In-vitro activity of pefloxacin compared to enoxacin, norfloxacin, gentamicin and new beta-lactams

The in-vitro activity of pefloxacin was compared with that of norfloxacin, enoxacin, nalidixic acid, gentamicin, cefotaxime, ceftazidime and, where appropriate, other beta-lactams against a total of 363 recent clinical isolates. An agar dilution procedure was used to determine MICs and two inocula (10(4) and 10(6) cfu) were used throughout. Pefloxacin inhibited 90% of isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, indole-positive Proteus spp., Enterobacter spp., Shigella sonnei, Salmonella typhi, Campylobacter jejuni, Staphylococcus aureus and Haemophilus influenzae at less than or equal to 0.5 mg/l. Serratia marcescens and Providencia stuartii were somewhat more resistant, 2 mg/l of pefloxacin being required to inhibit 90% of isolates of these species. Pefloxacin inhibited 90% of isolates of Pseudomonas aeruginosa at 4 mg/l and 90% of isolates of the Bacteroides fragilis group at 16 mg/l. The activity of enoxacin was similar to that of pefloxacin, with enoxacin being four-fold less active against Staph. aureus, two-fold less active against the Bacteroides fragilis group and most species of the Enterobacteriaceae, and two-fold more active against Ps. aeruginosa. Pefloxacin showed good activity against gentamicin-resistant Ps. aeruginosa and Enterobacteriaceae and against methicillin-resistant Staph. aureus. Strains with decreased susceptibility to norfloxacin tended to be less susceptible to both pefloxacin and enoxacin.     

Laboratory evaluation of enoxacin: comparison with norfloxacin and nalidixic acid

Enoxacin displayed activity similar to that of norfloxacin against enterobacteria, Pseudomonas aeruginosa, staphylococci, streptococci and Bacteroides spp. The activity of enoxacin against many strains was reduced in acid conditions, but the pH effect was not so marked as that seen with norfloxacin. Nalidixic acid was found to be more active in acid conditions, particularly against staphylococci, Streptococcus faecalis and Ps. aeruginosa. In conditions simulating the treatment of bacterial cystitis, a single dose of enoxacin, achieving a peak concentration of 50 mg/l, suppressed growth of nalidixic acid-sensitive and -resistant Gram-negative bacilli for periods of between 18 and 25 X 5 h. Reduced susceptibility of bacteria surviving exposure to enoxacin was observed in one nalidixic acid-resistant strain of Escherichia coli and in nalidixic acid-sensitive strains exposed to low doses (peak concentration = 5 mg/l) of enoxacin. These results are similar to those obtained with norfloxacin and substantially better than those obtained with nalidixic acid.     

In-vitro activity of enoxacin (CL-919), a new quinoline derivative, compared with that of other antimicrobial agents

The in-vitro activity of enoxacin (CI-919), a new synthetic quinoline derivative was compared with that of three other quinolines ofloxacin, norfloxacin and nalidixic acid. In addition beta-lactams and gentamicin were also included when appropriate. The MICs of enoxacin for 90% of Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus spp., Providencia stuartii, Pseudomonas aeruginosa and Staphylococcus aureus were less than 4 mg/l, for Haemophilus influenzae less than 0.25 mg/l and Neisseria gonorrhoeae less than 0.03 mg/l. Bacteroides fragilis and streptococci (including Streptococcus pneumoniae) were less susceptible, MIC90 16 mg/l. Against many of the common Enterobacteriaceae enoxacin displayed a similar degree of activity as gentamicin. Gentamicin-resistant strains of common bacterial pathogens were susceptible to enoxacin as were methicillin-resistant Staph. aureus. The protein binding of enoxacin (concentration 5 mg/l) was 18%.     

