Global surveillance through PROTEKT: the first year.

The increasing antimicrobial resistance amongst bacterial pathogens causing community-acquired respiratory tract infections (CARTIs) necessitates surveillance at the local, regional, national and international levels to provide information to guide empiric antimicrobial therapy. PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a longitudinal, global, multicenter surveillance study designed to monitor the worldwide development of antimicrobial resistance and disseminate up-to-date information via the internet to assist in the choice of empiric therapy at the local level. In this paper, the results for the first year of PROTEKT are presented from a global perspective. Streptococcus pneumoniae, followed by Haemophilus influenzae and Moraxella catarrhalis, are the principal organisms responsible for the majority of CARTIs. The global prevalence of penicillin G resistance in S. pneumoniae has risen to an alarming 36.3% (high-level resistance 22.1%, intermediate-level 14.2%) with the highest prevalence found in Asia (68%). In all regions, macrolide resistance is greater than penicillin G resistance with a global prevalence rate of 31.2%. High resistance rates were also found for tetracycline (30.5%) and co-trimoxazole (43.9%), and multiresistance was found between penicillin G, macrolides, tetracycline and co-trimoxazole. The prevalence of beta-lactamase-producing H. influenzae and M. catarrhalis was found to be similar to previous reports. Macrolide resistance in S. pyogenes was 0.3% overall. Telithromycin demonstrated excellent in vitro activity against all organisms and is a potential new candidate for the empiric therapy of CARTIs. The first year of PROTEKT has provided valuable information on the prevalence of antimicrobial resistance of bacterial agents causing CARTIs that can be used for guiding empiric therapy and policies. The rapidly developing and geographically varying resistance observed in this study further emphasizes the need for accurate up-to-date surveillance data.

The Alexander Project 1996-1997: latest susceptibility data from this international study of bacterial pathogens from community-acquired lower respiratory tract infections.

The Alexander Project was established in 1992 to examine antimicrobial susceptibilities of bacterial isolates from community-acquired infections of the lower respiratory tract. Testing of a range of compounds was undertaken in a central laboratory. From 1992 to 1995, isolates were collected from geographically separated areas in countries in the European Union and various states in the USA. In 1996, the study was extended to include centres in Mexico, Brazil, Saudi Arabia, South Africa, Hong Kong and other European countries not included previously. Data generated by the project during 1996-1997 confirm France and Spain as European centres with high rates of resistance to penicillin among isolates of Streptococcus pneumoniae. Both intermediate (MIC 0. 12-1 mg/L) and resistant (MIC 2 mg/L) phenotypes are present. Combined resistance rates (intermediate and resistant) were >/=50% in 1997. Combined resistance rates in excess of 20% were found in the Republic of Ireland, Portugal, the Slovak Republic and Hungary. Penicillin resistance continues to evolve in the USA, with combined resistance rates of 16.4% (1996) and 18.6% (1997). In the new, non-European centres, e.g. Mexico and, in particular, Hong Kong (where resistant strains accounted for 50% of all isolates of S. pneumoniae in 1996 and 55.5% in 1997), there are centres where rates of resistance are high. Macrolide resistance is increasing generally among both penicillin-resistant and penicillin-susceptible isolates of S. pneumoniae. There is variation between countries, and in four out of the 16 centres for which both 1996 and 1997 data are available, rates of macrolide resistance have fallen. Overall, the percentage of S. pneumoniae strains that is resistant to macrolides exceeds the percentage that is resistant to penicillin. In 1996, 16. 5% of all S. pneumoniae isolates were resistant to macrolides compared with 10.4% resistant to penicillin, and in 1997 respective rates were 21.9% and 14.1%. beta-Lactamase production was the principal mechanism of resistance observed among isolates of Haemophilus influenzae. However, considerable variation in the percentage of isolates producing beta-lactamase (0-37.1%) was observed within this species. Within Europe, in the Republic of Ireland, France and Belgium, more than 15% of isolates were beta-lactamase producers. In Spain rates were as high as 31.7%. Outside Europe and the USA high rates were described in Mexico (25%), Saudi Arabia (27.9%, 16.7%) and Hong Kong (37.1%, 28.9%). Of H. influenzae from the USA, 30.4% were beta-lactamase producers in 1996 and 23.3% in 1997. beta-Lactamase production among isolates of Moraxella catarrhalis was observed in >90% of the isolates tested in 1996 and 1997.

