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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.

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 β -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 ≥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 .

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.

A review of the published literature detailing the clinical use of amoxycillin/clavulanic acid spanning the period 1979 to 1992 was undertaken to assess the clinical efficacy of the product and to determine whether any changes had occurred during this time. In the 415 publications meeting the selection criteria a total of over 38,500 patients were treated with amoxycillin/clavulanic acid. Analysis of the data confirms the efficacy of amoxycillin/clavulanic acid over a wide range of clinical indications and annual and triennial groupings of publications suggests that there has been little change in the clinical effectiveness of amoxycillin/clavulanic acid. Clinical efficacy rates (cure or improved) with amoxycillin/clavulanic acid were 88% and 92% in comparative and uncontrolled trials, respectively. Gastro-intestinal side effects are the most common adverse event but have been relatively infrequent. Amoxycillin/clavulanic acid should continue to be a useful antibiotic for upper and lower respiratory tract infections, skin structure infections, dental, head and neck infections, and selected urinary tract infections.

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.

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.

Summary We report a case of clostridial bacteraemia with infection of a prosthetic hip joint. The patient was successfully treated with iv benzyl penicillin and fucidin followed by oral amoxycillin and probenicid, without surgical intervention. She had no recurrence of her infection in the 19 months before her death. This is believed to be the first reported case of clostridial infection affecting a prosthetic joint.

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 body temperature is measured routinely and carefully charted in our own and presumably all units. Pyrexia is normal after bypass and is discounted on the basis of clinical experience in the first few days. If this pyrexia persists, a search for infection may be instigated and discharge from the hospital may be delayed. A clinical trial of antibiotic prophylaxis provided the opportunity to collect and collate 6-hourly temperature observations for 314 patients for 1 week after operation. The length of bypass and the presence of lower respiratory tract infection were positively correlated with the duration of postoperative fever. However, neither surgical sepsis nor urinary tract infection had any consistent effect on the duration or magnitude of postoperative fever in the first week.

Summary Teicoplanin, a new glycopeptide antibiotic, has been used to treat twelve patients with bacterial endocarditis due to Gram-positive organisms. Teicoplanin has activity against Gram-positive bacteria similar to vancomycin but therapeutic levels are maintained by a single daily dose, given as an intravenous bolus. Of six patients with native valve infections, two cases, due to viridans streptococci, were successfully treated with teicoplanin alone and two others, caused by Streptococcus faecalis, were cured by combinations including teicoplanin. One of these patients sustained high tone hearing loss during treatment. The remaining two patients were drug addicts with endocarditis due to Staphylococcus aureus which recurred despite repeated multiple therapy. Of six prosthetic valve infections, antibiotic combinations including teicoplanin cured three cases, caused by streptococci. Infection persisted or treatment was curtailed in three cases of Staphylococcus epidermidis endocarditis. In this small open study, teicoplanin appeared as effective as vancomycin in the treatment of endocarditis but had the considerable advantage of ease of administration.

In a randomised controlled trial 45 children (47 episodes of urinary-tract infection) with radiologically normal urinary tracts were given either low-dose prophylactic co-trimoxazole or nitrofurantoin or no prophylaxis after each had been treated with a short course of co-trimoxazole. During prophylaxis none of the 25 children had a further infection whereas half of the 22 who received no prophylaxis had a further infection within a similar period. 8 (32%) of those children who received prophylaxis had a further infection within 1 yr of completing the course of prophylactic treatment compared with 13 (59%) of the no-prophylaxis group in the year following the initial course of co-trimoxazole. 24 children had had a previous urinary-tract infection. All 6 of these who did not receive prophylaxis had a further infection whereas only 8 of the 18 (44%) who had received prophylaxis had a further infection after the course of prophylactic treatment. 24 mos after the start of the study, 68% of the prophylactic group and 36% of those who received no prophylaxis were recurrence-free. Differences in symptomatology and timing of reinfections and possible contributory factors are discussed.