The in-vitro activity of CI-934 compared with that of other new 4-quinolones and nalidixic acid

The in-vitro activity of CI-934, a new 4-quinolone compound, was compared with that of the other new 4-quinolones, enoxacin and ciprofloxacin, and also with that of nalidixic acid. CI-934 was more active than any of the other 4-quinolones tested against Gram-positive aerobic organisms including Staphylococcus aureus (MICs 0.06-0.25 mg/l), beta-haemolytic streptococci (MICs 0.12-0.5 mg/l), Streptococcus pneumoniae (MICs 0.25-0.5 ml/l), viridans streptococci (MICs 0.06-0.5 mg/l) and most enterococci (MICs 0.12-0.5 mg/l), although some ampicillin-resistant isolates of Str. faecium were slightly less susceptible (MICs 2 mg/l). All three of the newer 4-quinolones tested were highly active against Enterobacteriaceae, Aeromonas sp., Haemophilus influenzae and Neisseria gonorrhoeae (MICs mostly less than 1 mg/l). The other Gram-negative aerobes tested were in general somewhat less susceptible, although for Acinetobacter and Pseudomonas aeruginosa MICs seldom exceeded 8 mg/l. CI-934 was more active than enoxacin against Gardnerella vaginalis (MICs 1-8 mg/l) although it was a little less active than ciprofloxacin. Bacteroides species (including about half of the fragilis group) were susceptible to CI-934 (MICs mostly 1-8 mg/l): ciprofloxacin had similar activity but enoxacin was less active. Other anaerobes tested were mostly highly susceptible to CI-934 (MICs 1 mg/l or less) but were somewhat less susceptible to enoxacin and ciprofloxacin.     

In-vitro antimicrobial activity of enoxacin in combination with eight other antibiotics against Pseudomonas aeruginosa, Enterobacteriaceae and Staphylococcus aureus

Susceptibilities of 28 strains of Pseudomonas aeruginosa, 32 strains of Enterobacteriaceae and 24 strains of Staphylococcus aureus were tested against combinations of enoxacin with either cefsulodin, piperacillin, or amikacin, enoxacin with either aztreonam, latamoxef or amikacin, and enoxacin with either oxacillin, clindamycin or vancomycin, respectively. Synergy was detected by the agar dilution technique and was defined as a four-fold decrease in the inhibitory concentration of both drugs (sigma FIC less than or equal to 0.5). Against Ps. aeruginosa, synergy occurred in 28.5% of the strains for enoxacin plus cefsulodin, 17.6% for enoxacin plus piperacillin, and 3.7% for enoxacin plus amikacin. Against the Enterobacteriaceae, synergy was detected with enoxacin plus aztreonam, latamoxef or amikacin in 9.3%, 3.1% and 0% of strains, respectively. Against Staph. aureus, no synergy was demonstrable with enoxacin plus oxacillin, clindamycin or vancomycin. No antagonism was detected for any combination tested. Selected strains demonstrating synergy by the agar dilution method for enoxacin plus cefsulodin or piperacillin failed to show synergy in kinetic studies.     

The in-vitro activity of EN 272, a quinolone-7-carboxylic acid, in comparison with other quinolones

The in-vitro activity of EN 272, a quinolone-7-carboxylic acid was determined and compared with that of enoxacin, ofloxacin, norfloxacin, ampicillin, cephalexin and trimethoprim. EN 272 inhibited the majority of the Enterobacteriaceae at concentrations of less than or equal to 1.6 mg/l. EN 272 was four- to 32-fold less active than the other new quinolones, but it inhibited organisms resistant to nalidixic acid, ampicillin and cephalexin. EN 272 had poor activity against Pseudomonas aeruginosa and streptococcal species, but it did inhibit most staphylococci at less than or equal to 6.3 mg/l. EN 272 was less active at pH 5.5 and in urine as are other quinolones.     

Genetic and physiological characterization of ciprofloxacin resistance in Pseudomonas aeruginosa PAO.