The role of glycopeptide antibiotics in the treatment of infective endocarditis.

There are several sets of guidelines for the treatment of infective endocarditis, reflecting the need for differing treatment in various countries and times. This review considers the need for differing treatment modalities and in particular the utility of the glycopeptide antibiotics vancomycin and teicoplanin. Specific recommendations are offered as to when to consider the use of glycopeptides, appropriate dosage, length of treatment course and whether to use monotherapy or combined therapy. Used judiciously, the glycopeptides give results as good as can be achieved with other antimicrobial agents without exceptional toxicity. The potential of teicoplanin for use in the outpatient treatment of infective endocarditis is considered.

Differences between the activity of penicillin, amoxycillin, and co-amoxyclav against 5,252 Streptococcus pneumoniae isolates tested in the Alexander Project 1992-1996.

A number of published studies have shown that the MICs of amoxycillin and/or co-amoxyclav are lower than those of ampicillin and/or penicillin for Streptococcus pneumoniae. Other published studies have concluded that the activities of amoxycillin and co-amoxyclav are comparable with that of penicillin for S. pneumoniae. A collection of 5252 S. pneumoniae isolates obtained during a 5 year period (1992-1996) was analysed to determine differences between the MICs of penicillin, amoxycillin and co-amoxyclav. Among the isolates analysed, 3788 (72%) were penicillin-susceptible, 615 (12%) were penicillin-intermediate and 849 (16%) were penicillin-resistant. Differences between the agents were assessed by examination of MIC distribution functions and simultaneous 95% CIs. In addition, penicillin-intermediate and -resistant isolates were analysed to determine the number and percentage of isolates which had an amoxycillin and co-amoxyclav MIC less than, equal to, or greater than the penicillin MIC. Results showed that the amoxycillin and co-amoxyclav MIC90s were one two-fold dilution lower than those of penicillin for all isolates collected between 1992-1993 and 1994-1996. Simultaneous 95% CIs showed that the mean differences between MICs of amoxycillin and penicillin, and between MICs of co-amoxyclav and penicillin, were less than zero. The majority of the penicillin-intermediate and penicillin-resistant isolates had an amoxycillin and co-amoxyclav MIC less than the penicillin MIC. In conclusion, amoxycillin and co-amoxyclav MICs were shown to be lower than the penicillin MICs for the S. pneumoniae isolates analysed in this study.

Chairman's introduction--the importance of good quality surveillance data today.

The Alexander Project is a continuing, international, multicenter, longitudinal study of the antimicrobial susceptibility of pathogens commonly associated with community-acquired lower respiratory tract infections (LRTI). The study began in 1992 to provide high-quality surveillance data, comparable between regions and through time. As antimicrobial resistance becomes more prevalent, reliable surveillance data are required for clinical decision-making. Accurate current susceptibility data are required to predict clinical success through the determination of pharmacodynamic breakpoints. The Alexander Project provides the information required for clinicians to improve the likelihood of microbiological and clinical cure in the antibiotic treatment of LRTI.

The role of antibiotics in the treatment of chronic prostatitis: a consensus statement.

