Role of novel hormonal therapies in the management of non-metastatic castration-resistant prostate cancer: a literature-based meta-analysis of randomized trials.

BACKGROUND: Novel hormonal therapies have been recently investigated in non-metastatic castration-resistant prostate cancer (CRPC). We performed a meta-analysis to assess the efficacy and safety of novel hormonal therapies in non-metastatic CRPC. MATERIALS AND METHODS: The primary outcome was metastasis-free survival (MFS). The secondary endpoints were overall survival (OS), time to PSA progression and safety. We planned a subgroup analysis according to the PSA doubling time (> 6 vs < 6 months), Eastern Cooperative Oncology Group (ECOG) performance status (1 vs 0) and concomitant use of bone-targeting agent (yes vs no). RESULTS: Pooled analysis of novel hormonal therapies revealed significantly increased MFS compared with placebo (hazard ratio (HR): HR = 0.32, 95% CI 0.25-0.41; p < 0.00001). The subgroup analysis showed a statistically significant MFS advantage in favour of men with the lower ECOG performance status. Other secondary endpoints favoured the novel hormonal therapies. The relative risk (RR) of grade ≥ 3 adverse events and ≥ 3 hypertension was 1.31 and 1.39, respectively. CONCLUSIONS: This study confirmed the efficacy and safety of the novel hormonal therapies in non-metastatic CRPC.

Nanoparticle albumin-bound paclitaxel: a big nano for the treatment of gastric cancer.

Gastric cancer (GC) is the third cause of cancer-related death worldwide. Patients with unresectable GC can be treated with chemotherapy such as paclitaxel, which is a microtubule stabilizer. The use of nanoparticle albumin-bound paclitaxel (nab-ptx) avoids hypersensitivity reactions due to the absence of solvent needed to dissolve paclitaxel and it can be administered at higher doses. The ABSOLUTE randomized phase-3 clinical trial showed the non-inferiority of the nab-ptx used every week compared to the solvent-based paclitaxel used every week. This review describes the current advancements of the use of nab-ptx in GC in preclinical and clinical study investigations. The possibility of combining nab-ptx with other medications to improve response of patients to their specific molecular needs will also be debated.

Transcriptional subtyping and CD8 immunohistochemistry identifies poor prognosis stage II/III colorectal cancer patients who benefit from adjuvant chemotherapy.

PURPOSE: Transcriptomic profiling of colorectal cancer (CRC) has led to identification of four consensus molecular subtypes (CMS1-4), which have prognostic value in stage II/III disease. More recently, the Colorectal Cancer Intrinsic Subtypes (CRIS) classification system has helped to define the biology specific to the epithelial component of colorectal tumors. However, the clinical value of these classifications in predicting response to standard-of-care adjuvant chemotherapy remains unknown. PATIENTS AND METHODS: Using samples from 4 European sites, we assembled a novel stage II/III CRC patient cohort and performed transcriptomic profiling on 156 samples, targeted sequencing and generated a tissue microarray to enable integrated "multi-omics" analyses. We also accessed data from 2 published stage II/III CRC patient cohorts: GSE39582 and GSE14333 (479 and 185 samples respectively). RESULTS: The epithelial-rich CMS2 subtype of CRC benefitted significantly from adjuvant chemotherapy treatment in both stage II and III disease (p=0.02 and p<0.0001 respectively), while the CMS3 subtype significantly benefitted in stage III only (p=0.00073). Following CRIS sub-stratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from adjuvant chemotherapy in stage II and III disease (p=0.0081 and p<0.0001 respectively), while CRIS-D significantly benefitted in stage III only (p=0.0034). We also observed that CRIS-C patients with low levels of CD8+ tumor-infiltrating lymphocytes were most at risk of relapse in both stage II and III disease (p=0.0031). CONCLUSION: Patient stratification using a combination of transcriptional subtyping and CD8 immunohistochemistry analyses is capable of identifying poor prognostic stage II/III patients who benefit from adjuvant standard-of-care chemotherapy. These findings are particularly relevant for stage II disease, where the overall benefit of adjuvant chemotherapy is marginal.

Association of the HLA-G 3'UTR polymorphisms with colorectal cancer in Italy: a first insight.