Spontaneous ciprofloxacin-resistant mutants of Pseudomonas aeruginosa PAO2 were isolated on ML agar containing 0.5 microgram of ciprofloxacin per ml (2 times the MIC). The mutants were 8- to 64-fold more resistant to ciprofloxacin and showed complete cross resistance to nalidixic acid, ofloxacin, enoxacin, and norfloxacin. Two chromosomal resistance genes, cfxA and cfxB, were mapped between eda-9001 and phe-2 and near pyrB52 distal to proC130, respectively. The cfxB mutation was identical to a nalB mutation and conferred cross resistance to novobiocin, tetracycline, carbenicillin, and chloramphenicol, suggesting that there is an effect on permeability. DNA gyrase A and B subunits were purified from strain PAO2 (wild type), PAO236 nalA2, PAO4704 cfxA2, and PAO4700 cfxA1 cfxB1. Inhibition of gyrase-mediated DNA supercoiling by ciprofloxacin or nalidixic acid was greatly reduced in preparations derived from each of the mutants. Inhibition studies on reconstituted heterologous gyrase subunits showed that decreased inhibition was dependent on the mutant gyrase A subunit. We conclude that ciprofloxacin resistance in P. aeruginosa PAO2 can occur by mutation in the nalB gene or the gene for DNA gyrase A (formerly nalA).     

Comparative evaluation of recently developed quinolone compounds--with a note on the frequency of resistant mutants

The antibacterial activity of the new quinolone compounds enoxacin, norfloxacin, ofloxacin and ciprofloxacin was evaluated in 300 Enterobacteriaceae, 50 Pseudomonas aeruginosa, 30 Acinetobacter spp., 15 Haemophilus influenzae, 50 Streptococcus faecalis, and 70 Staphylococcus aureus isolates and compared to that of nalidixic acid, gentamicin and various beta-lactam compounds. Moreover, the rate of spontaneous mutants resistant to quinolone compounds was evaluated. In concentrations only insignificantly exceeding the minimal inhibitory concentrations (MIC), mutants could be isolated rather frequently (approx. 10(-6) fold); in concentrations of at least 10 times the MIC resistant mutants were barely detectable. In general, the mutants exhibited a 4- to 8-fold increase of the MIC as compared to the wild strain. In S. faecalis mutants were not detectable, whereas they occurred in low frequency (less than 10(-8) fold) in S. aureus strains. In all mutants there was almost, but not entirely, complete cross-resistance between the quinolone derivatives.     

In-vitro activity of WIN 57273 compared to the activity of other fluoroquinolones and two beta-lactam antibiotics.

WIN 57273, a new fluoroquinolone, was four to 128-fold more active than ciprofloxacin and ofloxacin against Gram-positive bacteria. The MIC90 for Staphylococcus aureus was 0.015 mg/l and for S. epidermidis, 0.03 mg/l. All Lancefield group A, B, C, & G streptococci, Streptococcus bovis and S. pneumoniae were inhibited by less than or equal to 0.06 mg/l compared to 0.5 mg/l for tosufloxacin and 2 mg/l for ciprofloxacin. For anaerobic bacteria WIN 57273 had an MIC90 for bacteroides of 1 mg/l, and for Clostridium spp. 0.015.mg/l. WIN 57273 was less active than ciprofloxacin against Enterobacteriaceae, with an MIC90 of 1 mg/l, including aminoglycoside and cephalosporin-resistant isolates. The MIC90 of WIN 57273 for Pseudomonas aeruginosa was 2 mg/l, compared to 0.5 mg/l for ciprofloxacin. Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, and Legionella spp. were inhibited by 0.06 mg/l. WIN 57273 was more active against Gram-negative bacteria at acid pH, but activity was decreased by magnesium ions and an increase in inoculum. Resistant strains were selected after passage on antibiotic-containing agar.     

The in-vitro activities of enoxacin and ofloxacin compared with that of ciprofloxacin

The in-vitro activities of enoxacin and ofloxacin were compared with that of the other new 4-quinolone, ciprofloxacin. All three compounds were highly active against Enterobacteriaceae, Haemophilus influenzae and Neisseria gonorrhoeae (MICs mostly less than 1 mg/l). The other Gram-negative aerobes tested were in general less susceptible, though for Acinetobacter and Pseudomonas species (including aeruginosa) MICs seldom exceeded 8 mg/l. Ofloxacin and ciprofloxacin were more active against Gardnerella vaginalis (MICs 0.5-2 mg/l) than was enoxacin (MICs 8-32 mg/l). Staphylococci were susceptible to ofloxacin (MICs 0.12-1 mg/l) and enoxacin (MICs 0.5-2 mg/l) as well as to ciprofloxacin. Streptococci also were mostly sensitive to the compounds though the MICs of enoxacin (4-64 mg/l) were noticeably higher than those of ofloxacin (1-4 mg/l). Anaerobes were in general susceptible though, as with streptococci, ofloxacin, with activity similar to that of ciprofloxacin, was more active than enoxacin. Variants of Enterobacteriaceae with reduced susceptibility were readily selected in the laboratory with either enoxacin or ofloxacin as the selective agent. The MICs of all the 4-quinolones were usually increased four- to 16-fold for these strains; they could therefore be regarded as remaining susceptible to the newer compounds.     

