Biomedical subjects
Publications and source records attributed to A P Wilson.
Falciparum malaria can cause immune suppression sufficient to allow opportunistic infection during the recovery phase. A patient is described who died from a disseminated infection with Aspergillus flavus and Absidia corymbifera, unresponsive to treatment with amphotericin and voriconazole.
Sitafloxacin is a new quinolone active against multi-resistant Gram-positive pathogens. An open study was conducted in patients with serious systemic infections with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococcus (VRE). Patients with MRSA were recruited if treatment with glycopeptides had failed. Of 11 patients with MRSA infection, four were cured, six failed treatment and one was indeterminate. Of nine patients with VRE infection (one patient had both pathogens), five were cured and four failed. Fifteen adverse events in 12 patients were potentially related to the study drug. Sitafloxacin was effective in VRE and some recalcitrant MRSA infections.
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The glycopeptide antibacterial teicoplanin has become increasingly popular in the last decade with the rise in infections related to methicillin-resistant Staphylococcus aureus. Teicoplanin has 6 major and 4 minor components. It is predominantly (90%) bound to plasma proteins. Of the several methods available to measure concentrations in serum, fluorescence polarisation immunoassay has high reliability and specificity. Teicoplanin is not absorbed orally, but intravenous and intramuscular administration are well tolerated. Teicoplanin is eliminated predominantly by the kidneys and only 2 to 3% of an intravenously administered dose is metabolised. Total clearance is 11 ml/h/kg. Steady state is reached only slowly, 93% after 14 days of repeated administration. Elimination is triexponential, with half-lives of 0.4 to 1.0, 9.7 to 15.4 and 83 to 168 hours. Volumes of distribution are 0.07 to 0.11 (initial phase), 1.3 to 1.5 (distribution phase) and 0.9 to 1.6 (steady state) L/kg. A standard dosage regimen of 6 mg/kg every 12 hours for 3 doses, then daily, will produce therapeutic serum concentrations of > or = 10 mg/L in most patients. Higher dosages may be required in certain patients, for example intravenous drug abusers or those with burns, because of unpredictable clearance. Concentrations in bone reach 7 mg/L at 12 hours after a dose of teicoplanin 6 mg/kg, but reach only 3.5 mg/L in the cartilage. Doses of 10 mg/kg are necessary to achieve adequate bone concentrations. There is little penetration into cerebrospinal fluid or the aqueous or vitreous humour. In fat, concentrations may be subtherapeutic (0.5 to 5 mg/L) after a dose of 400mg. A single prophylactic dose of 12 mg/kg is sufficient to maintain therapeutic concentrations during cardiopulmonary bypass or burns surgery. High loading doses reduce the delay to attaining therapeutic concentrations. Premature neonates require a loading dose of 15 mg/kg and a maintenance dosage of 8 mg/kg daily to ensure therapeutic serum concentrations. Children need loading with 10 mg/kg every 12 hours for 3 doses followed by maintenance with 10 mg/kg/day. Clearance is reduced predictably in renal failure, and dosage adjustments can be based on the ratio of impaired clearance to normal clearance. In patients on haemodialysis, 3 loading doses of 6 mg/kg at 12-hour intervals followed by maintenance doses every 72 hours produced trough plasma concentrations of 8 mg/L in most patients at 48 hours. The monitoring of serum concentrations is not necessary to avoid toxicity, but can be helpful in certain patient groups to ensure therapeutic concentrations are present, especially in those not responding to treatment.
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Intraoperative bacteraemia has been used as an indicator of the efficacy of prophylactic antibiotics. Two clinical isolates of Staphylococcus aureus in nutrient broth, with or without human serum, were exposed to teicoplanin (50 mg/L) and, either immediately or after 30 min, inoculated into blood culture bottles. Bottles with and without resin were used and the experiment was repeated five times with one strain. In the absence of teicoplanin, an inoculum of 10 cfu/mL produced growth in both resin and non-resin bottles. In the presence of teicoplanin, an inoculum of at least 10(5) cfu/mL was required in non-resin bottles to obtain growth, but this was reduced to 10(2)-10(3) cfu/mL for resin bottles. Intraoperative blood cultures overestimate the efficacy of bacterial killing by prophylactic antibiotics during surgery.
Improvements in the treatment of compromised patients have resulted in their prolonged survival in a debilitated state. Patients have repeated courses of antibiotics and become colonised with multiresistant pathogens during a stay in the intensive care unit. Surgical wound infections can then be very difficult to treat. Methicillin-resistant Staphylococcus aureus is now common although wide variations in prevalence exist between countries and regions. Klebsiella spp with multiple resistance is a common cause of septicemia and can be associated with cephalosporin use. Acinetobacter spp and vancomycin-resistant enterococci can cause infections resistant to all readily available antibiotics. The prevalence of infection with each of these pathogens is increasing. Control measures should include hand washing, universal precautions for infection control, source isolation, restrictive antibiotic policy and antibiotic rotation. Although new agents currently in trials may be effective in the long term, the future for antibiotic treatment or prophylaxis of surgical infections is in doubt.