Practical guidelines for the diagnosis and treatment of chronic prostatitis are presented. Chronic prostatitis is classified as chronic bacterial prostatitis (culture-positive) and chronic inflammatory prostatitis (culture-negative). If chronic bacterial prostatitis is suspected, based on relevant symptoms or recurrent UTIs, underlying urological conditions should be excluded by the following tests: rectal examination, midstream urine culture and residual urine. The diagnosis should be confirmed by the Meares and Stamey technique. Antibiotic therapy is recommended for acute exacerbations of chronic prostatitis, chronic bacterial prostatitis and chronic inflammatory prostatitis, if there is clinical, bacteriological or supporting immunological evidence of prostate infection. Unless a patient presents with fever, antibiotic treatment should not be initiated immediately except in cases of acute prostatitis or acute episodes in a patient with chronic bacterial prostatitis. The work-up, with the appropriate investigations should be done first, within a reasonable time period which, preferably, should not be longer than 1 week. During this period, nonspecific treatment, such as appropriate analgesia to relieve symptoms, should be given. The minimum duration of antibiotic treatment should be 2-4 weeks. If there is no improvement in symptoms, treatment should be stopped and reconsidered. However, if there is improvement, it should be continued for at least a further 2-4 weeks to achieve clinical cure and, hopefully, eradication of the causative pathogen. Antibiotic treatment should not be given for 6-8 weeks without an appraisal of its effectiveness. Currently used antibiotics are reviewed. Of these, the fluoroquinolones ofloxacin and ciprofloxacin are recommended because of their favourable antibacterial spectrum and pharmacokinetic profile. A number of clinical trials are recommended and a standard study design is proposed to help resolve some outstanding issues.

The Nearchus project: antibiotic susceptibility of respiratory pathogens and clinical outcome in lower respiratory tract infections at 27 centres in the UK.

Community-acquired respiratory infections are usually treated empirically by the primary care physician. Increasing antibiotic resistance, for example, in pneumococci, prompted a UK survey of antibiotic susceptibility of three major lower respiratory tract pathogens, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Each of 27 centres was asked to collect up to 100 isolates of the three species and submit them for confirmation of identity and for susceptibility testing to a central laboratory. In addition, general practitioners were asked for demographic details on the patient, their treatment and the clinical outcome. Of 1689 viable pathogens collected, there were 1078 (64%) strains of H. influenzae, 258 (15%) of M. catarrhalis and 353 (21%) of S. pneumoniae. Production of beta-lactamase was detected in 163 (15%) of 1078 isolates of H. influenzae and in 243 (94%) isolates of M. catarrhalis. For S. pneumoniae, moderate resistance to penicillin (MIC 0.12-1 mg/l) was found in 12 (3.4%) isolates and high level resistance (MIC > or = 2 mg/l) in 13 (3.7%) isolates. The most common individual treatments were amoxycillin, amoxycillin/clavulanate (amoxyclav) , and erythromycin. Complete or partial clinical resolution was achieved in 88% of 809 patients infected with H. influenzae, 83% of 197 infected with M. catarrhalis and 90% of 255 infected with S. pneumoniae.

Antimicrobial susceptibility of community-acquired lower respiratory tract bacterial pathogens isolated in the UK during the 1995-1996 cold season.

The antimicrobial susceptibility of 1078 isolates of Haemophilus influenzae, 348 Streptococcus pneumoniae and 258 Moraxella catarrhalis was determined. Overall 15.1% of H. influenzae produced beta-lactamase; 98.8% were susceptible to co-amoxiclav, 85.8% to cefaclor, 96% to clarithromycin and 100% to ciprofloxacin. The majority (94.2%) of M. catarrhalis produced beta-lactamase. The overall prevalence of low-level penicillin resistance (MIC = 0.12-1 mg/L) amongst isolates of S. pneumoniae was 3.4% and that of high-level resistance (MIC > or = 2 mg/L) was 3.7%. Most (96.3%) of the isolates of S. pneumoniae were susceptible to amoxycillin (MIC < or = 0.5 mg/L), 96% to cefaclor (MIC < or = 8 mg/L), 90.7% to clarithromycin (MIC < or = 0.25 mg/L) and 89% to ciprofloxacin (MIC < or = 1 mg/L).

Clinical relevance of a European collaborative study on comparative susceptibility of gram-positive clinical isolates to teicoplanin and vancomycin.