HR 810 and BMY-28142, two new cephalosporins with broad-spectrum activity: an in-vitro comparison with other beta-lactam antibiotics

The in-vitro activity of the new parenteral cephalosporins, HR 810 (HR) and BMY-28142 (BMY), was compared with that of other beta-lactam antibiotics, including cefotaxime, against a total of 315 recent clinical isolates and characterized beta-lactamase producers. An agar dilution procedure was used to determine MICs and two inocula (10(4) and 10(6) cfu) were used throughout. Against all species of the Enterobacteriaceae tested, both HR and BMY were as active as, or slightly more active than, cefotaxime. HR differed from cefotaxime mainly in being eight-fold more active against Pseudomonas aeruginosa and two-fold more active against Staphylococcus aureus. BMY was also eight-fold more active than cefotaxime against Ps. aeruginosa but was two-fold less active than the latter against Staph. aureus. Both new compounds had good activity against Haemophilus influenzae, including the beta-lactamase producing strains of that species, and both had poor activity against the Bacteroides fragilis group (MIC90 greater than 128 mg/l).     

Norfloxacin (MK-0366) treatment of urinary tract infections in hospitalized patients

Norfloxacin (MK-0366) is a new antibacterial agent, closely related to nalidixic acid, with broad spectrum activity against Gram-positive and Gram-negative organisms, including Pseudomonas aeruginosa. A clinical study was conducted on forty hospitalized patients with bacteriologically proven urinary tract infections; 20 patients were given norfloxacin and 20 co-trimoxazole. Clinical results were excellent in both groups; norfloxacin was effective in infections due to Ps. aeruginosa and other multi-resistant pathogens. No side effects were reported.     

Aztreonam in patients with acute purulent exacerbations of chronic bronchitis: failure to prevent emergence of pneumococcal infections

A group of 36 patients, all requiring hospital admission because of acute purulent exacerbations of chronic bronchitis, were treated with 1 or 2 g intramuscular injections of aztreonam for ten days. Patients with Streptococcus pneumoniae infections were excluded from the study. Sputum cultures before treatment revealed the other usual respiratory pathogens but repeat cultures on days 3, 10 and 17 sometimes yielded Str. pneumoniae, occasionally combined with Haemophilus influenzae or Branhamella catarrhalis. Ten patients had to be given other antimicrobial agents for Str. pneumoniae infections which developed during the study or follow-up periods. Pseudomonas aeruginosa failed to respond well to aztreonam. All the H. influenzae strains were sensitive to aztreonam (MIC 0.25 mg/l, or less) but all strains of Str. pneumoniae were resistant (MIC greater than 32 mg/l). Ps. aeruginosa strains were moderately resistant (MIC generally 4-16 mg/l) and Bran. catarrhalis strains only moderately sensitive (MICs generally 0.5-4 mg/l). Peak serum concentrations averaging approximately 37 mg/l were observed after the 1 g injections (55 mg/l after 2 g) and the corresponding mean peak concentrations in the sputum were 1.3 mg/l and 2.5 mg/l, respectively. The penetration from blood to sputum was thus approximately 3.5% and 4.6% after the 1 g and 2 g doses. No unwanted local or general reactions were observed. The disappointing clinical results (only 23 out of 36 patients with excellent or good clinical results) one week after the end of the treatment were mainly due to the emergence of pneumococcal infections during (and immediately after) therapy. Considering that Str. pneumoniae is still one of the most important organisms associated with acute purulent exacerbations of chronic bronchitis, and that conventional sputum cultures may not always reveal its presence, there is considerable doubt if aztreonam has any place in the treatment, especially as the results in Ps. aeruginosa infections have also been much poorer than expected.     