285 women found to have bacteriuria during pregnancy were treated and subsequently seen at frequent intervals until discharge from the postnatal clinic, when all had sterile urine. Of these patients 157 were re-examined two to four years later and 43 (27%) had bacteriuria. These 43 patients could be further divided into two groups according to whether or not they had responded to the first course of chemotherapy given during pregnancy, and this showed that infection was more than twice as likely to be present in the group who had failed than those who had responded. Increased urinary white-blood-cell excretion was found in 31 (72%) of the 43 women but only 21 (49%) complained of urinary symptoms. Radiological abnormalities were found at long-term follow-up in 26 (37%) of the 71 women examined, and these were also related to failure of treatment early in pregnancy. Chronic pyelonephritis was detected in 11 women and in 10 of these the original antenatal infection had proved resistant to treatment. Patients infected at long-term follow-up were given a seven-day course of treatment and 56% responded. However, further analysis showed that those women who had previously failed the first course of treatment in pregnancy were also much less likely to respond. The characteristics of the organisms isolated from 56% of the patients with infection at follow-up suggested that a single episode of infection had not persisted but rather that these patients were susceptible to recurrent episodes of infection. In the other 44% of patients the organism was indistinguishable from that isolated in pregnancy.

Despite antibiotic prophylaxis in cardiac surgery, gram-positive bacteria can be isolated in up to 10% of intraoperative blood cultures. During a prospective randomized trial, blood was collected from the oxygenator at the end of bypass in 58 patients given teicoplanin and in 60 others given flucloxacillin and tobramycin. Coagulase-negative staphylococci were cultured from 16 patients given teicoplanin but in only four cases after flucloxacillin and tobramycin (Fisher's exact test, P = 0·005). In contrast, Propionibacterium spp. or coryneforms were isolated from 22 patients given flucloxacillin and tobramycin and from only one patient in the teicoplanin group. There were no cases of prosthetic valve endocarditis. After 3 h exposure to 4 × MIC of teicoplanin there was only a 10–60 fold reduction in cfus of Staphylococcus epidermidis , which may partly explain the excess of these organisms.

Wound infection after clean surgery prolongs hospital stay but the organism most commonly isolated from wound discharge, Staphylococcus epidermidis, is often dismissed as a contaminant or commensal. The wounds of 517 patients were assessed, after cardiac surgery, by a wound-scoring method (‘ASEPSIS’) and a close comparison was made of the appearance and clinical outcome of 89 wounds, from which bacteria were isolated. There was no significant difference in the scores of 49 wounds, where S. epidermidis was the sole isolate (9.5 per cent of all wounds, 95 per cent CI 6.9-12.0 per cent), and 13 wounds infected with Staphylococcus aureus (2.5 per cent, 95 per cent CI 1.2-3.9 per cent). Repeat cultures were obtained from 21 of the 49 wounds and, in 16 of these, the second isolate showed the same biochemical reactions and antibiotic resistance pattern as the first. Infection of sternal wounds is commoner with coagulase-negative staphylococci than with S. aureus and, clinically, is just as severe.

In this study, the pharmacokinetics of teicoplanin have been studied in serum, fat and bone during and after cardiac surgery with two dose (400 and 200 mg) and three dose (400 mg each) regimens in a total of 49 patients. For comparison, 20 other patients, who had received a regimen of flucloxacillin (500 mg qds for five days) and tobramycin (1.5 mg/kg initially then 80 mg tds for three days), were similarly investigated. The lowest mean serum level of teicoplanin during operation was 6.9 mg/l in the two dose regimen and 9.7 mg/l with the three dose regimen. Mean serum levels of flucloxacillin and tobramycin fell to 7 and 1.4 mg/l respectively by the end of operation. At the end of bypass, fat washings contained a mean of 1.2 mg/l of teicoplanin and bone washings a mean of 6.3 mg/l. Mean tobramycin levels were 0.4 and 0.9 mg/l respectively and flucloxacillin less than 1 mg/l in washings from both tissues. The low levels of teicoplanin in fat may explain an excess of Gram-positive sternal infections in the accompanying clinical trial.

A survey was conducted of the current practice of antibiotic prophylaxis in cardiac surgery throughout the United Kingdom. Most surgeons (84%) use a regimen covering a broad spectrum of bacterial species that is continued for two to three days after the operation. The most used regimens are a combination of beta lactamase resistant penicillin with an aminoglycoside (44%) or a single broad spectrum cephalosporin (30%). Just 16% of surgeons preferred a narrow spectrum regimen effective against only the Gram positive organisms commonly responsible for postoperative infection in these patients. Antibiotic prophylaxis has been adopted by all cardiac surgeons in the United Kingdom but is sometimes continued longer than is indicated by the clinical or experimental evidence.