Seventy laboratories in nine European countries (Belgium, France, Germany, Italy, The Netherlands, Portugal, Spain, Switzerland and the UK) each collected 100 consecutive gram-positive bacterial pathogens during 1995. MICs were determined by a co-ordinating laboratory in each country using an agar incorporation method with Mueller Hinton medium (NCCLS). Quality control was ensured by distribution of five test strains to the co-ordinating laboratories. A total of 7078 isolates was collected: 2885 Staphylococcus aureus, 1706 enterococci, 1480 coagulase-negative staphylococci (CNS), 932 Streptococcus spp. (including 289 strains of S. pneumoniae) and 75 miscellaneous species. Of these, the country coordinators successfully re-tested 6824 isolates. Using NCCLS interpretive criteria, overall 39 isolates (including 28 strains of enterococci) were teicoplanin-resistant (0.57%) and 38 (mostly CNS; 0.56%) were intermediate, whilst 32 isolates (including 30 strains of enterococci) were resistant to vancomycin (0.47%) and 7 (all enterococci; 0.10%) were intermediate. The overall resistance rate was < or = 0.5%. The two glycopeptides were essentially active against the major pathogens encountered in the survey. The only real difference with clinical implications from previously reported susceptibility data is the emergence and spread of resistance in enterococci, particularly in E. faecium. Resistance was highest in SSTI, UTI, bloodstream and GI infections; no resistance was encountered in RTI, gynaecological infections or central nervous system infections. This resistance was also geographically diverse: Resistance to vancomycin in E. faecalis was present only in France, Germany, Italy, Portugal and Spain (Italy and Spain only for teicoplanin), whilst resistance to teicoplanin and vancomycin in E. faecium was present in all countries except Spain. Eight isolates (0.5% of all enterococci) were vancomycin-resistant but teicoplanin-susceptible, exhibiting the vanB phenotype. These were four strains of E. faecalis and four strains of E. faecium. Whilst isolates of S. haemolyticus had higher MIC of teicoplanin than other CNS, and were more susceptible to vancomycin, overall resistance to teicoplanin was low (3.3% in S. haemolyticus; 0.6% in CNS). S. haemolyticus was a relatively rare pathogen, accounting for 6.3% of all CNS isolates, and 1.4% of all gram-positives collected. The results of this survey show that, despite occasional nosocomial problems (e.g. with enterococci and S. haemolyticus), teicoplanin or vancomycin remain adequate therapy for infections caused by gram-positive pathogens in the 1990s.

In-vitro activity of trovafloxacin, a new fluoroquinolone, against recent clinical isolates.

Trovafloxacin (CP-99,219) was very active against Gram-negative species examined including Haemophilus influenzae, Moraxella catarrhalis, Legionella spp., Neisseria spp. and Escherichia coli (MIC90s < or = 0.03 mg/L). In general trovafloxacin was twice as active as ofloxacin but only half as active as ciprofloxacin against Gram-negative species. Trovafloxacin was active against Gram-positive organisms, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes and Enterococcus faecalis (MIC90s < or = 0.25 mg/L). Against these organisms activity was eight to 16 times greater for trovafloxacin than for either ofloxacin or ciprofloxacin. In addition, Chlamydia spp., Mycoplasma spp. and Ureaplasma urealyticum were eight to 16 times more susceptible to trovafloxacin than to either ofloxacin or ciprofloxacin. These in-vitro data show that trovafloxacin is a broad-spectrum fluoroquinolone with greater activity against clinically important Gram-positive species compared with ofloxacin or ciprofloxacin.

Anti-gram-positive agents. What we have and what we would like.

The usefulness of many anti-Gram-positive antibiotics is being compromised by the spread of antibiotic resistance in bacteria. The most reliable agents for serious infections are the glycopeptide agents vancomycin and teicoplanin. The appropriate maintenance dosage for teicoplanin in serious infections is 6 mg/kg/day, i.e. usually 400 mg/day. There are 3 exceptions for which the daily maintenance dosage should be 12 mg/kg/day and these are intravenous drug abusers, septic arthritis (but not osteomyelitis), and Staphylococcus aureus endocarditis treated with teicoplanin monotherapy. When teicoplanin is given at these doses, it achieves clinical and bacteriological results that are equivalent to those obtained with vancomycin, irrespective of pathogen or type of infection. The toxicity profile favours teicoplanin over vancomycin, especially when other, potentially toxic, drugs are coadministered. Teicoplanin also has an advantage in terms of ease and convenience of administration, which, together with its lack of need for routine blood level monitoring, facilitates its use outside hospital. New agents hold some promise for the future; however, oral agents, if developed, could present the risk of being overused, which might compromise their long term utility.