Pefloxacin in acute exacerbations of chronic bronchitis

Forty-three patients admitted to hospital with acute purulent exacerbations of chronic bronchitis were treated with 400 mg pefloxacin twice daily for ten days. The first 20 patients were given the first dose of the drug as a 60 min intravenous infusion. Serum and sputum concentrations of pefloxacin were measured microbiologically at intervals on the first treatment day and the sputum was cultured before, during, and after the course of pefloxacin. Two patients died from unrelated causes during the follow-up and one refused to continue treatment. All strains of Haemophilus influenzae and Branhamella catarrhalis were eradicated at end-of-treatment but eight strains of Streptococcus pneumoniae and three of Pseudomonas aeruginosa were cultured and the sputum remained purulent despite the pefloxacin. Peak serum concentrations averaged approximately 4.5 mg/l after the infusion and 5 mg/l on oral administration, the corresponding sputum concentrations being 3.8 and 4.6 mg/l, respectively. MICs for H. influenzae were 0.06 mg/l, or less. Mode MICs for the pre- and post-treatment strains of Str. pneumoniae were 4 and 16 mg/l, and the corresponding values for Ps. aeruginosa were 2 and 16 mg/l. The poor results in pseudomonas and pneumococcal infections could largely be explained by the degree of resistance among these organisms.     

Temafloxacin in acute purulent exacerbations of chronic bronchitis

Temafloxacin hydrochloride, a new fluoroquinolone, was given orally in doses of 300 or 600 mg twice daily for ten days to 36 patients, all hospitalized because of severe acute purulent exacerbations of chronic bronchitis. Sputum cultures before, during and after treatment showed that the infection was eliminated in 12/18 evaluable patients given 300 mg and in 13/16 receiving the 600 mg doses. Haemophilus influenzae, Branhamella catarrhalis and Streptococcus pneumoniae were effectively eliminated, but only half the Pseudomonas aeruginosa infections were eradicated. MICs for most pathogens were 1 mg/l or less (including the majority of the pneumococci) but the MICs for Ps. aeruginosa ranged from 0.5 to greater than 16 mg/l, those for 10 of the 22 strains being greater than 2 mg/l. Pharmacokinetic studies on serum and sputum specimens showed serum Cmax values of 3.5 and 6.0 mg/l, the sputum Cmax being 2.35 and 4.17 mg/l after the different doses. No interaction with concomitant theophylline could be found. Two patients complained of moderate nausea or water-brash. Temafloxacin can be considered safe and effective at these dosages, but for Ps. aeruginosa infections higher dosages need to be investigated.     

In-vitro activity of ofloxacin, a quinolone carboxylic acid compared to other quinolones and other antimicrobial agents

Ofloxacin is a new quinolone carboxylic acid compound. Its activity against 900 bacterial isolates was determined. It inhibited 90% of Escherichia coli, Klebsiella sp., Aeromonas hydrophila, Salmonella spp., Shigella spp., Citrobacter spp., Enterobacter spp., Morganella morganii, Proteus mirabilis, Yersinia enterocolitica at less than or equal to 0.8 mg/l. Branhamella catarrhalis, Haemophilus sp., Neisseria sp. were inhibited by less than or equal to 0.1 mg/l. Pseudomonas aeruginosa and other Pseudomonas species were inhibited by less than or equal to 6.3 mg/l. Although most staphylococcal species, including methicillin-resistant staphylococci were inhibited by 3.1 mg/l, many streptococcal species had higher MIC values, and most Bacteroides species were inhibited at less than or equal to 6.3 mg/l. The overall activity of ofloxacin was similar to enoxacin and norfloxacin. Ofloxacin inhibited organisms resistant to nalidixic acid, ampicillin, cephalexin, piperacillin, and gentamicin including Enterobacter spp., Citrobacter freundii and Serratia marcescens resistant to cefotaxime. The activity of ofloxacin was lower at an acid pH and in urine, but serum had no effect on MICs or MBCs. Increase in ofloxacin MICs for various bacteria could be achieved by repeated subculture in the presence of ofloxacin.     

