusc 2006; 8: 223–6. 3. Terblanche M, Almog Y, Rosenson RS, et al. Statins and sepsis: multiple modifications at multiple levels. Lancet Infect Dis 2007; 7: 358– 68.
691
4. Jerwood S, Cohen J. Unexpected antimicrobial effect of statins. J Antimicrob Chemother 2008; 61: 362–4. 5. Wiegand I, Hilpert K, Hancock RE. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat Protoc 2008; 3: 163–75. 6. Rego AC, Araujo Filho I, Damasceno BP, et al. Simvastatin improves the healing of infected skin wounds of rats. Acta Cir Bras 2007; 22 (Suppl 1): 57–63.
DOI: 10.3109/00313020903305860
Superficial myofibroblastoma of the lower female genital tract in the uterine cervix showing focal pseudosarcomatous morphology Sir, A wide variety of unusual mesenchymal lesions may arise in the lower female genital tract. Among these are aggressive angiomyxoma, angiomyofibroblastoma, cellular angiofibroma and fibroepithelial stromal polyp. Accurate histological diagnosis may be due to their relative rarity and overlapping morphological features. A new entity was added in 2001, presenting as a polypoid or nodular masses arising in the superficial lamina of the cervix and vagina, and called ‘superficial cervicovaginal myofibroblastoma’ (SCVM).1 In 2005, Ganesan et al., proposed the term ‘superficial myofibroblastoma of the lower female genital tract’ instead of SCVM since some of the neoplasms had a vulvar location.2 There are only three small series that have been published in the English literature,1–3 encompassing 31 lesions. Most (26 cases) were in the vagina, while two cases were in the vulva and only three cases in the cervix. The present case is the fourth case with cervical origin. A 45-year-old woman, gravida 8, para 7, presented with a history of pelvic pain and menometorrhagia. Preoperative vaginal examination revealed an enlarged cervix, with a mass lesion clinically consistent with a cervical leiomyoma. The patient was not pregnant and did not have any significant medical conditions. The patient underwent a total abdominal hysterectomy with bilateral salpingooophorectomy. The patient was discharged to regular follow-up. There was no evidence of recurrence of the uterine cervical tumour 8 years post-surgery. On gross examination, the uterine cervix measured 9 6 8 6 4 cm in overall dimension. Serial sectioning revealed a circumscribed submucosal tumour measuring 6.5 cm in maximum diameter with a uniform, grey-white, solid, fibrous cut surface, similar in consistency to a leiomyoma. No areas of necrosis were present. Histologically, the tumour was well circumscribed but unencapsulated, and composed of alternating hypercellular and hypocellular areas of fusiform to stellate neoplastic cells (Fig. 1). The hypercellular areas were concentrated centrally within the tumour. These were foci of abrupt transformation to myxoid or oedematous areas (Fig. 2). Areas of collagenisation with wavy collagen fibres were seen, and the few fascicles of smooth muscle were present peripherally. The fusiform to stellate neoplastic cells possessed plump, oval, vesicular nuclei with inconspicuous nucleoli. Scattered multinucleated neoplastic cells and scattered neoplastic cells possessing large pleomorphic
CORRESPONDENCE
689
FIG. 1 Effect of spiked carbamazepine in serum on Abbott TDx and Abbott Axsym TCA assays.