This study aimed to explore functional and regulatory polymorphisms and haplotypes at the HLA-G 3'UTR region in colorectal cancer development. The presence of nonpolymorphic variants was also evaluated. Three-hundred and eight patients with colorectal cancer and 294 healthy controls were analysed at the germinal level. We found an association with increased risk of colorectal cancer for +2960 14-bp INDEL, +3196 C>G SNPs and UTR-2 haplotype, and a 'protective' role for +3003 T>C, +3010 C>G polymorphisms and UTR-4 haplotype. We detected in 3 distinct patients, a novel nucleotide change (+3037 C>A) and 2 already described rare variants, +3032 G/C (EUR MAF = 0.1%) and +3092 G/T (EUR MAF = 0%). This is the first study showing associations between different polymorphisms in the HLA-G 3'UTR and colorectal cancer susceptibility.

MTHFR-1298 A>C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin.

Adjuvant treatment based on fluoropyrimidines (FL) improves the prognosis of stage II/III colorectal cancer (CRC). Validated predictive/prognostic biomarkers would spare therapy-related morbidity in patients with a good prognosis. We compared the impact of a set of 22 FL-related polymorphisms with the prognosis of two cohorts of CRC patients treated with adjuvant FL with or without OXA, including a total of 262 cases. 5,10-Methylentetrahydrofolate reductase (MTHFR) MTHFR-1298 A>C (rs1801131) polymorphism had a concordant effect: MTHFR-rs1801131-1298CC genotype carriers had a worse disease free survival (DFS) in both the cohorts. In the pooled population MTHFR-rs1801131-1298CC carriers had also a worse overall survival. We computed a clinical score related to DFS including MTHFR-rs1801131, tumor stage, sex and tumor location, where rs1801131 is the most detrimental factor (hazard ratio=5.3, 95% confidence interval=2.2-12.9; P-value=0.0006). MTHFR-rs1801131 is a prognostic factor that could be used as an additional criteria for the choice of the proper adjuvant regimen in stage II/III colorectal cancer patients.

Prognostic factors in primary and iterative surgery of colorectal liver metastases.

The aim of this study was to evaluate the results of surgery of colorectal liver metastases and assess prognostic factors influencing the outcome. A total of 135 hepatic resections performed in 107 patients was reviewed. The following prognostic factors were analyzed: primary tumor localization, Dukes stage, number and presence of metastases in one or two lobes, synchronous or metachronous occurrence, type of resection, use and modality of chemotherapy. The perioperative morbidity rate was 6.5% and mortality was 1.9%. Overall survival was 41.2% and disease-free survival 31.5% at 5 years. Survival at 5 years was better for patients with metachronous than for those with synchronous lesions (60.9% vs 28.1%; p<0.05). There were no significant differences in terms of long-term survival between patients with synchronous metastases that were excised simultaneously or with a delay of 3-6 months (p=n.s.). Site of the primary tumor, Dukes stage, number of metastases and type of resection did not influence survival. A favorable survival trend was observed in those patients who underwent both neoadjuvant and adjuvant chemotherapy. The overall survival rate at 5 years was 45.3% for patients undergoing a second hepatic resection and 50% for those with a third or a fourth hepatic resection. Liver resection remains the "gold standard" for the treatment of patients with colorectal liver metastases, with metachronous type having a better outcome than synchronous. Simultaneous or delayed surgery for synchronous metastases does not influence prognosis. Iterative resection is very encouraging and justifies an aggressive surgical approach.

Bimonthly chemotherapy with oxaliplatin, irinotecan, infusional 5-fluorouracil/folinic acid in patients with metastatic colorectal cancer pretreated with irinotecan- or oxaliplatin-based chemotherapy.

