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.

Should the temperature chart influence management in cardiac operations? Result of a prospective study in 314 patients.

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.

Antibiotic sensitivities of urinary pathogens, 1971-8.

The sensitivites of urinary pathogens from general practice and from hospital to a range of antimicrobial drugs have been recorded for the period 1971-8. There have been changes in the proportions of the different bacterial species and in their sensitivites to antibiotics. In particular, the position of ampicillin/amoxycillin and cephalosporins has deteriorated, partly because more resistant species have somewhat increased in prevalence and partly because the usually sensitive species, such as Escherichia coli, have become more resistant. Over the period 1971-8 the sensitivity of urinary pathogens, whether in general practice or in hospital, to co-trimoxazole and to trimethoprim has been maintained at a high level.

Susceptibility of urinary pathogens to various antimicrobial substances: a four-year study.

The results of testing all urinary pathogens from general practice and hospital practice for their sensitivity to a range of antimicrobial agents over the four years 1971-74 are presented. The changes observed in each situation with the passage of time are discussed. Resistance has become more frequent to those drugs to which resistance is commonly R factor-mediated. Less change has been observed in resistance to other antimicrobial agents.

Recurrent urinary infections in general practice.

Repeated episodes of acute, symptomatic urinary tract infections in domiciliary patients have been shown to be due to reinfection in 71% of instances and to recrudescence of the original infection in 29%. Fresh episodes occurring at intervals of less than eight weeks from the original infection were due to reinfection or to recrudescence of infection in roughly equal numbers but those at intervals of eight weeks or more were due to reinfection.

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.

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.

Comparative in vitro activity of lomefloxacin, a difluoro-quinolone.

Lomefloxacin is a new difluoro-quinolone. In this study, we have determined the in vitro activity of lomefloxacin against a wide range of clinical bacterial isolates and compared it with that of other fluoro-quinolones and some unrelated antimicrobials. Lomefloxacin was very active against Enterobacteriaceae (MIC90, 0.5 micrograms/ml) with activity comparable to that of ofloxacin (MIC90, 0.25 micrograms/ml). Lomefloxacin was moderately active against isolates of Pseudomonas aeruginosa (MIC90, 4 micrograms/ml), and again the activity was comparable to ofloxacin (MIC90, 4 micrograms/ml) but was eightfold less than ciprofloxacin (MIC90, 0.5 micrograms/ml). Lomefloxacin was also active against isolates of Staphylococcus aureus (MIC90, 1 micrograms/ml), irrespective of methicillin susceptibility, and this activity was most comparable to ofloxacin (MIC90, 0.5 micrograms/ml) and ciprofloxacin (MIC90, 0.5 micrograms/ml). Lomefloxacin was fourfold less active than either ofloxacin or ciprofloxacin against isolates of Enterococcus faecalis (MIC90, 8 micrograms/ml) and Streptococcus pneumoniae (MIC90, 8 micrograms/ml). In common with ofloxacin and ciprofloxacin, lomefloxacin was very active against isolates of Neisseria spp. (MIC90, less than or equal to 0.06 micrograms/ml), Haemophilus spp. (MIC90, less than or equal to 0.06 micrograms/ml), Legionella spp. (MIC90, less than or equal to 0.06 micrograms/ml), Vibrio spp. (MIC90, less than or equal to 0.06 micrograms/ml), and Campylobacter jejuni (MIC90, 1 microgram/ml). Lomefloxacin showed poor activity against isolates of Bacteroides spp. (MIC90, 16 micrograms/ml) or Clostridium difficile MIC90, 32 micrograms/ml) and was only moderately active against isolates of Clostridium perfringens (MIC90, 2 micrograms/ml), Peptostreptococcus spp. (MIC90, 4 micrograms/ml), Chlamydia trachomatis (MIC90, 4 micrograms/ml), Mycoplasma hominis (MIC90, 2 micrograms/ml), and Urea-plasma urealyticum (MIC90, 8 micrograms/ml). Lomefloxacin was found to be bactericidal at concentrations generally close to the MIC with greater than 3 log10 reduction in viability of exponentially dividing cultures of Escherichia coli and S. aureus within 5 hr of exposure to concentrations at eight times the MIC. These results indicate a potential clinical role for lomefloxacin in the treatment of genitourinary tract infections caused by Gram-positive and Gram-negative bacteria, respiratory tract infections caused by susceptible organisms, and soft tissue infections caused by S. aureus.

Motility of enterococci isolated from the urinary tract and from other sources.

The identity and motility of enterococci isolated as urinary pathogens were compared with those of strains from other sources. The majority of isolates from all sources proved to be Streptococcus faecalis of S. faecium but eight of 117 urinary strains and seven of 127 non-urinary strains belonged to a group intermediate between S. faecium. Of the seven "intermediate" strains from non-urinary sources, four were motile. None of the urinary enterococci was motile. The results do not indicate that urinary enterococci are more likely to be motile than are non-urinary strains.

The influence of antibiotic treatment on resistance patterns of coliform bacilli in childhood urinary-tract infection.