carbamazepine solution and the corresponding blank control were plotted against carbamazepine concentration. A linear positive interference by carbamazepine was observed at concentration 4–42 mmol/L (Fig. 1). That covered its therapeutic interval of 17–51 mmol/L.2 In clinical practice, it is not infrequent to encounter patients on both carbamazepine and TCAs. Carbamazepine can cause in vivo reduction of many TCAs via stimulation of hepatic CYP3A4 activity.3 However, therapeutic monitoring for this drug interaction would be hampered by the analytical interference as observed above. Our finding is supported by a similar report describing carbamazepine causing false positive TCA results in children with epilepsy.4 That is contrary to both the Abbott TDx and Abbott Axsym package inserts claims of detectable interference at a much higher level, i.e., in the toxic range of 127 mmol/L (29 972 ng/mL). Clinically significant cross-reactivity by quetiapine on the Abbott TDx TCA assay has also been reported.5 The imprecision/inaccuracy of this assay for therapeutic monitoring of specific TCA should also be considered. Although the manufacturer claims their assay is designed for diagnosis and monitoring of TCA overdose, it has been used by some laboratories for therapeutic monitoring. This technique should be adopted with caution and guidelines must be offered to clinicians for sensible result interpretation. The limitations of the Abbott TDx TCA assay in therapeutic drug monitoring were highlighted by a study comparing high performance liquid chromatography (gold standard) versus Abbott TDx TCA assay. This study showed that the Abbott TDx TCA assay can produce satisfactory results for desipramine, imipramine, nortriptyline and trimipramine but not for other TCAs with significant over-estimation.6 David Song Weldon Chiu Department of Chemical Pathology, Labplus, Auckland City Hospital, Auckland, New Zealand
Contact Dr D. Song. E-mail: [email protected] 1. Tricyclic antidepressants—blood level measurements and clinical outcome: an APA Task Force report. Am J Psychiatry 1985; 142: 155–62. 2. Burtis C, Ashwood ER. Teitz Textbook of Clinical Chemistry. Philadelphia: WB Saunders, 1999. 3. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2005; 61: 246–55. 4. Saidinejad M, Law T, Ewald MB. Interference by carbamazepine and oxacarbazepine with serum and urine screening assays for tricyclic antidepressants. Pediatrics 2007; 120: 504–9. 5. Cerullo MA, Albertz AA, Bell JN, Anthenelli RM, Delbello MP. Tricyclic antidepressant immunoassay may reflect quetiapine adherence. Am J Psychiatry 2008; 165: 919–20. 6. Hackett LP, Dusci LJ, Ilett KF. A comparison of high-performance liquid chromatography and fluorescence polarization immunoassay for therapeutic drug monitoring of tricyclic antidepressants. Ther Drug Monit 1998; 20: 30–4.
DOI: 10.3109/00313020903305878
Antimicrobial action of atorvastatin and rosuvastatin Sir, Statins are potent lipid lowering agents, well established in the management of cardiovascular disease. Recent literature suggests these drugs may be the panacea for ill health, with reported benefits in such diverse conditions as cancer, stroke, dementia, multiple sclerosis, and sepsis.1 Plausible biological mechanisms exist for many of these potential clinical benefits and several reviews have evaluated possible mechanisms for any impact in sepsis.2,3 A recent report demonstrated a direct antimicrobial effect of simvastatin and to a lesser extent fluvastatin against methicillinsusceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA).4 If the apparent antimicrobial activity represents a class effect, we hypothesised that two other commonly used
Pathology Downloaded from informahealthcare.com by Nyu Medical Center on 01/08/15 For personal use only.
690
CORRESPONDENCE
statins, atorvastatin and rosuvastatin, may also have antimicrobial action in vitro against a variety of both Gram positive and Gram negative organisms. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of atorvastatin (pure drug obtained from Pfizer and crushed commercially available tablets) and rosuvastatin (pure drug obtained from Astra Zeneca) was determined using a microtitre plate broth dilution method, based on the method described in Wiegand et al.5 Into each well of a 96 well microtitre plate an equal volume (100 mL) of statin solution and bacterial inoculum was added to a final volume of 200 mL. The concentration of statin in adjacent wells varied using doubling dilutions. For atorvastatin the concentrations tested ranged from 0.06 mg/L to 500 mg/L. For rosuvastatin the concentrations tested were 0.024–800 mg/L. These concentrations were chosen as they included and exceeded the peak plasma concentrations in routine use. A stock solution of 2 g/L was prepared for both rosuvastatin and atorvastatin. Atorvastatin was dissolved in solvent (both methanol and ethanol stock solutions were prepared) whilst rosuvastatin was dissolved in sterile water. Stock solution was added to appropriate volumes of Mueller Hinton broth to obtain the desired final concentrations. Each statin was tested against six different American Type Culture Collection (ATCC) organisms. These were Pseudomonas aeruginosa ATCC 27853 (Pseudomonas); Escherichia coli ATCC 25922 (E. coli); Vancomycin sensitive Enterococcus faecalis ATCC 29212 (VSE); vancomycin resistant Enterococcus faecalis ATCC 51299 (VRE); methicillin susceptible Staphylococcus aureus ATCC 25923 (MSSA), methicillin resistant Staphylococcus aureus ATCC 49476 (MRSA). These organisms were stored at 7708C on Protect beads (Technical Services Consultants, UK) and reconstituted for use onto 7% horse blood agar (HBA). The organisms were incubated on HBA at 358C for 24 h to check for purity and viability before use. A final inoculum density of 5 6 105 colony-forming units (CFU)/mL was achieved using serial dilutions of a 0.5 McFarland standard (1.5 6 108 CFU/mL). Growth, broth sterility and matched solvent controls were included on every microtitre plate. Each plate was repeated in triplicate. After incubation overnight at 358C, the presence of visible turbidity or sediment in the wells indicated growth of the organism. The MIC was defined as the lowest concentration of statin that prevented visible growth. As each microtitre plate was repeated in triplicate, the lowest concentration of statin across all three plates was deemed to be the MIC. To determine the MBC, subcultures were obtained from each well and inoculated on to HBA plates. The plates were incubated overnight at 358C and the MBC was determined as the lowest concentration of statin that prevented growth on all three HBA plates. Our results demonstrate that both rosuvastatin and atorvastatin in vitro have some bacteriostatic activity (Fig. 1). The MIC of pure atorvastatin-ethanol was 250 mg/L against MSSA, MRSA, VSE, VRE, E. coli and Pseudomonas. Subcultures from these wells demonstrated growth of all six bacterial strains, suggesting that this was a bacteriostatic rather than bactericidal effect. The higher concentration of 500 mg/L pure atorvastatin in ethanol
Pathology (2009), 41(7), December
FIG. 1 The MIC for atorvastatin (pure drug) and rosuvastatin (pure drug) against all six organisms tested. These were Escherichia coli (Ecoli), Pseudomonas aeruginosa (Pseud), methicillin susceptible Staphylococcus aureus (MSSA), methicillin resistant Staphylococcus aureus (MRSA), vancomycin sensitive Enterococcus faecalis (VSE) and vancomycin resistant Enterococcus faecalis (VRE).
