Early antibiotic selection and efficient rooting and acclimatization improve the production of transgenic plum plants (Prunus domestica L.).

We describe here an improved system for routinely developing transgenic plum plants (Prunus domestica L.) through the use of Agrobacterium tumefaciens. The production of non-transformed "escapes" has been virtually eliminated, and rates of plant establishment in the greenhouse have been dramatically improved. The system is based on the regeneration of shoots from hypocotyls extracted from mature seed. The shoot regeneration medium is Murashige and Skoog (MS) salts and vitamins supplemented with 7.5 microM thidiazuron and 0.25 microM indole-butyric acid. Transferring the explants after co-cultivation to shoot regeneration medium containing 80 mg l(-1) of kanamycin and 300 mg l(-1) of Timentin reduced the total number of regenerated shoots without affecting the transformation rate. Transformation rates using the described system averaged 1.2% of the hypocotyl slices producing transgenic plants, with a range of 0-4.2%. The transgenic shoots rooted at a rate of 90% on half-strength MS salts and vitamins supplemented with 5 microM alpha-naphthaleneacetic acid and 0.01 microM kinetin. Plantlets were transferred to a greenhouse directly from culture tubes with a 90% average survival.

[The good use of antibiotics in intensive care: results of a program for rationalization of prescriptions]. / Du bon usage des antibiotiques en réanimation: résultats d'un programme de rationalisation de la prescription.

OBJECTIVE: To assess the impact of an antibiotic prescribing programme in a intensive therapy unit. TYPE OF STUDY: Prospective comparative study. METHODS: We compared antibiotic prescriptions and bacterial susceptibility to antimicrobial agents before and after introduction of a programme focusing on injection control and therapeutic indications. RESULTS: The introduction of the programme resulted in a major decrease in antibiotic administration. Moreover, the susceptibility of Pseudomonas aeruginosa to ticarcillin increased from 40 to 68%, and susceptibility of Staphylococcus aureus to methicillin increased from 55 to 73%. CONCLUSIONS: Antibiotic control policies must be considered integral to any effort to decrease resistance and cost of therapy with antibiotics.

Stenotrophomonas maltophilia: emergence of multidrug-resistant strains during therapy and in an in vitro pharmacodynamic chamber model.

Emergence of Stenotrophomonas maltophilia as a nosocomial pathogen is becoming increasingly apparent. Pleiotropic resistance characterizes S. maltophilia. Furthermore, a slow growth rate and an increased mutation rate generate discordance between in vitro susceptibility testing and clinical outcome. Despite original susceptibility, drug-resistant strains of S. maltophilia are often recovered from patients receiving beta-lactams, quinolones, or aminoglycosides. Given the disparity among various in vitro susceptibility methods, this study incorporated a unique pharmacodynamic model to more accurately characterize the bacterial time-kill curves and mutation rates of four clinical isolates of S. maltophilia following exposure to simulated multidose regimens of ceftazidime, ciprofloxacin, gentamicin, and ticarcillin-clavulanate. Time-kill data demonstrated regrowth of S. maltophilia with all four agents. With the exception of ticarcillin-clavulanate, viable bacterial counts at the end of 24 h exceeded the starting inoculum. Ciprofloxacin only reduced bacterial counts by less than 1.0 log prior to rapid bacterial regrowth. Resistant mutant strains, identical to their parent strain by pulsed-field gel electrophoresis, were observed following exposure to each class of antibiotic. Mutant strains also had distinct susceptibility patterns. These data are consistent with previous reports which suggest that S. maltophilia, despite susceptibility data that imply that the organism is sensitive, develops multiple forms of resistance quickly and against several classes of antimicrobial agents. Standard in vitro susceptibility methods are not completely reliable for detecting resistant S. maltophilia strains; and therefore, interpretation of these results should be done with caution. In vivo studies are needed to determine optimal therapy against S. maltophilia infections.

Transgenic white clover. Studies with the auxin-responsive promoter, GH3, in root gravitropism and lateral root development.