The occurrence of coliform bacilli carrying resistance-transfer factors (R factors) in children was studied. The frequency of R+ coliform bacilli as causes of urinary-tract infection acquired outside hospital was found to be similar to that in adults from the same geographical area and in the same years. The frequency of R+ coliform bacilli in the faeces in our children was also similar to that in the adult population, and oral chemotherapy produced similar changes in the faecal flora.

Relationship between sexual intercourse and urinary-tract infection in women attending a clinic for sexually transmitted diseases.

The prevalence of urinary-tract infection (UTI), diagnosed by examination of a single midstream urine from sexually active women was found to be 6.4%. Significant bacteriuria was most common in women who presented within 24 h of coitus but was not related to the number of sexual partners. UTI occurred significantly more often in women who presented within 4 days of intercourse than in women seen after a longer interval. Whether frequency of intercourse affects the prevalence of UTI remains to be determined.

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.

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.

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.

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.

In vitro studies with combinations of sulfamoxole and trimethoprim (co-trifamole).

Chequerboard studies with sulfamoxole and trimethoprim against urinary pathogens showed that the combination was never antagonistic but usually showed little or no synergistic effect. An exception was with the inherently sulphonamide-resistant Strep. faecalis in which marked synergism (F.I.C. Index less than 0.3) was shown with all strains tested. This synergism is thought to be clinically relevant. Experiments were undertaken with a new in vitro test system to establish whether the combination of sulfamoxole with trimethoprim will prevent the emergence of bacterial resistance. Using concentrations of the drugs attained in the blood during treatment, it was shown that trimethoprim monotherapy was likely to result in the emergence of trimethoprim-resistant pathogens, whereas treatment with sulfamoxole and trimethoprim resulted in the elimination of the test bacteria without the emergence of resistance. Using urinary concentrations of drugs, the "urinary' pathogen was shown to be eliminated by trimethoprim alone or in combination with sulfamoxole, without the emergence of resistant bacteria. This would not necessarily preclude the emergence of resistant bacteria in commensal sites exposed to lesser, sun-inhibitory drug concentrations.

Teicoplanin in the treatment of infection caused by gram-positive organisms.

Teicoplanin was used to treat 94 hospital in-patients of confirmed or presumed Gram-positive infections over a period of 12 months. Eighty-five patients were subsequently found to be evaluable; 31 had soft tissue infections, 10 endocarditis, 8 urinary tract infections, 12 septicaemias, 2 chest infections, 7 osteomyelitis or septic arthritis, and 15 were immunosuppressed patients with infected Hickman line site infections. The cure rate of the 85 evaluable episodes was 90% (76 cured). Teicoplanin was well tolerated intravenously and intramuscularly. Adverse reactions occurred in five patients. One patient suffered high tone hearing loss, two patients suffered transient rash, one developed a drug fever and one patient who had concomitant gentamicin developed vestibular damage. It is concluded that teicoplanin is a relatively safe and effacacious treatment for Gram-positive infection.

A clinical trial of teicoplanin compared with a combination of flucloxacillin and tobramycin as antibiotic prophylaxis for cardiac surgery: the use of a scoring method to assess the incidence of wound infection.

A prospective randomized clinical trial is in progress to compare the efficacy of teicoplanin with flucloxacillin and tobramycin in the prevention of endocarditis and wound infection following cardiac surgery. To date, 198 patients have completed the trial, of whom 95 have received teicoplanin and 103 flucloxacillin and tobramycin. One patient developed prosthetic valve endocarditis 3 months after surgery covered by flucloxacillin and tobramycin. There was no significant difference in the incidence of sternal wound infection (P = 0.15). Severe sternal sepsis occurred in four patients in the teicoplanin group and two in the flucloxacillin/tobramycin group. There were more postoperative urinary tract infections among those given teicoplanin (15 of 95 patients compared to six of 103 patients P less than 0.05). The trial continues.

The effect of antibiotic prophylaxis and topical antiseptics on the bacterial flora of the skin after cardiac surgery.

A controlled trial of antibiotic prophylaxis in cardiac surgery compared a two-dose regimen of teicoplanin with a longer conventional course of flucloxacillin and tobramycin. In 12 patients the susceptibility of the bacterial skin flora of four different sites to each of the three antibiotics was determined and the results are reported here. Less than 1% of the Gram-positive colonies showed reduced sensitivity to teicoplanin (MIC greater than or equal to 4 mg l-1). Before operation, 99% inhibition of Gram-positive growth was achieved at 26 (54%) of 48 sites by 1 mg l-1 of flucloxacillin and 13 (27%) sites by 2 mg l-1 tobramycin. By the 7th day after operation there was a significant reduction in the number of sites showing similar sensitivity to flucloxacillin [16 (33%) sites, P less than 0.05]. The use of teicoplanin was not associated with the emergence of Gram-negative skin flora but tobramycin promoted acquisition of aminoglycoside-resistant strains.

Contamination of blood during cardiopulmonary bypass: the effect of antibiotic prophylaxis.

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 x 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.