Accurate information on the prevalence of surgical wound infection is difficult to obtain; outpatient follow-up is often inadequate. For two months in 1993 and again in 1995, surgical wounds throughout one hospital were examined by the same observer with the intention of comparing different methods for assessing wound infection. Two standard definitions [Centers for Disease Control (CDC), USA and National Prevalence Survey (NPS), UK] were compared with ASEPSIS and the Southampton method. In 1993, 325 wounds in 230 patients were examined with follow-up of 203 (88%) patients. In 1995, 559 wounds were surveyed in 375 patients with follow-up in 364 (97%). Patient groups in the two years were similar. ASEPSIS identified 92 (13%) wounds as having scored over 20 points indicating infection, and another 16.5% having disturbance of healing. There was no significant difference between the two surveys. The two scoring methods were more sensitive than the standard definitions but CDC and NPS did not differ significantly from each other. Between 44 and 47% of clean wounds identified as infected by standard definitions were classed as disturbance of healing by ASEPSIS. All methods were labour-intensive and to implement any one of them on a regular basis would require a full-time investigator. The first surveillance program with feedback of results to the surgeons did not significantly affect the rates two years later.
Teicoplanin have different safety profiles which can affect choice. Nephrotoxicity is significantly less likely to occur during treatment with teicoplanin than vancomycin when an aminoglycoside is being given concurrently. 'Red man' syndrome is a troublesome effect of vancomycin infusion which is extremely uncommon with teicoplanin use. Rash and fever can be dose-related phenomena but patients reacting to one glycopeptide may not react to both. Although thrombocytopenia is more frequent with teicoplanin, it is reversible and seldom seen at standard doses.
To determine if ovarian cancer patients would be suitable for MAGE-peptide vaccine-based immunotherapy, the frequency of expression of the MAGE-1-4 genes in ovarian tumours was assessed using reverse transcription polymerase chain reaction (RT-PCR) and product verification with digoxigenin-labelled oligonucleotide probes specific for each MAGE gene. In addition, the frequency of expression of more recently discovered tumour antigens (BAGE, GAGE -1, -2 and GAGE -3, -6) was established using RT-PCR and ethidium bromide staining. In this study 1/16 normal ovarian tissue specimens and 11/25 benign lesions expressed MAGE-1. In non-malignant tissue there was preferential expression of MAGE-1 in premenopausal women. A total of 15/27 malignant specimens expressed MAGE-1, including 10/14 serous cystadenocarcinomas. Expression of other tumour antigens was infrequent. The finding of MAGE-1 expression in both benign and malignant tissue questions previous assumptions regarding the role of MAGE genes in carcinogenesis. In addition, preferential MAGE-1 gene expression in non-malignant premenopausal tissue suggests that the MAGE genes may be involved in cellular proliferation as opposed to carcinogenesis or possibly that MAGE gene expression is under cyclical hormonal control. Finally, this study indicates that serous cystadenocarcinomas may be suitable tumours for MAGE-1 peptide immunotherapy.
BACKGROUND: Clinical deterioration after burn wound manipulation may be related to the release of cytokines including tumour necrosis factor-alpha (TNF) and interleukin-6 (IL-6). METHODS: The two cytokines were assayed by immunoenzymetric assay in blood samples taken before and during manipulation of the burn wound. An antibiotic, teicoplanin, was administered to half the patients at the start of the procedure in a randomized fashion as part of a separate trial. FINDINGS: Sixty patients with a median burn size of 8% (range 1-56%) were studied during dressing change (n = 40) or burn excision (n = 20). There was little change in TNF levels between preoperative and recovery samples but IL-6 concentrations increased three-fold, particularly in those with large recent burns or bacteraemia, and were correlated with poor clinical outcome. The presence of teicoplanin did not significantly affect the levels of either cytokine. INTERPRETATION: The systemic cytokine response to burn wound dressing or debridement is predominantly that of IL-6 and it is not significantly reduced by preventing Gram-positive bacteraemia during the procedure.
Attachment of coagulase-negative staphylococci to plastic surfaces by means of hydrophobic interaction and slime production may be important in producing catheter associated infections. In continuous ambulatory peritoneal dialysis (CAPD), the relationship between these properties and disease is unclear and the effect of dialysate fluid is not considered. For a collection of coagulase-negative staphylococci from CAPD patients, slime production and adherence were measured by colorimetric methods and hydrophobicity was determined by autoaggregation in ammonium sulphate solution. Comparison of 73 nasal isolates with 69 isolates from peritonitis showed no significant differences with respect to three properties, with the exception of a greater adherence of peritoneal isolates in dialysate because of a greater proportion of staphylococcal species other than Staphylococcus epidermidis. Fewer strains showed adherence in dialysate (12/142 8.5%) than in broth (94/142 66%) but the proportion of strains producing slime was similar. The milieu of the bacteria rather than the organisms themselves may be of greater importance in the establishment of infection.