We report improved method for white clover (Trifolium repens) transformation using Agrobacterium tumefaciens. High efficiencies of transgenic plant production were achieved using cotyledons of imbibed mature seed. Transgenic plants were recovered routinely from over 50% of treated cotyledons. The bar gene and phosphinothricin selection was shown to be a more effective selection system than nptII (kanamycin selection) or aadA (spectinomycin selection). White clover was transformed with the soybean auxin responsive promoter, GH3, fused to the GUS gene (beta-glucuronidase) to study the involvement of auxin in root development. Analysis of 12 independent transgenic plants showed that the location and pattern of GUS expression was consistent but the levels of expression varied. The level of GH3:GUS expression in untreated plants was enhanced specifically by auxin-treatment but the pattern of expression was not altered. Expression of the GH3:GUS fusion was not enhanced by other phytohormones. A consistent GUS expression pattern was evident in untreated plants presumably in response to endogenous auxin or to differences in auxin sensitivity in various clover tissues. In untreated plants, the pattern of GH3:GUS expression was consistent with physiological responses which are regarded as being auxin-mediated. For the first time it is shown that localised spots of GH3:GUS activity occurred in root cortical tissue opposite the sites where lateral roots subsequently were initiated. Newly formed lateral roots grew towards and through these islands of GH3:GUS expression, implying the importance of auxin in controlling lateral root development. Similarly, it is demonstrated for the first time that gravistimulated roots developed a rapid (within 1 h) induction of GH3:GUS activity in tissues on the non-elongating side of the responding root and this induction occurred concurrently with root curvature. These transgenic plants could be useful tools in determining the physiological and biochemical changes that occur during auxin-mediated responses.

Piperacillin/tazobactam compared with ticarcillin/clavulanate in community-acquired bacterial lower respiratory tract infection.

The efficacy and safety of a new combination parenteral antibiotic, piperacillin/tazobactam, was compared with that of parenteral ticarcillin/clavulanate in the treatment of adult patients with community-acquired lower respiratory tract infections. A total of 299 patients were enrolled in this multicentre, double-blind, comparative study; 177 received piperacillin/tazobactam and 122 received ticarcillin/clavulanate. Of these, 119 met the evaluability criteria (69, piperacillin/tazobactam and 50, ticarcillin/clavulanate). The study drugs (piperacillin/tazobactam 3 g/375 mg or ticarcillin/clavulanate 3 g/100 mg) were given every 6 h by slow iv infusion for a minimum of 5 days. The favourable clinical response (cured and improved) rates of evaluable patients were 84% and 64% at endpoint (P < 0.01) for piperacillin/tazobactam and ticarcillin/clavulanate, respectively. The favourable bacteriological response at the early follow-up (eradicated and presumed eradicated) were 91% and 67% for piperacillin/tazobactam and ticarcillin/clavulanate, respectively (P < 0.01). At endpoint, 84% and 64%, respectively (P = 0.02) had a favourable response. The most common adverse experiences involved the gastrointestinal tract and occurred in 31.6% of the piperacillin/tazobactam group compared with 20.5% in the ticarcillin/clavulanate group (P = 0.02). These events were mild and generally did not affect therapy. Piperacillin/tazobactam appears to be more effective than ticarcillin/clavulanate in this patient population and is generally well tolerated.

P-nitrophenylglycerol in susceptibility testing media alters the MICs of antimicrobials for Pseudomonas aeruginosa.

Diagnostic microbiology laboratories in Australia and the UK commonly incorporate p-nitrophenylglycerol (PNPG) into solid susceptibility testing media in order to prevent the swarming of Proteus spp. We have investigated the effects of PNPG and adjusting the cation concentrations of the media to physiological levels on the MICs of aminoglycosides and other antibiotics for 128 strains of Pseudomonas aeruginosa isolated from the sputa of children with cystic fibrosis. The addition of PNPG to the media led to higher MICs of gentamicin and tobramycin for up to 23% of the isolates. Depending on the base medium, supplementation with the cations, calcium and magnesium, also increased the MICs of these aminoglycosides for 12-27% of the strains tested. Both incorporation of PNPG and cation adjustment led to higher MICs for 25-53% of isolates, again depending on the base medium. The MICs of ticarcillin, ciprofloxacin and colistin (on Iso-Sensitest agar) for significant numbers of strains were lower in the presence of PNPG, while those of ceftazidime varied from higher to lower, according to the concentration of the drug and the base medium. In many instances these changes would have altered the way in which the susceptibilities of the organisms would have been reported. PNPG clearly exerts an important effect when the in-vitro activities of various antibiotics against P. aeruginosa are determined by the agar dilution method. Recommendations for the inclusion of PNPG in susceptibility testing media should therefore be reviewed.

Efficacy of ticarcillin-clavulanic acid for treatment of experimental Staphylococcus aureus endocarditis in rats.