This study was conducted to assess the tolerability and efficacy of a ternary bimonthly irinotecan (CPT-11) - oxaliplatin (OHP) - infusional 5-fluorouracil (5-FU)/folinic acid (FA) combination in advanced colorectal cancer patients who had received prior CPT-11 and/or OHP-based chemotherapy regimen. Colorectal cancer patients were given bimonthly CPT-11 as a 90-min infusion, followed by OHP (85 mg/m(2)), FA (200 mg/m(2)) 2-h infusions and 5-FU (48-h infusion). CPT-11 and 5-FU doses were escalated as reported below. 26 patients were recruited. Fourteen patients had received a prior CPT-11-, 6 patients a prior OHP-based chemotherapy regimen and 6 patients both regimens. Three dose levels were investigated: CPT-11 100, 120 and 140 mg/m(2) and 5-FU 1500, 1800 and 2100 mg/m(2) in 6, 12 and 8 patients, respectively. All patients were evaluable for toxicity, 24 for antitumor activity. At all dose levels toxicity was acceptable. Grade 4 toxicity occurred in two patients only (neutropenia in one case and stomatitis in another one, 3.8%). Grade 3 toxicities included nausea and vomiting (34.6%), asthenia (26.9%), neurosensory toxicity (15.4%), neutropenia (3.8%) and diarrhea (3.8%). Hematological toxicity was infrequent and generally mild. At the third dose level, a higher, although not significantly different incidence of hematological and neurosensory toxicity (both occurring in 62.5% of cases, all grades) was observed compared to the other two, while nausea and vomiting were significantly less frequent (37.5% vs 100%). Overall, we observed 2 complete responses, 9 partial responses (OR 45.8%), 8 stable disease (33.3%), and 5 disease progression (20.8%). Median overall survival was 18 months and median time-to-progression 5.5 months. This combination showed moderate toxicity and promising antitumor activity in CPT-11 and/or OHP pretreated colorectal cancer patients. The second dose level using CPT-11 at 120 mg/m(2) and 5-FU at 1800 mg/m(2) is recommended for further phase II studies in this patient population.

Postoperative chemotherapy in resected gastric cancer: results of a single center experience.

Gastric cancer remains a major health problem despite its decline in incidence in Western countries. Although radical surgery represents the primary curative option for gastric cancer patients, most of them relapse and die due to their disease despite an R0 resection. At present the routine use of postoperative adjuvant therapy to reduce disease recurrence is still considered an investigational approach. Out of a total of 275 patients (stage IB through IV M0 AJCC/UICC) who underwent surgery for gastric cancer at our Surgery Unit between 1993 and 2001, 156 were eligible for adjuvant chemotherapy, of whom only 52 accepted to undergo this treatment. This group of patients was retrospectively compared with a control group (1:2) and overall survival was assessed using hazard ratio and Kaplan-Meier estimates. Five-year survival was 40% in the chemotherapy group and 37.8% in the group which underwent surgery alone. Indeed, chemotherapy did not reduce the risk of death (HR 0.87, 95% CI = 0.57-1.34, p=0.54). Serosal involvement and the invasion of more than 6 lymph nodes were the main independent prognostic factors identified by multivariate analysis. The current study did not show a clear advantage of chemotherapy over surgery alone. However, our results can help to define strategies for future clinical trials with the use of new regimens based on more effective and less toxic drugs.

Pharmacological strategies for overcoming multidrug resistance.

Multidrug resistance (MDR) is a major obstacle to the effective treatment of cancer. One of the underlying mechanisms of MDR is cellular overproduction of P-glycoprotein (P-gp) which acts as an efflux pump for various anticancer drugs. P-gp is encoded by the MDR1 gene and its overexpression in cancer cells has become a therapeutic target for circumventing multidrug resistance. A potential strategy is to co-administer efflux pump inhibitors, although such reversal agents might actually increase the side effects of chemotherapy by blocking physiological anticancer drug efflux from normal cells. Although many efforts to overcome MDR have been made using first and second generation reversal agents comprising drugs already in current clinical use for other indications (e.g. verapamil, cyclosporine A, quinidine) or analogues of the first-generation drugs (e.g. dexverapamil, valspodar, cinchonine), few significant advances have been made. Clinical trials with third generation modulators (e.g. biricodar, zosuquidar, and laniquidar) specifically developed for MDR reversal are ongoing. The results however are not encouraging and it may be that the perfect reverser does not exist. Other approaches to multidrug resistance reversal have also been considered: encapsulation of anthracyclines in liposomes or other carriers which deliver these drugs selectively to tumor tissues, the use of P-gp targeted antibodies such as UIC2 or the use of antisense strategies targeting the MDR1 messenger RNA. More recently, the development of transcriptional regulators appears promising. Also anticancer drugs that belong structurally to classes of drugs extruded from cells by P-gp but that are not substrates of this drug transporter may act as potent inhibitors of MDR tumors (e.g. epothilones, second generation taxanes). Taking advantage of MDR has also been studied. Bone marrow suppression, one of the major side effects of cancer chemotherapy, can compromise the potential of curative and palliative chemotherapy. It is conceivable that drug resistance gene transfer into bone marrow stem cells may be able to reduce or abolish chemotherapy-induced myelosuppression and facilitate the use of high dose chemotherapy. Clinical trials of retroviral vectors containing drug resistance genes have established that the approach is safe and are now being designed to address the therapeutically relevant issues.