Postoperative wound infection can greatly prolong hospital stay after cardiac surgery, so the identification of predisposing factors may help in prevention or early institution of treatment. Transfer of organisms from the leg to the sternum during coronary artery surgery has been proposed as a major additional cause of sepsis. The definition of wound infection is not standardised and therefore makes comparison between centres difficult. In a prospective study of 517 patients, a wound scoring method (ASEPSIS) has been used to register all abnormal wounds to maximise the chances of identifying factors predisposing to infection. Abnormal healing was noted in 99 (19%) sternal wounds and 29 (8%) leg wounds. Obesity was the principal risk factor (P less than 0.005). Diabetes, reoperation, length of preoperative hospital stay, age, sex, or previous cardiac surgery had little effect on wound healing. The range of bacteria isolated from chest wounds after coronary artery surgery was similar to that after valvular surgery, but the rate of isolation was significantly greater. With careful attention to technique, leg wound infection rarely presented a clinical problem and did not appear to be a source of bacteria infecting the chest wound.

Two prospective trials suggested that teicoplanin was less effective in preventing Gram-positive wound infections after cardiac surgery than a combination of flucloxacillin and an aminoglycoside. The initial dose of 400 mg was associated with a subinhibitory concentration of teicoplanin in fat at the end of operation. In this study, the behaviour of a higher initial dose (12 mg/kg) was investigated in ten patients during coronary artery surgery. As in the earlier trials, a second dose (400 mg) was given after 24 h. The mean concentration at the end of cardiopulmonary bypass was 15 mg/l in serum, 6 mg/kg in fat and 9 mg/kg in skin, all in excess of the expected break-point for staphylococci (4 mg/l). The higher dose regimen might be more successful in surgical prophylaxis.

Antibiotic-resistant coagulase-negative staphylococci are a frequent cause of infection in indwelling central venous (Hickman) catheters. Teicoplanin has been evaluated in the treatment of 19 immunosuppressed patients with staphylococcal Hickman catheter infections, nine of whom were septicaemic. All infections were eradicated, with minimal side effects. In 16 cases, the catheter was retained until no longer required. Two recurrent infections were eradicated by a second course of teicoplanin. We conclude that teicoplanin is an effective and well-tolerated antibiotic in the treatment of Hickman catheter infections in immunosuppressed patients.

Experiments have been performed using rifampicin (RIF) and tetracycline (TET) to establish whether the use of the combination prevents the emergence of bacterial resistance to either drug. Experiments were performed using repeated 4-hour cycles of exposure of large bacterial populations to varying concentrations of antibiotics in order to reproduce in vitro the conditions of treatment of a systemic infection in man. When exposed to both RIF and TET the doubly-sensitive test organism was eliminated from the test cultures in 92 h without emergence of resistance. When the organism was exposed to RIF alone it became massively RIF-resistant in 20 h. The organism was eliminated in 104 h when exposed to TET alone. Under the test conditions there was no significant difference in experimental outcome when RIF was added to TET compared to that when TET alone was used.

8907 patients had their urine screened for significant bacteriuria at their first visit to the antenatal clinic. The incidence of bacteriuria was 4.4%. Short-term chemotherapy (eight days) reduced the incidence of acute pyelonephritis in 285 patients with bacteriuria during pregnancy to 2.8%. Patients whose infection failed to respond to primary treatment were more likely to develop acute pyelonephritis. Despite adequate courses of chemotherapy, birth-weights of infants of bacteriuric patients were significantly lower than in control patients without bacteriuria. Persistent infection increased the risk, and the smallest infants were born to women whose infection failed to respond to multiple courses of antibiotic therapy. The rate of fetal loss was also higher in patients whose infections were refractory to treatment. Short-term chemotherapy was as effective as long-term therapy in the treatment of bacteriuria of pregnancy (75% were cured by one course, and a further 16% by a second course of therapy). A major advantage of using short courses of chemotherapy is that it facilitates recognition of the group of women in whom the incidence of acute pyelonephritis, small infants, and fetal loss will be greater than in other women.

In a study of patients with acute symptomatic urinary infection in domiciliary practice, the urinary strain Escherichia coli was isolated from the rectal, vaginal, and periurethral flora in nearly all cases. The urinary type has been found to predominate in the E. coli flora in all three sites. Although chemotherapy may eradicate the infecting organism from the urinary tract it did not usually eradicate it from the rectum, vagina, or periurethral skin.

To compare antibiotic regimens for their effectiveness in preventing or treating wound sepsis, well-defined criteria for outcome are needed. A method of assessing wound healing has been devised that defines carefully the characteristics to be considered and how they are to be awarded points. Objective criteria are also included in the assessment. Points are given for the need for Additional treatment, the presence of Serous discharge, Erythema, Purulent exudate, and Separation of the deep tissues, the Isolation of bacteria, and the duration of inpatient Stay (ASEPSIS).