The efficacy of ticarcillin-clavulanic acid was compared with the efficacies of standard antistaphylococcal agents (flucloxacillin, oxacillin, nafcillin, and vancomycin) and ticarcillin in an experimental model of Staphylococcus aureus endocarditis. Therapy was either initiated soon (8 h) after infection, when numbers of bacteria in aortic valve vegetations were relatively low (approximately 6 to 8 log10 CFU/g), or delayed until 24 h after infection, when the vegetations usually contained greater than 9 log10 CFU/g. Doses of the antibiotic were selected to produce peak concentrations in rat serum similar to those achievable in humans after administration of parenteral therapeutic doses. Ticarcillin-clavulanic acid was more effective overall than ticarcillin alone against endocarditis caused by beta-lactamase-producing strains of S. aureus, illustrating the beta-lactamase-inhibitory activity of clavulanic acid in vivo. Ticarcillin-clavulanic acid was as effective as the standard antistaphylococcal beta-lactam agents flucloxacillin, oxacillin, and nafcillin in these infections, whereas vancomycin was generally less active. These results illustrate the clinical potential of ticarcillin-clavulanic acid in the prophylaxis or therapy of severe staphylococcal infections.

Antistaphylococcal activity of amoxicillin and ticarcillin when combined with clavulanic acid. Evaluation of oxacillin-resistant and oxacillin-susceptible isolates.

The beta-lactamase inhibitor, clavulanic acid, was combined with amoxicillin and with ticarcillin for in vitro studies with 586 staphylococci: 97 stock cultures of oxacillin-resistant strains recovered before 1982, and 489 blood or wound isolates collected from 40 separate medical centers during 1987-1988 (300 were oxacillin resistant). Over 92% of the staphylococci produced beta-lactamase enzymes and were thus resistant to both penicillins. However, with the addition of clavulanic acid, oxacillin-susceptible strains were rendered susceptible to low concentrations of amoxicillin and ticarcillin. Staphylococcus aureus strains with borderline or partial borderline resistance to penicillinase-resistant penicillins occurred infrequently (72 of 325 S. aureus isolates). Those strains were susceptible to both clavulanic acid combinations, because their methicillin resistance is thought to be due to an excess beta-lactamase production. Strains with chromosomally mediated intrinsic heteroresistance were relatively resistant to both drug combinations. Minimal inhibitory concentration (MIC) breakpoints that best separated those heteroresistant strains from oxacillin-susceptible isolates were as follows: amoxicillin/clavulanic acid, less than or equal to 2.0/1.0 micrograms/ml for susceptible; and ticarcillin/clavulanic acid, less than or equal to 4.0/2.0 micrograms/ml for susceptible. When the broth was supplemented by 2% NaCl, MICs for both drug combinations were increased by less than one doubling dilution. Although oxacillin and methicillin broth microdilution tests were more reliable when 2% NaCl was added, tests with the two drug combinations were only minimally improved by adding 2% NaCl to the broth medium.

Implications of beta-lactamase-inhibitor combinations.

Resistance of many species of bacteria to beta-lactam antibiotics is mediated via inactivation by beta-lactamase. Beta-lactamase inhibitors irreversibly bind to beta-lactamases and thus can prevent the destruction of active beta-lactam antibiotics. In the United States three beta-lactam-antibiotic/beta-lactam-inhibitor combinations are commercially available--the orally absorbed amoxicillin/clavulanic acid (A/C), the parenteral formulations of ampicillin/sulbactam (A/S) and ticarcillin/clavulanate (T/C). In a multicenter study that focused on T/C, the in vitro activity of amoxicillin (AMOX), ampicillin (AMP) and ticarcillin (TIC) against Neisseria gonorrhoeae and Haemophilus influenzae was obliterated when beta-lactamase-positive strains were tested, but all tested strains were susceptible to the antibiotics in combination with their respective beta-lactamase inhibitors. Clavulanic acid improved the activity of TIC against most species of Enterobacteriaceae but not against those Enterobacteriaceae that elaborate type I beta-lactamase or against non-Enterobacteriaceae gram-negative bacilli (except for Pseudomonas maltophilia). Staphylococci are generally beta-lactamase positive and considered resistant to AMP and TIC, but greater than 99% of 1,137 Staphylococcus aureus isolates and 92% of coagulase-negative staphylococcal isolates were susceptible to T/C, with comparable figures obtained for A/C and A/S. The activity of TIC against Bacteroides fragilis was improved up to 64-fold by clavulanic acid, with a definite but less pronounced effect on the non-fragilis Bacteroides species. Ninety-seven percent of strains of other anaerobic genera were susceptible to both TIC and T/C.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro anaerobic data on ticarcillin/clavulanate. A review of an ongoing survey.