Cellular pharmacology of gemcitabine.

Gemcitabine (2',2'-difluoro 2'-deoxycytidine, dFdC) is the most important cytidine analogue developed since cytosine arabinoside (Ara-C). The evidence of its potent antitumor activity in a wide spectrum of in vitro and in vivo tumor models has been successfully confirmed in the clinical setting. Despite structural and pharmacological similarities to Ara-C, gemcitabine displays distinctive features of cellular pharmacology, metabolism and mechanism of action. Following influx through the cell membrane via nucleoside transporters, gemcitabine undergoes complex intracellular conversion to the nucleotides gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP) responsible for its cytotoxic actions. The cytotoxic activity of gemcitabine may be the result of several actions on DNA synthesis. dFdCTP competes with deoxycytidine triphosphate (dCTP) as an inhibitor of DNA polymerase. dFdCDP is a potent inhibitor of ribonucleoside reductase, resulting in depletion of deoxyribonucleotide pools necessary for DNA synthesis and, thereby potentiating the effects of dFdCTP. dFdCTP is incorporated into DNA and after the incorporation of one more nucleotide leads to DNA strand termination. This extra nucleotide may be important in hiding the dFdCTP from DNA repair enzymes, as incorporation of dFdCTP into DNA appears to be resistant to the normal mechanisms of DNA repair. Gemcitabine can be effectively inactivated mainly by the action of deoxycytidine deaminase to 2,2'-difluorodeoxyuridine. Also, 5'-nucleotidase opposes the action of nucleoside kinases by catalysing the conversion of nucleotides back to nucleosides. Additional sites of action and self-potentiating effects have been described. Evidence that up- or down-regulation of the multiple membrane transporters, target enzymes, enzymes involved in the metabolism of gemcitabine and alterations in the apoptotic pathways may confer sensitivity/resistance to this drug, has been provided in experimental models and more recently also in the clinical setting. Synergism between gemcitabine and several other antineoplastic agents has been demonstrated in experimental models based on specific pharmacodynamic interactions. Knowledge of gemcitabine cellular pharmacology and its molecular mechanisms of resistance and drug interaction may thus be pivotal to a more rational clinical use of this drug in combination regimens and in tailored therapy.

Treatment of locally advanced hepatocellular carcinoma by hepatic intra-artery chemotherapy: a pilot study.

BACKGROUND: Hepatocarcinoma is one of the most common malignant tumours world-wide with poor prognosis. Treatment of locally advanced hepatocarcinoma is still controversial. Transcatheter arterial (chemo-)embolisation of hepatocarcinoma are widely used methods but some aspects regarding their use and usefulness have not yet been clarified. Systemic remedies have not yet been proven to affect patient survival. AIMS: To determine if intra-arterial chemotherapy with 5-flurouracil and folinic acid in locally advanced hepatocarcinoma is a viable alternative to existing therapies. PATIENTS: Twenty-four inoperable consecutive patients with locally advanced hepatocarcinoma were enrolled. They all underwent intra-arterial chemotherapy via a surgically implanted port-a-cath, and folinic acid (100 mg/m2) and 5-flurouracil (up to 550 mg/m2) were administered with a 1-week or a 2-week schedule. RESULTS: Nineteen patients completed the study: 2 showed a complete positive response, 11 a partial response, 6 stable disease, while 4 showed a disease progression. Median survival time was 19 (range 4-85) months. Child A patients showed a significant longer survival. CONCLUSIONS: Intra-arterial chemotherapy using folinic acid and 5-flurouracil may be useful in the treatment of locally advanced hepatocarcinoma in cirrhotic patients even in the presence of thrombosis. This treatment could be also useful in comparing transarterial chemoembolisation to a curative treatment.

Oxaliplatin plus raltitrexed in the treatment of patients with advanced colorectal cancer: a phase II study.

