J. M. T. Hamilton-Miller

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.

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.

Incidence and Mechanisms of Resistance to Trimethoprim in Clinically Isolated Gram-Negative Bacteria

Over an 18-month period (October 1973 to April 1975), 133 strains of gram-negative bacteria with acquired resistance to trimethoprim (TM) were isolated from infected urines cultured at the Royal Free Hospital. The overall frequency of resistance was 3.2%. A disproportionately high number of resistant strains (63.1%) were Kebsiella aerogenes. Resistance to TM mediated by R plasmids occurs infrequently (9% of all resistant strains); the majority of TMR plasmids isolated belonged to one incompatability group (W). Chromosomally mediated resistance to TM in most Escherichia coli and K. aerogenes strains appears to be due mainly to production of a dihydrofolate reductase with a reduced susceptibility to TM. In some strains, increased activity of the DHFR was also a contributing factor. Increase in enzyme level alone was only great enough to account for the level of resistance to TM in a small number of cases.

Effect of amoxicillin-clavulanate and cephradine on the fecal flora of healthy volunteers not exposed to a hospital environment.

A 7-day course of either cephradine or amoxicillin-clavulanate treatment caused no significant change in fecal flora composition, except that staphylococci were virtually eliminated in both groups. Some amoxicillin-resistant coliforms were isolated after treatment in both groups, but cephradine- or amoxicillin-clavulanate-resistant coliforms were rarely isolated.

Antibacterial oxazolidinones: In vitro activity of a new analogue, E3709

The oxazolidinone compound E3709, which contains a 4-pyridyl group, was found to be more active in vitro than other members of this series, such as DuP 721. MIC90 for staphylococci(including methicillin-resistant isolates), streptococci (including Enterococcus faecalis), Clostridia, and diphtheroids was less than 0.5 micrograms/ml. Haemophilus influenzae, Moraxella catarrhalis, and Bacteroides fragilis were less susceptible, with an MIC90 between 2 and 8 micrograms/ml. E3709 MICs of Gram-negative species ranged from 100 to greater than 1000 micrograms/ml. At a concentration of 10 micrograms/ml, E3709 was bactericidal for selected Gram-positive species. A postantibiotic effect of 3 hr was observed against staphylococci. Resistance to E3709 was not detected.

Urinary Tract Infections

Urinary tract infection (UTI) is a cause of significant discomfort, acute and long-term morbidity, and loss of productivity, resulting in 7 million to 8 million office visits with an estimated 100,000 episodes annually of pyelonephritis requiring hospitalization.1 Among children, 1 in 20 females and 1 in 50 males have a UTI each year.2

General survey of trimethoprim combinations in the treatment of urinary tract infections

SummaryThe properties of trimethoprim (TM), reviewed here, show it to be an excellent antimicrobial agent in its own right. However, with very few exceptions, TM has been made available clinically only in combination with a sulphonamide, usually sulphamethoxazole (SMX). We present evidence to suggest that the decision so to restrict the availability of TM was mistaken. Synergy between TM and SMX can be shown clearly in vitro, but there is no evidence from clinical trials that it plays a significant therapeutic role in urinary infections. Also, there is no evidence that combining the two antibiotics suppresses the emergence of resistance. Recently, sulphonamides other than SMX have been proposed as partners for TM, mainly on pharmacokinetic grounds. Compounds other than sulphonamides may also be logical partners for TM: we have made extensive studies on TM + rifampicin, for instance, and have obtained excellent results in certain clearly-defined patient groups. Only clinical trials of these new combinations will reveal whether they are superior to TM/SMX. There is already sufficient evidence to suggest that TM alone will be as effective as, and more acceptable than, TM/SMX. We propose that further large-scale clinical trials with TM alone be carried out, both to treat acute urinary infections and in prophylaxis.ZusammenfassungDie hier besprochenen Eigenschaften von Trimethoprim (TM) zeigen, daß es für sich allein ein vorzügliches antimikrobielles Mittel ist. Jedoch ist TM mit sehr wenigen Ausnahmen klinisch nur in Verbindung mit einem Sulfonamid, für gewöhnlich Sulfamethoxazol (SMX) zur Verfügung gestellt worden. Wir stellen Faktoren vor, aus denen geschlossen werden kann, daß es falsch war, die Verfügbarkeit von TM so einzuschränken. Der Synergismus zwischen TM und SMX kann in vitro eindeutig nachgewiesen werden, doch gibt es aus klinischen Untersuchungen keine Beweise dafür, daß er bei Harnwegsinfektionen eine wesentliche therapeutische Rolle spielt. Auch kann nicht bewiesen werden, daß die Kombination der beiden Antibiotika die Resistenzentwicklung vermindert. In jüngerer Zeit wurden vorwiegend aus pharmakokinetischen Gründen andere Sulfonamide als SMX als Partner für TM vorgeschlagen. Außer Sulfonamiden können auch andere Verbindungen sinnvolle Partner für TM sein. Wir haben beispielsweise ausgedehnte Untersuchungen an TM + Rifampicin durchgeführt und bei bestimmten klar umrissenen Patientengruppen ausgezeichnete Ergebnisse erzielt. Nur klinische Untersuchungen über diese neuen Kombinationen werden klären, ob sie dem TM/SMX überlegen sind. Es gibt bereits genügend Belege für die Annahme, daß TM allein ebenso wirksam sein wird wie TM/SMX und zugleich zufriedenstellender. Wir machen den Vorschlag, daß weitere umfangreiche klinische Versuche mit TM allein zur Behandlung von akuten Harnwegsinfektionen und zur Prophylaxe durchgeführt werden.