Results of the Alexander Project: a continuing, multicenter study of the antimicrobial susceptibility of community-acquired lower respiratory tract bacterial pathogens.

In 1992, an ongoing, international multicenter study was established to investigate the antimicrobial susceptibility of community-acquired lower respiratory tract bacterial pathogens: the Alexander Project. Isolates cultured from patients living in geographically separated areas, ten in the European Union (EU) and five in the United States (US), were collected and tested using standard methods in a central laboratory. A total of 4,155 isolates of Haemophilus influenzae was collected during the period 1992-1994. beta-lactamase production was the principal mechanism of resistance observed with overall rates in the US (1992 = 26.3%; 1993 = 28.2%; and 1994 = 30.1%) generally twice those seen in the EU (1992 = 12.3%; 1993 = 14.4%; and 1994 = 15.5%). Chloramphenicol resistance was generally low except in Spanish centers where rates ranging from 4.0 to 15.9% were observed during the study period. One thousand one hundred ninety-three isolates of Moraxella catarrhalis were tested. beta-lactamase production was the only mechanism of resistance of any importance detected, with the vast majority of isolates producing the enzyme. Two thousand eight hundred twenty-nine isolates of Streptococcus pneumoniae were tested. French and Spanish centers provided isolates with the highest rates of either low-level (intermediate) or high-level penicillin resistance, which in 1994 ranged from 10.2 to 31.4% and 30.4 to 40.1% for each resistance category, respectively. With the exception of the fluoroquinolones, rates of resistance to other antimicrobials including the macrolides, doxycycline, chloramphenicol, and trimethoprim/sulfamethoxazole were high, generally, in centers with a high prevalence of penicillin resistance. However, in some centers (Toulouse, France and Genoa, Italy) this association was not complete for the macrolides.

A multicentre collaborative study of the antimicrobial susceptibility of community-acquired, lower respiratory tract pathogens 1992-1993: the Alexander Project.

The Alexander Project is a unique, international, collaborative antimicrobial susceptibility surveillance study of bacterial pathogens causing community-acquired lower respiratory tract infection. Fifteen centres, ten in the European Union (EU) and five in the USA, each submitted up to 400 isolated per year for 2 years (1992 and 1993) to a central laboratory for re-identification and determination of MICs of 15 antimicrobials using the Sensititre microbroth incorporation technique. Of the total of 6385 isolates collected, Haemophilus influenzae (2718), Streptococcus pneumoniae (1856) and Moraxella catarrhalis (818) were the most frequently identified pathogens. Staphylococcus aureus (690). Haemophilus parainfluenzae (183) and Klebsiella pneumoniae (120) were identified less commonly. High-level penicillin resistance in S. pneumoniae (MIC > or = 2 mg/L) was found in 222 isolates, an overall prevalence of 12% which varied from < 1% in Germany, Italy, UK and two of the five USA centres, to 3.8-40.4% in the remainder, with the highest prevalence found in France and Spain. Intermediate penicillin resistance (MIC 0.12-1 mg/L) was identified in 228 isolates of S. pneumoniae, an overall prevalence of 12.3%, with individual centre prevalence varying widely (EU, 0-52.3%; USA, 0-20.9%) and not always following that of high-level resistance. Resistance to other, unrelated, antimicrobials, except notably the fluoroquinolones, was strongly associated with beta-lactam resistance. beta-lactamase production was detected in 492 isolates of H. influenzae, an overall prevalence of 18.1%. Rates of detection varied widely between centres from 1.4% in Weingarten, Germany in 1993 to 38.5% in Barcelona, Spain in 1992. In general, the prevalence of beta-lactamase production was higher and less variable in USA centres than in those of the EU. beta-Lactamase was detected consistently in the majority of isolates of M. catarrhalis with an overall prevalence of 81.7%. Virtually no other resistance phenotype was recognised in this species. Of the 690 collected, most isolates of S. aureus produced beta-lactamase with rates of detection varying from 52.2%-89.1%. Isolates from two centres, Genoa, Italy in 1992 and Paris, France in 1993, were associated with a high prevalence of methicillin-resistance (34.8% and 43.8%, respectively). Combined isolates of H. parainfluenzae and K. pneumoniae accounted for only 4.7% of the total collection. Although the current data are insufficient to allow analysis of trends in resistance, the study participants have continued to collect further isolates in 1994 and 1995 which will be reported in the future.