In-vitro activity of pefloxacin compared with six other quinolones

The in-vitro antimicrobial activity of pefloxacin was compared with that of three of the newer fluorated quinoline derivates: ciprofloxacin, norfloxacin and enoxacin, as well as with those of the earlier analogues: nalidixic acid, pipemidic acid and cinoxacin, against almost 750 recent patient isolates of medically important bacteria. MIC90S of pefloxacin were less than or equal to 2 mg/l for Enterobacteriaceae, less than or equal to 8 mg/l for Pseudomonas aeruginosa, less than or equal to 4 mg/l for other nonfermenters and 0.5 mg/l for Staphylococci. Most streptococcal strains were resistant to pefloxacin. Of all the fluorated quinolones, ciprofloxacin was overall the most active compound. The older non-fluorated quinolone analogues had activity against the Enterobacteriaceae only at levels achievable in urine.     

Interaction of subminimal inhibitory concentrations of clindamycin and gram-negative aerobic organisms: effects on adhesion and polymorphonuclear leukocyte function

The effect of pre-incubation of Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus mirabilis with sub-inhibitory concentrations (sub MICs) of clindamycin on the adherence of these organisms was studied. Culturing these organisms in the presence of clindamycin (4 mg/l) resulted in significant enhancement of adherence for Ps. aeruginosa and Pr. mirabilis and decreased adherence for K. pneumoniae. Furthermore, the effect of pre-exposure to clindamycin on polymorphonuclear leukocyte (PMNLs) function against these organisms was determined. Filtrates of Pr. mirabilis pre-exposed to clindamycin promoted PMNL chemotaxis. No effect on chemotaxis was noted with the filtrates of clindamycin treated Ps. aeruginosa and K. pneumoniae. PMNL phagocytosis for all the organisms was increased after they were pre-exposed to clindamycin.     

Efficacy and safety of cefpirome (HR810)

Sixty adult patients with suspected systemic bacterial infections were treated with cefpirome 1 g or 2 g twice daily for 5-22 days. Forty-seven patients were evaluable for clinical efficacy. Diagnoses in evaluable patients were urinary tract infections (20), pneumonia (10), soft tissue infections (17), and bone and joint infections (4); four patients had two infections each. Nine patients were bacteraemic and all were cured; the responsible bacteria were Escherichia coli (6), Streptococcus pneumoniae (1), Pseudomonas aeruginosa (1), and Haemophilus influenzae (1). One patient with a soft tissue infection failed to respond clinically to cefpirome. Bacteriologically, 41 of 48 isolated pathogens (85%) were eradicated. In wound cultures, three strains of Staphylococcus aureus and one each of Ps. aeruginosa and Str. faecalis persisted. One Enterobacter sp. relapsed in urine. Of isolated strains, only Str. faecalis and methicillin resistant Staph, epidermidis were resistant to cefpirome. Staph, aureus strains were inhibited in vitro by 0.25 to 2 mg/l of cefpirome in agar dilution. Adverse effects, probably or possibly related to cefpirome, were skin reactions (3), fever (1), Clostridium difficile diarrhoea (2), and disturbed taste sensation (1). Tolerance was good. Cefpirome is suitable for large-scale comparative trials.     

In vitro activity of Bay 09867, a new quinoline derivative, compared with those of other antimicrobial agents.

The in vitro activity of Bay 09867, a new quinoline derivative, was compared with those of norfloxacin, nalidixic acid, ceftazidime, cefaclor, cefuroxime, gentamicin, and other antimicrobial agents, when appropriate, against 410 recent clinical isolates. The minimal inhibitory concentrations of Bay 09867 for 90% of Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria gonorrhoeae, streptococci, Staphylococcus aureus, and Bacteroides fragilis strains were between 0.008 and 2 micrograms/ml. Bay 09867 was considerably more active against the gram-negative bacteria tested than were other agents tested. Gentamicin-resistant Enterobacteriaceae, P. aeruginosa, and methicillin-resistant S. aureus were highly susceptible to Bay 09867. Strains less susceptible to nalidixic acid and norfloxacin tended to be less susceptible to Bay 09867. The protein binding of Bay 09867 was about 20%.