12.5% was bactericidal against E. coli and Pseudomonas but growth was detected for all Gram positive organisms tested. The crushed atorvastatin-methanol showed no inhibition of growth for Pseudomonas or E. coli at any concentration tested. MSSA had an MIC of 250 mg/L (12.5% methanol) and VSE had an MIC of 500 mg/L (25% methanol). No bactericidal effect was detected for any Gram positive or Gram negative organisms at the concentrations tested. Pure rosuvastatin was dissolved in water and showed an MIC of 100 mg/L against all six organisms. Rosuvastatin showed no bactericidal activity in vitro against any of the organisms studied at all concentrations up to 800 mg/L. Both ethanol and methanol controls demonstrated some bacteriostatic and bactericidal effects on all organisms tested. Ten percent ethanol was bactericidal against E. coli and Pseudomonas whilst 15% ethanol was bactericidal for MSSA and VSE. Better growth was observed for all organisms in methanol controls with an MBC of 15% for Pseudomonas, 25% for E. coli, 35% for MSSA and 50% for VSE. For atorvastatin dissolved in ethanol, the solvent is not responsible for the bacteriostatic effect as the percentage of ethanol in atorvastatin 250 mg/L (6.25%) is lower than the solvent control MIC against all organisms tested. However, solvent controls showed significant bactericidal effects. The observed MBCs for atorvastatin in ethanol or methanol could be explained by solvent bactericidal effect. Our study demonstrates that methanol has less impact on bacterial growth than ethanol and therefore would be the solvent of choice for further studies evaluating antibacterial properties in lipid soluble statin agents. This study suggests the observed antimicrobial effect of both atorvastatin and rosuvastatin is bacteriostatic rather than bactericidal. The MICs obtained in this study are considerably higher than those previously described for simvastatin in methanol against MSSA and MRSA.4 Both atorvastatin and rosuvastatin are fully synthetic compounds and previous authors have suggested that because simvastatin is derived from fungi it may contain more inherent antibacterial activity.4 Our results suggest the synthetic compounds do possess some antimicrobial
Pathology Downloaded from informahealthcare.com by Nyu Medical Center on 01/08/15 For personal use only.