The Alexander Project: using in-vitro susceptibility data for choosing empirical therapy in LRTI.

An international collaborative survey of susceptibility in community-acquired lower respiratory tract infection pathogens collected > 6000 strains from six countries during 1992 and 1993. The four major pathogens were Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus. MICs of 15 antibiotics were determined and sensitivity interpretations applied using breakpoints based on those of the NCCLS. This analysis highlighted some anomalies, notably for beta-lactams against S. pneumoniae and macrolides against H. influenzae, where apparent sensitivity proportions did not accord with the distribution of MICs. Further analyses were undertaken in order to rank the antibiotics in order of potential usefulness for empirical treatment of LRTI: these included in-vitro potency (mode MIC and MIC90) and a pharmacodynamic comparison, using the ratio Cmax (free drug): MIC90. According to study breakpoints, the most active agents overall were, for S. pneumoniae, cefuroxime, clarithromycin, ofloxacin and chloramphenicol; for H. influenzae, azithromycin, amoxycillin/ clavulanate, cefixime, ceftriaxone, quinolones and doxycycline. However, other analyses suggested that the most active agents overall were, for S. pneumoniae, amoxycillin (+/- clavulanate) and ceftriaxone, and, for H. influenzae, quinolones, ceftriaxone, cefixime and amoxycillin/clavulanate. Overall, the antimicrobial agents with the greatest potential usefulness for empirical treatment were amoxycillin/ clavulanate, ceftriaxone, cefuroxime, ofloxacin and co-trimoxazole. The choice of empirical therapy depends upon local epidemiology and clinician choice, but the Project data may be of value in the decision-making process.

A comparative study between teicoplanin alone and flucloxacillin, plus or minus fusidic acid, in the treatment of serious infections caused by methicillin-susceptible gram-positive bacteria.

A randomized trial compared teicoplanin alone against flucloxacillin, with or without fusidic acid, in the treatment of serious gram-positive infections. The majority of infections involved Staphylococcus aureus or Staphylococcus epidermidis, methicillin-resistant organisms were excluded. A total of 56 patients were evaluable for efficacy, with no significant differences between treatment groups. Clinical success (cure + improvement) was achieved in 24/27 patients on teicoplanin (89%), 16 on flucloxacillin (100%) and 8/9 receiving flucloxacillin/fusidic acid (89%). Adverse events occurred in 21% of patients (7 on teicoplanin and 6 receiving flucloxacillin +/- fusidic acid). All such events resolved spontaneously or following appropriate management. It is concluded that teicoplanin monotherapy, 400 mg once daily, shows similar efficacy and tolerability to multiple daily doses of flucloxacillin, with or without fusidic acid, in the treatment of methicillin-susceptible serious gram-positive infection.

Anti-infective treatment in intensive care: the role of glycopeptides.

Antibiotics are used in 80% of patients in the ICU, encouraging nosocomial infections with resistant organisms. If the antibiotic susceptibilities of the pathogen are known, a narrow-spectrum antibiotic is preferable to preserve the patient's resistance to colonization. However, treatment is often empirical and broad-spectrum combinations are commonly used. Gram-positive bacteraemia is associated with invasive monitoring or intravascular catheters. If the device cannot be removed easily, the glycopeptides are the only agents likely to be active against most strains of the commonest pathogen, the coagulase-negative staphylococcus. Long-stay patients are susceptible to infection with enterococci and methicillin-resistant Staphylococcus aureus, which are often resistant to all the usual agents other than glycopeptides. Vancomycin is long established, but is nephrotoxic, requires serum monitoring, must be administered as an infusion and can cause red man syndrome. Teicoplanin can be given as a single daily bolus without similar side-effects or monitoring. In deep-seated staphylococcal infection, the usual dose of teicoplanin is adequate if given in combination with other agents, but it may need to be doubled if used as monotherapy. Monitoring of the levels in the serum is helpful to ensure an adequate dose in patients with renal failure or in drug abusers, but is not needed to prevent toxicity.