Although a number of new antimicrobial agents described as "broad spectrum" have been introduced during the past several years, it should be recognized that each of them has its own unique spectrum of activity, strengths and weaknesses that define its appropriate clinical use. This report reviews the comparative susceptibility data on 495 bacterial isolates obtained from obstetric and gynecologic patients and on 522 Bacteroides fragilis group isolates. Susceptibility testing was conducted with broth microdilution using twofold dilutions of antimicrobials. The overall minimal inhibitory concentrations-90 (MIC90) for the 495 isolates were very low, and few resistant isolates were found. The MIC90 for cefotetan was 16 times greater than that for ticarcillin/clavulanate and ampicillin/sulbactam. Cephalosporins showed good activity against anaerobic cocci but variable activity against anaerobic gram-negative rods. A relatively high percentage of B fragilis group isolates were also resistant to clindamycin. The addition of 2 mg/mL of clavulanate to ticarcillin caused a 4- to 32-fold decrease in the MIC90 for various Bacteroides species. Less than 2% of the strains tested were resistant to clavulanate plus ticarcillin or amoxicillin. These results suggest that monotherapy with such agents could replace combination antibiotic therapy for mixed obstetric and gynecologic infections.

Salt-supplemented medium for testing methicillin-resistant staphylococci with newer beta-lactams.

The addition of 2% NaCl to cation-supplemented Mueller-Hinton broth (CSMHB) was evaluated for microdilution testing of the susceptibility of staphylococci to five cephalosporins, imipenem, amoxicillin-clavulanate, and ticarcillin-clavulanate. With Staphylococcus aureus, NaCl improved the recognition of methicillin (oxacillin) resistance to cefamandole, imipenem, or ticarcillin-clavulanate. Resistance to amoxicillin-clavulanate was readily determined, irrespective of the presence of added salt. The addition of 2% NaCl to CSMHB did not significantly improve detection of resistance to any of the beta-lactams among coagulase-negative staphylococci. Since the addition of NaCl did not have significant adverse effects on tests with coagulase-negative staphylococci, the routine addition of 2% NaCl to oxacillin or methicillin tests with staphylococci may be justifiable on the basis of convenience or standardization. However, addition of NaCl to susceptibility tests of other beta-lactams does not consistently improve recognition of resistance among staphylococci and thus cannot be recommended for routine use.

[Clinical studies of BRL 28500 (clavulanic acid/ticarcillin) in the treatment of pelvioperitonitis and Douglas' abscess].

Clinical studies were conducted on BRL 28500 (a formulation containing 15 parts ticarcillin plus 1 part clavulanic acid). BRL 28500 was administered at doses of 1.6 g or 3.2 g b.i.d., generally for 10 days by drip infusion to patients with pelvioperitonitis or Douglas' abscess. The results obtained were summarized as follows. 1. Clinical efficacy was evaluated in 18 patients (pelvioperitonitis 14, Douglas' abscess 4), but 8 patients out of a total of 26 patients were excluded. 2. In the evaluation of clinical improvement by doctors in charge, clinical improvement rates were 44.4% on day 3, 88.2% on day 5. 3. On the basis of committee judgement, the clinical efficacy rate was 100%. 4. The bacteriological eradication rate of causative organisms was 100% in 11 patients (15 strains). Five strains out of a total of 15 strains produced beta-lactamase. 5. As a side effect, nausea was observed in 1 case. In laboratory examination, liver function abnormalities were observed in 1 case. 6. Regarding usefulness as judged by doctors in charge, the satisfactory rate was 83.3%. From the above results, it has been concluded that BRL 28500 is very useful in the treatment of pelvioperitonitis and Douglas' abscess.

Comparison of the activity of antibiotic combinations in vitro with clinical outcome and resistance emergence in serious infection by Pseudomonas aeruginosa in non-neutropenic patients.