UNLABELLED: The combination of Oxaliplatin (OXA) and Raltitrexed (RTX) may represent a more convenient regimen as compared with OXA + 5-FU with Folinic acid (FA) modulation regimens. The present trial has been designed to explore the activity and tolerability of this combination in untreated and pretreated patients with advanced colorectal cancer (ACC). OXA and RTX were administered at the dose of 130 mg/m2 as i.v. 3-hour infusion and 3 mg/m2 over a 15-minute i.v. infusion, respectively, repeated every 21 days. Fifty patients were enrolled between February 1999 and March 2001. A total of 293 cycles were administered, with a median number of 6 cycles (range 1-14) per patient. The median dose intensity for OXA and RTX was 100% (50-100) and 86% (21-100), respectively. Reasons for RTX dose reduction were increases in transaminase serum levels and a reduction in creatinine clearance. Myelotoxicity was limited. A transaminase increase was observed in 74% of patients (14% grade 3 and 10% grade 4). Peripheral sensorial neurotoxicity was the most frequent side-effect (88%), although its intensity was mild in most patients (grade I 48%, grade II 24%, grade III 16%). Of 46 evaluable patients, 3 CR, 5 PR, 22 S and 16 P were observed. The CR + PR remission rate, according to the intention to treat analysis, was 16% with a 95% confidence limit of 7.2%-29.1%; in patients not pretreated for advanced disease the CR + PR rate was 26%, while only 2 out of 27 pretreated patients responded to the treatment (7%). The median time to progression was 5 months (2-11). The median survival was not reached after a median follow-up of 14 months. One-year survival is 60%. CONCLUSION: In this trial the OXA + RTX combination is confirmed to be active in ACC, although the level of activity seems to be lower than that of the other combination including OXA and 5-FU with or without FA modulation. The reasons for the low activity observed could at least in part be related to a reduction in the RTX dose intensity.

Oxaliplatin and protracted continuous 5-fluorouracil infusion in patients with pretreated advanced colorectal carcinoma.

BACKGROUND: Both OHP and 5-FU are clinically active as single agents in the treatment of metastatic colorectal cancer (MCRC). Clinical and laboratory studies suggest a synergistic interaction between these agents. This phase II study was performed to evaluate the activity of a schedule including OHP and protracted 5-FU infusion in 5-FU-resistant MCRC. PATIENTS AND METHODS: From October 1997 to January 2000, 50 patients with measurable progressive MCRC after one or more 5-FU-based regimens were treated. OHP (2-3-hour i.v. infusion) on day 1 and 5-FU (protracted i.v. infusion using elastomeric/electronic pump through a central venous catheter) on days 1-21 were administered every 3 weeks, at the following 4 dose levels: 1) OHP 100 mg/m2 + 5-FU 200 mg/m2 (21 patients); 2) OHP 100 mg/m2 + 5-FU 250 mg/m2 (3 patients); 3) OHP 130 mg/m2 + 5-FU 200 mg/m2 (10 patients); 4) OHP 130 mg/m2 + 5-FU 250 mg/m2 (6 patients). RESULTS: Objective responses were 1 (2%) CR; 10 (20%) PR, for a median duration of 8 months; 23 (46%) stable diseases, for a median duration of 6 months: 16 (32%) progressions. CR + PR was higher in patients who had previously received no more than one line of chemotherapy for metastatic disease as compared with patients who had received two or more lines of therapy (33% vs. 5%, P < 0.01). The median time to progression was four months (one to nine). All dose levels (313 cycles) were well tolerated with mild toxicity. Major toxicity (grade 3 WHO) included: anaemia in 1 patient (2%), nausea and vomiting in 1 patient (2%), diarrhoea in 4 patients (8%) and stomatitis in 1 patient (2%); grade I and 2 peripheral neuropathy were encountered, respectively, in 30 (60%) and 8 (16%) patients. The median survival was 13 months (9-17), with 32 patients still alive after a median follow-up of 8 months. CONCLUSIONS: This study suggests that 1) OHP plus protracted 5-FU infusion is an active combination in MCRC patients resistant to pre-treatment bolus 5-FU; 2) it has a good tolerability profile and 3) the optimum dose level is OHP 130 mg/m2 and 5-FU 250 mg/m2.

Preliminary results of a survey of the use of antimicrobial agents as prophylaxis in orthopedic surgery.