Use of teicoplanin in community medicine.

Administration of parenteral antibiotics to outpatients is increasingly used to reduce hospital costs, to reduce loss of earnings for the patient and to improve the quality of life in patients requiring prolonged antibiotic treatment. The glycopeptides are required for treatment of infections caused by methicillin resistant staphylococci and some enterococci, or for treatment of patients allergic to beta-lactam agents. For home therapy, teicoplanin has some advantages over vancomycin in that it requires only once-daily bolus administration, does not necessitate monitoring of serum concentrations and offers the choice of intravenous or intramuscular administration. Teicoplanin has been used to complete treatment of endocarditis at home in selected patients, streptococcal disease being the most suitable form of endocarditis for this treatment. In open trials, teicoplanin has been found effective in home therapy of osteomyelitis but, as with other agents, prolonged dosage can be associated with adverse effects. It has also been used for home treatment of infections of the respiratory tract, intravascular catheters and soft tissue. Despite its higher acquisition costs, teicoplanin is to be preferred over vancomycin because of the reduced administration and assay costs and fewer adverse effects.

Changes in urinary pathogens and their antibiotic sensitivities, 1971-1992.

Unselected urinary pathogens from general practice and hospital have been tested for sensitivity to a range of antimicrobial agents for the last 22 years. There have been substantial changes. In general practice there has been a considerable increase in the proportion of staphylococcal infections from 5.1% to a peak of 14.8% in 1982 and a more recent decline to 4.0%. There has also been a decrease in the proportion caused by proteus mirabilis, from 9.2% to 4.3%. Similar, but smaller, changes have been observed in the proportions of hospital urinary tract infections caused by these organisms, while the proportion of hospital infections due to Klebsiella spp. and Enterobacter spp. has fallen from 16.8% to 7.3%. These and other changes have been reflected in the changing patterns of sensitivity to antibiotics. In particular, sensitivity of urinary pathogens to ampicillin/amoxycillin has continued to fall both in general practice and in hospital. Nalidixic acid resistance is becoming more important as the proportion of Gram-positive urinary pathogens (especially enterococci) increases. More organisms were sensitive to ciprofloxacin than the other drugs tested, with little evidence of increasing resistance.

A critical review of the dosage of teicoplanin in Europe and the USA.

The glycopeptide antibiotic, teicoplanin, is increasingly used in Europe in the treatment of Gram-positive infection. It is administered as a bolus once daily, it has little potential for nephrotoxicity, and serum monitoring is usually unnecessary. However, poor results were reported in early trials at a daily dose of 200 mg and, more recently, at 400 mg/day in monotherapy of staphylococcal endocarditis. While 400 mg (6 mg/kg day(-1)) is now standard, US trials have tried very high doses in an attempt to improve its efficacy in monotherapy of deep-seated staphylococcal sepsis. European centres continue to use 6 mg/kg day(-1) as the usual maintenance dose and 6-12 mg/kg as the loading dose. For the more difficult cases, teicoplanin is used in combination with other agents. All available published and unpublished literature was reviewed to try to solve these problems. With the exception of endocarditis, failure rates in the 84 European open studies varied more between trials than between the dosages used. In 32 European and eight US randomized trials, a dose of 6 mg/kg day(-1) of teicoplanin was effective, except in staphylococcal endocarditis if teicoplanin was used as monotherapy. In that case, 12 mg/kg day(-1) or more was needed to achieve a cure rate similar to that of vancomycin. Treatment was most successful with trough levels over 20 mg/l. However, lower doses were effective in combination with aminoglycosides, as is common in clinical practice. An open trial suggested that 12 mg/kg day(-1) was needed for treatment of septic arthritis. It is suggested that 6 mg/kg day(-1) of teicoplanin be used for all indications except staphylococcal endocarditis and septic arthritis when it should be given in a dose of 12 mg/kg day(-1) or in combination with other agents.