Techniques for demonstrating synergy in vitro were compared in testing different beta-lactam-aminoglycoside combinations against 30 isolates of Pseudomonas aeruginosa. Poor concordance was noted among the results from chequerboard and 6 h and 24 h time-kill methods. Comparison of in-vitro synergy results with clinical outcome in 14 patients with pseudomonas infection showed that antagonism in the 24 h time-kill method was the most reliable prognostic indicator of clinical and bacteriological outcome. Although more than 70% of patients were cured clinically with cefsulodin or ticarcillin with tobramycin or amikacin, pseudomonas resistant to the beta-lactam emerged in 7 of 14 patients (50%); of those seven, three had poor clinical outcome. The rationale of adding aminoglycoside to beta-lactams against P. aeruginosa to prevent emergence of resistance needs closer examination.

[Clinical evaluation of timentin in intensive care]. / Evaluation clinique du timentin en réanimation.

16 patients admitted to a MICU were treated with timentin (ticarcillin + clavulanic acid) for bacterial infections: 11 cases of pulmonary infection, 3 cases of urinary tract infection, 2 septic shocks, 3 septicemias and 1 case of multifocal infection. The pathogens considered as a firmly established cause of infection were: 5 Acinetobacter, 12 Pseudomonas, 3 Serratia, 4 Klebsiella, 1 E. coli, 2 Proteus, 1 Providencia, 1 Staphylococcus aureus, 1 Staphylococcus epidermidis, 1 Streptococcus D and 1 Flavobacterium meningosepticum. The susceptibility of these pathogens to ticarcillin and timentin is reported. Timentin was prescribed alone in 9 cases and associated (with an aminoglycoside) in 7, in a daily dose of 9 to 18 g, for 6 to 45 days. 3 patients died. The value of timentin in infections due to multiresistant MICU pathogens is stressed.

Prospective randomized comparison of three antibiotic regimens for empirical therapy of suspected bacteremic infection in febrile granulocytopenic patients.

The standard regimen used by members of the European Organization for Research on Treatment of Cancer Antimicrobial Therapy Cooperative Group for empiric therapy of febrile neutropenic cancer patients has been treatment with ticarcillin plus amikacin. A three-arm prospective randomized controlled trial was performed to determine whether the extended-spectrum antipseudomonal penicillin azlocillin or the extended-spectrum cephalosporin cefotaxime had more or less efficacy than the beta-lactam in the ticarcillin-plus-amikacin regimen. A total of 742 patients from 22 institutions were evaluated. Single gram-negative rod bacteremias accounted for 83 episodes, and it was among these patients that the prognosis was least satisfactory, leading to a more intensive evaluation of this patient group. In these patients the azlocillin-plus-amikacin regimen resulted in a 66% response rate, compared with a 37% response rate for patients who received cefotaxime plus amikacin (P = 0.080) and a 47% response rate for patients who received ticarcillin plus amikacin (P = 0.207). The patients with gram-negative rod bacteremias and persistently profound granulocytopenia had substantially poorer response rates (37%) than the patients with rising granulocyte counts (73%; P = 0.004). A logistic regression analysis indicated that the following factors also affected infection resolution: beta-lactam utilization in the regimen (azlocillin was better than ticarcillin or cefotaxime), resolution of profound granulocytopenia (less than 100 cells per microliter) during therapy, and susceptibility to the beta-lactam antibiotic.

Timentin versus piperacillin in the therapy of serious urinary tract infections.

In a comparative study, 47 patients received Timentin, a combination of ticarcillin plus clavulanic acid, or piperacillin to treat serious urinary tract infections. Thirty-nine infections in 38 patients were clinically evaluable (21 in the Timentin-treated group and 18 in the piperacillin-treated group). These included pyelonephritis (10 in the Timentin-treated group and five in the piperacillin-treated group), bladder infections with sepsis (11 in the Timentin-treated group and 11 in the piperacillin-treated group) and bladder infections without fever (two in the piperacillin-treated group). The addition of clavulanic acid to ticarcillin greatly enhanced the susceptibility of five of the 28 evaluable pathogens in the Timentin-treated group (two Escherichia coli isolates, two Staphylococcus aureus isolates, and one Klebsiella pneumoniae isolate). The minimal inhibitory concentrations at which 50 and 90 percent of the bacterial growth was inhibited were 4 and 64 micrograms/ml, respectively, for Timentin, and 4 and 32 micrograms/ml, respectively, for piperacillin. All evaluable patients had a satisfactory symptomatic response at the end of the trial. Of 28 evaluable pathogens treated with Timentin, 18 were eradicated up through the one-week post-therapy evaluation period; of 27 evaluable pathogens treated with piperacillin, 18 were eradicated up through the same time period. Eradicated pathogens included E. coli (six of 13 in the Timentin-treated group and six of 11 in the piperacillin-treated group), other Enterobacteriaceae (three of three in the Timentin-treated group and eight of 10 in the piperacillin-treated group), Pseudomonas aeruginosa (two of four in the piperacillin-treated group), enterococcus (two of three in the Timentin-treated group and two of two in the piperacillin-treated group), staphylococcal species (four of five in the Timentin-treated group), and other organisms (three of four in the Timentin-treated group). Resistance did not develop in any of the persisting pathogens. Adverse effects thought possibly to be related to the study drugs were minimal and included rash in one Timentin-treated patient and diarrhea in another.