Trimethoprim Alone Compared to Co-trimoxazole in Lower Respiratory Infections: Pharmacokinetics and Clinical Effectiveness

24 patients, admitted to hospital with lower respiratory tract infection, were treated with either co-trimoxazole (800 mg sulphamethoxazole + 160 mg trimethoprim) or trimethoprim (200 mg) orally twice daily. All showed a clinical improvement and with one exception respiratory pathogens were eliminated. Pharmacokinetics in blood, sputum and saliva were studied in 11 patients taking trimethoprim and 9 taking co-trimoxazole. No sulphamethoxazole was detected in either the sputum or saliva. Trimethoprim was found in higher concentrations in the sputum than in the blood, although there were wide and significant variations in individual patients sputum pharmacokinetic profiles. Trimethoprim penetrates into the sputum at therapeutic concentrations in patients with chronic respiratory infections.

Microbiological studies on some bladder irrigation fluids

SummaryA 1.5% glycine solution has recently been introduced as a bladder irrigation fluid. In this study, glycine solution was compared with two other recognised bladder irrigants (chlorhexidine and noxythiolin) for its inhibitory activity against common urinary tract pathogens. Glycine solution supported the growth of nearly 50% of the bacterial strains tested whereas chlorhexidine and noxythiolin were completely inhibitory. In quantitative studies with selected strains it was found that growth could be initiated from as few as 200 organisms/ml. It was concluded that glycine solution was capable of supporting bacterial growth and thus, from a microbiological viewpoint, was unsuitable as a bladder irrigant.ZusammenfassungVor kurzer Zeit wurde die Glyzinlösung als Blasenspülflüssigkeit eingeführt. In der vorliegenden Untersuchung wurde die Glyzinlösung mit zwei anderen bewährten Blasenspülflüssigkeiten (Chlorhexidin und Noxythiolin) hinsichtlich ihrer Hemmwirkung gegenüber gewöhnlichen Krankheitserregern der Harnwege verglichen. Die Glyzinlösung förderte das Wachstum von nahezu 50% der geprüften Bakterienstämme, während Chlorhexidin und Noxythiolin vollständige Hemmwirkung zeigten. In quantitativen Versuchen mit ausgewählten Stämmen wurde festgestellt, daß sich Wachstum mit einer Konzentration von nur 200 Erregern pro ml in Gang setzen ließ. Es wurde gefolgert, daß Glyzinlösung bakterielles Wachstum fördern kann und aus mikrobiologischer Sicht somit als Blasenspülflüssigkeit ungeeignet ist.

Cefixime for Switch Therapy

Switch therapy, or step-down therapy, is the concept of switching from an intravenous antibiotic to an oral preparation after a few days, once the condition of the patient has improved and the pathogen and its susceptibility have been determined. The orally active third-generation cephalosporin cefixime is a primary candidate for switch therapy owing to its very good efficacy and safety profile. Preliminary studies have shown excellent clinical outcomes with switch therapy to cefixime after 2–3 days for a variety of serious infections. Importantly, dramatic cost benefits have also been found, particularly with respect to reduced length of hospital stays. However, guidelines are required to indicate under what conditions switch therapy is appropriate, and awareness must be developed within hospitals among physicians, pharmacists and administrators alike.