W. Brumfitt

WORLD-WIDE ANTIBIOTIC RESISTANCE IN METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS

Antibiotic resistance patterns were determined for 106 strains of methicillin-resistant Staphylococcus aureus (MRSA) from 21 countries. Resistance to gentamicin, tobramycin, netilmicin, amikacin, streptomycin, or erthromycin was recorded in more than 90% of strains. Resistance to the other compounds tested was as follows: tetracycline 86%, minocycline 76%, trimethoprim 69%, clindamycin 66%, neomycin 59%, chloramphenicol 39%, rifampicin 26%, fosfomycin 22%, ciprofloxacin 17%, fusidic acid 12%, bacitracin 2%, and novobiocin 1%. All the stains were sensitive to mupirocin, pristinamycin, ramoplanin, teicoplanin, and vancomycin. There were geographical patterns of resistance: MRSA from the UK and Australia were predominantly resistant to trimethoprim, whereas many strains from centres in Europe and the USA were sensitive. MRSA that were resistant to ciprofloxacin were of French and German origin. 15 strains, 12 of which came from France, Turkey, or Brazil, were resistant either to thirteen or to fourteen agents.

Changes in the pharmacokinetics of ciprofloxacin and fecal flora during administration of a 7-day course to human volunteers.

Twelve male subjects, aged 19 to 40 years, shown to be healthy by examination and laboratory tests, took 500 mg of ciprofloxacin every 12 h for 7 days. After the first and the last dose, blood and urine samples were taken and drug concentrations were determined by bioassay. There was a significant buildup in mean concentrations in serum from day 1 to day 7; mean peak levels (attained after 1 to 2 h) were 1.9 and 2.8 micrograms/ml, respectively. The terminal half-life was 3.5 to 4 h. About 40% of the drug was excreted into the urine during the 12-h period after dosing; minimum mean concentrations in urine were 105 micrograms/ml on day 1 and 174 micrograms/ml on day 7. Considerable amounts of ciprofloxacin were found in the feces on day 7 (185 to 2,220 micrograms/g). Marked changes in the aerobic part of the fecal flora were observed as a result of taking ciprofloxacin: coliforms were absent on day 7, and concentrations of streptococci and staphylococci were significantly reduced. There was no overgrowth by yeasts. One week later the fecal flora had returned to a state similar to that found before treatment. Anaerobes were little affected quantitatively but acquired resistance to ciprofloxacin. Side effects were mild and transient.

Double-blind Trial to Compare Ampicillin, Cephalexin, Co-trimoxazole, and Trimethoprim in Treatment of Urinary Infection

In order to test their value in urinary infection a double-blind trial was carried out using ampicillin, cephalexin, trimethoprim-sulphamethoxazole (co-trimoxazole), and trimethoprim. Eighty-three courses of treatment were given to hospital patients, 149 to pregnant women, and 107 to patients with dysuria and frequency seen in domiciliary practice. Thus infections of varying severity in defined groups of patients caused by organisms with different antibiotic sensitivities were treated. Analysis of the overall results (339 courses) was compared with those from the individual groups and considerable variation in response was found. In domiciliary infections and bacteriuria in pregnancy trimethoprim alone proved to be at least as effective as the other three compounds and caused fewer than half the number of side effects. In the hospital patients co-trimoxazole was superior to trimethoprim. The overall results for ampicillin and cephalexin were similar although cephalexin proved to be inferior in treating symptomatic domiciliary infections.

Cefoxitin and Cephalothin: Antimicrobial Activity, Human Pharmacokinetics, and Toxicology

Cefoxitin, a semisynthetic cephamycin, has been compared with the widely used parenteral cephalosporin, cephalothin, in terms of antibacterial activity, human pharmacokinetics, and toxicity. For both compounds, minimal inhibitory concentrations were within the therapeutic range against the 156 gram-positive cocci tested (except group D streptococci), but cephalothin was 8 to 20 times more active. Regarding the 313 gram-negative organisms tested, both antibiotics were of approximately equal activity against cephalothin-susceptible strains, but cefoxitin was outstandingly superior against Providencia spp. and indole-producing Proteus spp., and markedly better against Serratia marcescens and Bacteroides fragilis. Against these organisms, cefoxitin but not cephalothin would be expected to be therapeutically valuable. Antibiotic activity levels in the serum and urine of 18 human volunteers after parenteral administration were higher and more prolonged in the case of cefoxitin, which had an average terminal serum half-life of about 45 min and a urinary recovery of about 90%. Cefoxitin was entirely nontoxic and, given intramuscularly, slightly less painful then cephalothin. These preliminary results suggest that cephamycins may prove to be a significant chemotherapeutic advance.