An epidemiological survey of the use of antimicrobial prophylaxis in Italian hospitals was carried out under the auspices of the Journal of Chemotherapy. Out of 500 Italian orthopedic centers queried, 225 agreed to participate in this study. A total of 136,321 surgical procedures were reported in the 166 centers reporting complete answers on type of surgery. They comprised hip and knee prosthesis (13.9%), spine surgery (4%), hip endoprosthesis (5.2%), osteosynthesis (26.9%), arthroscopy (24.4%), and others (25.5%). Perioperative antimicrobial prophylaxis was used in 75% of operations (ranging from 57.1% to 99.4% in arthroscopy and joint prosthesis, respectively). Short term (<24 h) antimicrobial prophylaxis was performed in 38.4% of the 206 centers answering this question correctly. 61.1% of centers employed single agent prophylaxis and 70.8% of these prescriptions were betalactam antibiotics. Bacteriological analysis revealed gram-positive isolates in 73.3% of cases. Methicillin resistance was present in 45% of 915 tested strains. Out of 4221 patients with high risk of infectious complications (joint prosthesis surgery) given antimicrobial prophylaxis in 46 centers, the percentage of surgical wound infections was overall 2.1%, while that of non-surgical wound infections was 3.6%. The total infection rate was decreased by about half in association with long-term (>24 h) as compared to short-term (<24 h) antibiotic treatment (3.7% vs 7.6%, respectively), and with use of antibiotic drug combinations vs single antibiotic drugs (3.9 vs 6.6%, respectively). The incidence of surgical-site infection was not decreased by extending the chemoprophylaxis for more than the first 24 h after surgery, while it was reduced from 2.5 to 1.4% by use of combination antibiotic therapy.

Does surgical prophylaxis with teicoplanin constitute a therapeutic advance?

Antibiotic prophylaxis has become standard care not only in operations characterized by high infection rates but also in the vast majority of clean surgical procedures, including those that use foreign materials, grafts or prosthetic devices as well as non-implant surgery. While use of antibiotics in clean implant surgery is undisputed, it is still controversial in clean non-implant surgery. As antibiotic prophylaxis should be directed against expected pathogens, the glycopeptides are considered suitable alternative antibiotics to first and second generation cephalosporins in clean surgical procedures associated with a high risk of wound infections due to Gram-positive bacteria, including methicillin-resistant, and for patients allergic to beta-lactam antibiotics. In deciding whether to use a glycopeptide for prophylaxis, the current wound infection rates with methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis at single institutions need to be considered, to limit the use of glycopeptides to wards where the incidence of methicillin resistance is high. Of the two available glycopeptides, teicoplanin may be preferable to vancomycin for peri-operative prophylaxis because of its excellent tissue penetration, as indicated by the large volume of distribution, lower toxicity, and particularly long half-life, allowing single-dose administration in several surgical procedures. Clinical trials with teicoplanin prophylaxis in several types of clean surgical procedures including orthopedic, cardiac, vascular and dental operations, have shown it to be efficacious. This review focuses on results from clinical studies with this glycopeptide as prophylaxis in clean surgery.

Methicillin-resistant staphylococci in clean surgery. Is there a role for prophylaxis?

The incidence of infection in clean surgery (i.e. surgery with no major contamination of the operative site) should be less than 2%, although the incidence of postoperative infections can be higher in patients with various risk factors (namely insertion of foreign bodies, a compromised immune status or prolonged duration of surgery). Although antibiotic prophylaxis has been shown to reduce the incidence of postoperative infections in clean surgery, there is still no consensus regarding its use in this area. However, for clean surgical procedures that involve implantation of foreign material, grafts or prosthetic devices, prophylaxis is well accepted and justifiable, since this practice is indicated when the benefits exceed the expected risks. Staphylococcus aureus and coagulase-negative staphylococci are responsible for 70 to 90% of wound infections in this type of surgery. First and second generation cephalosporins are considered the drugs of choice for surgical prophylaxis. Cefazolin and other cephalosporins have good tissue penetration but poor coverage against methicillin-resistant staphylococci. The frequency with which methicillin-resistant staphylococci have been recovered in nosocomial infections has increased steadily during recent years. This provides a rationale for the use of alternative antibiotics, such as the glycopeptides (vancomycin and teicoplanin), for prophylaxis in clean surgery in hospitals where the prevalence of methicillin-resistant staphylococci is high. The effectiveness and tolerability of teicoplanin as prophylaxis for orthopaedic surgery involving joint replacement were analysed in 4 randomised controlled trials. Two compared teicoplanin with cefamandole, while the others compared teicoplanin with either cefuroxime or cefazolin. The overall early wound infection rates (within 3 months) in these studies were 1.1% for teicoplanin and 1.7% for the comparator cephalosporin. The overall late infection rate was 0.2% for both treatment groups. Adverse events were attributed to the drug in 1% of patients in both treatment groups. Therefore, on the basis of these trials, single dose teicoplanin is as efficacious and as well tolerated as multiple dose cephalosporin regimens for prophylaxis in prosthetic joint surgery.