Exit site infection is a major risk factor for the development of peritonitis in continuous ambulatory peritoneal dialysis. The frequency of infection can be reduced by scrupulous exit site care with or without topical antiseptics. A randomized trial was performed of 149 catheters in 130 patients to assess any additional benefits conferred by the use of povidine iodine dry powder spray at dressing changes over an existing strict protocol of exit care. Exit infections occurred in 14 (18%) of 77 patients using spray and in 15 (21%) of 72 patients not using spray. The risk of peritonitis was also similar in each group. The proportion of infections caused by Staphylococcus aureus was reduced in the spray group, but those caused by Pseudomonas aeruginosa were increased. Rash occurred in 6% of those using the spray. The use of the spray did not therefore seem justified.
Antibiotic treatment of patients developing infection after burns is principally based on experience with other surgical patients. Few comparative trials have been performed in burns patients despite the altered pharmacokinetics of antibiotics and the high incidence of Gram-positive infection in the first week. A randomized trial was performed to compare the cure rates of presumed Gram-positive infection in burns patients given teicoplanin (6 mg/kg every 12 h for three doses then daily) or flucloxacillin (1 g every 6 h i.v./p.o.). Both groups received gentamicin if additional Gram-negative infection was thought likely. A total of 64 patients were entered into the study representing 65 episodes of treatment of which 55 were completed. Clinical success was achieved in 22 (73%) of 30 evaluable patients given teicoplanin and in 21 (68%) of 31 evaluable patients given flucloxacillin (not significant). Of 51 patients assessable for bacteriological efficacy, clearance was achieved in 15 (63%) of 24 patients given teicoplanin and in 15 (56%) of 27 patients given flucloxacillin (not significant). Serum trough concentrations of teicoplanin were 9 mg/L in five patients at the steady state. Adverse events were recorded in 15 (48%) of episodes in the teicoplanin group and in 14 (41%) of episodes in the flucloxacillin group. Teicoplanin demonstrated similar efficacy and safety to flucloxacillin with or without gentamicin.
The bactericidal activities of teicoplanin and flucloxacillin in a 50:50 mixture of human serum and Iso-sensitest broth were compared in an in-vitro pharmacokinetic model, at serum concentrations present during surgical prophylaxis. The bactericidal activity of teicoplanin with and without serum was also compared. Six strains of Staphylococcus aureus were tested. The bactericidal rate of teicoplanin in serum was significantly lower than the rate in broth alone. However, there was no significant difference in the bactericidal rates in serum of teicoplanin compared with flucloxacillin, an antibiotic which is commonly used as prophylaxis for certain surgical procedures.
BACKGROUND: Burn wound surgery or change of dressings commonly causes bacteraemia. The use of antibiotic prophylaxis has not been tested adequately in a controlled trial. METHODS: A randomized double-blind placebo-controlled study was performed to determine the effect on Gram-positive bacteraemia and clinical outcome of a single dose of teicoplanin (12 mg/kg intravenously) given at burns surgery or change of dressings. RESULTS: A total of 134 patients were entered into the study, representing 220 episodes of dressing or debridement (110 episodes in each group). There was a significant difference between the groups with respect to perioperative Gram-positive bacteraemia: eight episodes (7 per cent) in the teicoplanin group versus 51 (46 per cent) in the placebo group (P < 0.001). However, good clinical outcome was similar in both groups (80 of 110 versus 77 of 110 respectively, P = 0.7). Only eleven patients had bacteraemia caused by Gram-negative species alone. Bacteriological response in terms of wound culture showed no significant difference between the groups: 63 (57 per cent) of 110 episodes versus 58 (53 per cent) of 110 respectively respectively. CONCLUSION: Prevention of Gram-positive bacteraemia did not affect postoperative recovery.
We have investigated the capacity of N- and C-terminally truncated and chimeric human (h) IgE-derived peptides to inhibit the binding of 125I-labeled hIgE, and to engage cell lines expressing high and low affinity receptors (Fc-epsilon-RI/II). The peptide sequence Pro343-Ser353 of the hC-epsilon-3 domain is common to all h-epsilon-chain peptides that recognize hFc-epsilon-RI. This region in IgE is homologous to the A loop in C-gamma-2 that engages the rat neonatal IgG receptor. Optimum Fc-epsilon-RI occupancy by hIgE occurs at pH 6.4, with a second peak at 7.4. N- or C-terminal truncation has little effect on the association rate of the ligands with this receptor. Dissociation markedly increases following C-terminal deletion, and hFc-epsilon-RI occupancy at pH 6.4 is diminished. His residue(s) in the C-terminal region of the epsilon-chain may thus contribute to the high affinity of interaction. Grafting the homologus rat epsilon-chain sequence into hIgE maintains hFc-epsilon-RI interaction without conferring binding to rat Fc-epsilon-RI. hFc-epsilon-RII interaction is lost, suggesting that these residues also contribute to hFc-epsilon RII binding. h-epsilon-chain peptides comprising only this sequence do not block hIgE/hFc-epsilon-RI interaction or engage the receptor. Therefore, sequences N- or C-terminal to this core peptide provide structures necessary for receptor recognition.