Periurethral enterobacterial carriage preceding urinary infection.

The periurethral enterobacterial flora was identified before infective episodes in 56 patients with recurrent urinary infection. There were 91 episodes of infection, with colonisation by aerobic gram-negative bacilli in 60. In only 31 (34%) episodes were patients colonised with the infective strain. In 31 episodes there was no colonisation of the perineum and in 29 there was heterologous colonisation. In another group of 54 women investigated during an enterobacterial infection of the urine there was colonisation with the infecting organism in 55 (86%) of 64 episodes; in 2 there was no colonisation; and 7 (11%) were associated with a heterologous strain. Women who have recurrent urinary infections are susceptible to perineal and periurethral colonisation with gram-negative bacteria but the infection need not be with the colonising enterobacteria.

Cefoxitin, a New Semi-synthetic Cephamycin: An In-vitro and In-vivo Comparison with Cephalothin

The activity of cefoxitin was compared with that of cephalothin against 229 bacterial strains. Cefoxitin was more active against most Gram-negative strains, notably against indole-producing Proteus spp., which are usually resistant to the cephalosporins. Cefoxitin was not susceptible to any significant extent to degradation by β-lactamases produced by Gram-negative organisms. Against Gram-positive organisms, however, cefoxitin was considerably less active than cephalothin, but minimum inhibitory concentrations for Staphylococcus aureus were well within therapeutically attainable blood levels. Pharmacokinetic studies in 18 volunteers showed a higher and longer sustained antibiotic activity in serum and urine after injections of cefoxitin than after equal doses of cephalothin. Urinary recovery of cefoxitin activity was also much higher than that of cephalothin. No evidence of toxicity due to cefoxitin was found. Cefoxitin was slightly less painful after intramuscular injection than cephalothin.

Newer Aminoglycosides—Amikacin and Tobramycin: An in-vitro Comparison with Kanamycin and Gentamicin

Tobramycin and amikacin are new aminoglycoside antibiotics which resemble gentamicin and kanamycin respectively in pharmacokinetic, toxicological, and some microbiological respects. Minimum inhibitory concentrations for these four antibiotics have been determined against 393 bacterial strains (13 species from eight genera) isolated from clinical material Kanamycin was the least active, 89% of the Pseudomonas aeruginosa strains being resistant. Resistance was also found in 21% of the Klebsiella aerogenes, 16% of the indoleproducing Proteus species, 4% of the E. coli and 3% of the Enterobacter spp. tested. Providenca stuartii strains were often resistant to gentamicin and tobramycin. Apart from these exceptions, however, all the organisms tested were sensitive to all four compounds, gentamicin and tobramycin usually showing the highest intrinsic activity. Amikacin was the most active compound against a selection of strains chosen because of their resistance to one or more of the aminoglycosides. Thus, amikacin represents a significant advance over kanamycin and seems to be superior to gentamicin in terms of its in-vitro properties. This is especially the case in those unusual circumstances when gentamicin-resistant strains are a problem. We suggest that amikacin warrants further investigation since it may prove to be a valuable alternative to gentamicin in the treatment of life-threatening infections.

Single dose and conventional treatment for acute bacterial and non-bacterial dysuria and frequency in general practice