CORRESPONDENCE
properties although a molecular basis for the antibacterial action it not currently known. The MIC of crushed atorvastatin tablets yielded results different to those seen with pure drug. No inhibition of Gram negative organisms and a higher MIC (500 mg/L) against VSE was seen with crushed tablet preparation. This may reflect the potential for loss of drug in the mortar and pestle reflecting the difficulty in preparing accurate stock solution concentrations when compared to using pure drug in a fine powdered form, or an interaction or dilution effect of the filler used to stabilise the tablets. The MICs achieved in this study far exceed the typical peak plasma concentration of statins when used to lower cholesterol and would preclude systemic usage as antimicrobial agents. For pure atorvastatin the MIC of 250 mg/L is 25 000-fold higher than a typical peak plasma concentration of 0.01 mg/L. For pure rosuvastatin the MIC of 100 mg/L is 2700-fold higher than a typical peak plasma concentration of 0.037 mg/L. A recent report investigating topical simvastatin application in an animal model of infected skin wound healing demonstrated a reduced bacterial load and improved healing.6 It is interesting to speculate that a topical preparation at these higher concentrations may have antibacterial effects and warrants further investigation. This study demonstrates that statins have a reproducible bacteriostatic effect in vitro. This may be a class effect as antimicrobial activity has now been demonstrated for atorvastatin, rosuvastatin, simvastatin and fluvastatin, a combination of fully synthetic and fungal derived drugs. This effect is probably not relevant in current clinical practice as the high concentrations required to achieve a reliable antimicrobial effect are well above those achieved in routine use to lower cholesterol. Anne-Marie Welsh* Peter Kruger*{ Joan Faoagali{ Departments of *Intensive Care and {Microbiology, Princess Alexandra Hospital, Woolloongabba, Brisbane, and {University of Queenland, Brisbane, Queensland, Australia Contact Dr P. Kruger. E-mail: [email protected] ACKNOWLEDGEMENTS We would like to thank Mrs S. Kleinschmidt for her invaluable assistance in the laboratory. This work was supported in part by a grant from Princess Alexandra Hospital Foundation. Pure compound was kindly supplied by the manufacturers, Pfizer (atorvastatin) and Astra Zeneca (rosuvastatin). Neither company had any role in the experimental design, performance of the study or analysis of results.
1. Kruger PS, Kostner K, Venkatesh B. Statins in critical illness. In: Vincent JL, editor. Yearbook of Intensive Care and Emergency Medicine. Berlin: Springer Verlag, 2005; 477–87. 2. Kruger PS. Statins: the next anti-endotoxin. Crit Care Resusc 2006; 8: 223–6. 3. Terblanche M, Almog Y, Rosenson RS, et al. Statins and sepsis: multiple modifications at multiple levels. Lancet Infect Dis 2007; 7: 358– 68.
691
4. Jerwood S, Cohen J. Unexpected antimicrobial effect of statins. J Antimicrob Chemother 2008; 61: 362–4. 5. Wiegand I, Hilpert K, Hancock RE. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat Protoc 2008; 3: 163–75. 6. Rego AC, Araujo Filho I, Damasceno BP, et al. Simvastatin improves the healing of infected skin wounds of rats. Acta Cir Bras 2007; 22 (Suppl 1): 57–63.
DOI: 10.3109/00313020903305860
Superficial myofibroblastoma of the lower female genital tract in the uterine cervix showing focal pseudosarcomatous morphology Sir, A wide variety of unusual mesenchymal lesions may arise in the lower female genital tract. Among these are aggressive angiomyxoma, angiomyofibroblastoma, cellular angiofibroma and fibroepithelial stromal polyp. Accurate histological diagnosis may be due to their relative rarity and overlapping morphological features. A new entity was added in 2001, presenting as a polypoid or nodular masses arising in the superficial lamina of the cervix and vagina, and called ‘superficial cervicovaginal myofibroblastoma’ (SCVM).1 In 2005, Ganesan et al., proposed the term ‘superficial myofibroblastoma of the lower female genital tract’ instead of SCVM since some of the neoplasms had a vulvar location.2 There are only three small series that have been published in the English literature,1–3 encompassing 31 lesions. Most (26 cases) were in the vagina, while two cases were in the vulva and only three cases in the cervix. The present case is the fourth case with cervical origin. A 45-year-old woman, gravida 8, para 7, presented with a history of pelvic pain and menometorrhagia. Preoperative vaginal examination revealed an enlarged cervix, with a mass lesion clinically consistent with a cervical leiomyoma. The patient was not pregnant and did not have any significant medical conditions. The patient underwent a total abdominal hysterectomy with bilateral salpingooophorectomy. The patient was discharged to regular follow-up. There was no evidence of recurrence of the uterine cervical tumour 8 years post-surgery. On gross examination, the uterine cervix measured 9 6 8 6 4 cm in overall dimension. Serial sectioning revealed a circumscribed submucosal tumour measuring 6.5 cm in maximum diameter with a uniform, grey-white, solid, fibrous cut surface, similar in consistency to a leiomyoma. No areas of necrosis were present. Histologically, the tumour was well circumscribed but unencapsulated, and composed of alternating hypercellular and hypocellular areas of fusiform to stellate neoplastic cells (Fig. 1). The hypercellular areas were concentrated centrally within the tumour. These were foci of abrupt transformation to myxoid or oedematous areas (Fig. 2). Areas of collagenisation with wavy collagen fibres were seen, and the few fascicles of smooth muscle were present peripherally. The fusiform to stellate neoplastic cells possessed plump, oval, vesicular nuclei with inconspicuous nucleoli. Scattered multinucleated neoplastic cells and scattered neoplastic cells possessing large pleomorphic