SummaryA five day course of calvulanate-potentiated amoxicillin (Augmentin®) has been compared with a single oral dose of fosfomycin trometamol in the treatment of patients complaining of symptoms suggesting urinary tract infection. The study took place in a single urban general practice of 15,000 patients in Cheshire. The microbiology was performed at a London Teaching Hospital. 141 patients entered the trial. 65 had a significant bacteriuria, 62 of which were assessable for the ability of the trial drugs to eradicate bacteriuria: 29 patients received clavulanate-potentiated amoxicillin and 33 fosfomycin trometamol. The cure rates, assessed at five to ten days and at four to six weeks post treatment, were 72% and 65%, respectively for clavulanate-potentiated amoxicillin and 85% and 81%, respectively for fosfomycin trometamol. Side effects, assessed in all 141 patients, occurred in 11.6% receiving clavulanate-potentiated amoxicillin and in 8.3% receiving fosfomycin. Statistically there is no difference between any of these findings and the effect of sample size is discussed. 69 patients were symptomatic but did not have a significant bacteriuria (“urethral syndrome”). These patients were assessed for the effect of treatment in relieving symptoms: 33 received fosfomycin trometamol and 36 clavulanate-potentiated amoxicillin. The success and speed of relieving the symptoms were very similar in the two groups. The finding that both groups responded equally well appears to refute an aetiological role for lactobacilli and diphtheroids in the “urethral syndrome”, since these organisms are resistant to fosfomycin but sensitive to clavulanate-potentiated amoxicillin.ZusammenfassungPatienten, die Beschwerden einer Harnwegsinfektion hatten, wurden entweder fünf Tage lang mit Amoxicillin-Clavulansäure (Augmentan®) oder mit einer oralen Einzeldosis von Fosfomycin Trometamol behandelt. Die Studie wurde in einer Allgemeinpraxis in Cheshire durchgeführt, die 15 000 Patienten versorgt. 141 Patienten wurden in die Studie aufgenommen. 65 hatten eine signifikante Bakteriurie, davon konnten 62 in die Auswertung bezüglich Eradikation der Bakteriurie durch das Prüfmedikament einbezogen werden; 29 Patienten erhielten Amoxicillin-Clavulansäure und 33 Fosfomycin Trometamol. In der ersten Gruppe waren am 5.–10. Tag und vier bis sechs Wochen nach Therapieende 72% beziehungsweise 65% geheilt, die entsprechenden Zahlen für Fosfomycin Trometamol waren 85% und 81%. Bei 11,6% der insgesamt ausgewerteten 141 Patienten traten Nebenwirkungen unter Amoxicillin-Clavulansäure und bei 8,3% unter Fosfomycin Trometamol auf. Ein statistischer Unterschied zwischen diesen Befunden besteht nicht, die Bedeutung der Probengröße hierfür wird diskutiert. 69 Patienten klagten über Beschwerden, hatten jedoch keine signifikante Bakteriurie (urethrales Syndrom). Sie wurden im Hinblick auf eine Linderung ihrer Beschwerden durch Fosfomycin Trometamol (n=33) oder Amoxicillin-Clavulansäure (n=36) geprüft. In beiden Gruppen war der Einfluß auf die Beschwerden nach Grad und Geschwindigkeit sehr ähnlich. Das vergleichbar gute Ansprechen der beiden Gruppen scheint gegen eine ätiologische Bedeutung von Laktobazillen und Diphtheroiden beim „urethralen Syndrom“ zu sprechen, denn diese Bakterien sind gegen Fosfomycin Trometamol resistent, gegen Amoxicillin-Clavulansäure hingegen empfindlich.

LACTOBACILLI DO NOT CAUSE FREQUENCY AND DYSURIA SYNDROME

Mid-stream specimens (MSU) of urine were collected from 142 healthy women (pregnant and non-pregnant) and cultured for lactobacilli and other fastidious bacteria. The latter either require CO2 or are obligate anaerobes. Lactobacilli were present in counts of 10(4)/ml or more in 34.8% of the women, and in counts of 10(5)/ml or more in 20.2%. Besides lactobacilli, which were the bacteria most frequently isolated, anaerobic gram-positive cocci (peptococci and peptostreptococci) were often found. This flora is typical of that of the lower vagina, and none of these women had either symptoms of urinary infection of pyuria. Therefore, the bacteria isolated were commensals or contaminants. Cultures of MSUs taken from 26 women with symptoms of dysuria and/or frequency, but without significant numbers of conventional pathogens such as Escherichia coli, contained commensals and contaminants of the same variety and in similar numbers. Urine samples from 50% of these patients contained at least 10(4) lactobacilli/ml and 27% had 10(5) or more/ml. Lactobacilli were absent from the suprapubic urine specimens cultured from a further 44 women. There was no significant difference between the isolation rate of lactobacilli in urine cultures from healthy women and the rate in women with dysuria and frequency.

Diminished effect of gentamicin under anaerobic or hypercapnic conditions.

The in-vitro activity of gentamicin, judged by M.I.C. determinations, was much reduced when a normal aerobic atmosphere was replaced either by air +4% CO2 or by anaerobic conditions. The phenomenon was greatest for Staphylococcus aureus, where a decrease in activity of up to 20-fold was found. For Escherichia coli, Klebsiella aerogenes, Enterobacter spp., and Proteus spp. the factor of decrease was between 15-fold and 2-5-fold. Changes in medium pH, as a result of bacterial growth, can explain these findings for some, but not all, the species tested.