[Clinical evaluation of a ticarcillin-clavulanic acid combination in severe infections in adults]. / Evaluation clinique de l'association ticarcilline-acide clavulanique dans les infections sévères de l'adulte.

Timentin (ticarcillin (TCR) + clavulanic acid (AC)) was given for severe bacterial infections to sixteen hospitalized patients (10 male and 6 female; 16 to 75 years of age; normal renal function in 12). Infections included 8 septicemias (of which 4 were secondary to pyelonephritis), 6 pyelonephritis (in addition to the four above-mentioned cases), and 3 suppurated cellulitis of the lower limbs (with septicemia in one case). The following bacteria were recovered: 10 Escherichia coli, 1 Pseudomonas aeruginosa, 1 Enterobacter cloacae, 1 Providencia stuartii, 1 Salmonella typhi, 1 Klebsiella pneumoniae, and 1 Staphylococcus aureus. The sixteen strains were all susceptible to timentin (MICs determined by agar dilution: TCR + AC 4 mg/l: 0.5-16 mg/l; TCR + AC 8 mg/l: 0.2-16 mg/l). Thirteen strains were susceptible to TCR (MIC less than or equal to 16 mg/l), and three (1 E. coli, 1 K. pneumoniae, and 1 S. aureus) were resistant to TCR (MIC greater than or equal to 256 mg/l). 14 patients received timentin alone, while two were also given dibekacin. Timentin was given in one-hour IV infusions in a dosage of 9.6 g/24 h (3.2 g X 3) in 10 patients and 6.4 g/24 h (3.2 g X 2) in 6. Duration of therapy was 14 to 16 days in half of cases (range 5 to 21 days). At termination of the infusion, serum concentrations of ticarcillin and clavulanic acid (determined in ten patients) were greater than 50 mg/l and 3-7.4 mg/l respectively, and serum bactericidal activity (evaluated in ten cases) was consistently less than 1/2.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum bactericidal activity as a therapeutic guide in severely granulocytopenic patients with gram-negative septicemia.

The peak and trough levels of bactericidal activity of the serum of 74 severely granulocytopenic patients (less than or equal to 500 polymorphonucleates per microliter) with hematologic malignancies and Gram-negative septicemia were measured using the patient's infectious organism and serum containing the given antibiotics. When the peak titer of bactericidal activity in the serum was greater than 1:8 the septicemia was cured in more than 90% of the cases. However, in order to achieve a satisfactory rate of cure, patients with less than 100 polymorphonucleates/microliter required higher peak levels than patients with 100-500 polymorphonucleates/microliter. Serum bactericidal activity was influenced by the in vitro susceptibility of the offending pathogen and by the presence of in vitro synergism between the given antibiotics. These two variables showed a correlation with the clinical outcome that proved to be increasing with the degree of granulocytopenia. Furthermore, synergistic combination of the antibiotics appeared essential when the in vitro susceptibility shown by the offending pathogen was moderate. These data suggest (i) that determination of the bactericidal activity of the serum may prove to be a useful method to predict the clinical outcome in severely granulocytopenic patients with Gram-negative septicemia; and (ii) under the same conditions, antibiotic combinations that have demonstrable in vitro synergy against the offending pathogen should be given the utmost consideration.

Clinical trial of the efficacy and safety of ticarcillin and clavulanic acid.

Forty-three hospitalized patients were treated with a new antibiotic combination containing ticarcillin plus the beta-lactamase inhibitor, clavulanic acid, in a fixed combination for intravenous use. A variety of infections were treated, including pneumonia, bacteremia, urinary tract infection, and osteomyelitis. Of 50 episodes of infection in 43 patients, 44 clinical cures were obtained, with 5 patients improving and 1 patient failing to respond to treatment. In vitro susceptibility testing of 101 clinical isolates was notable for the rarity of resistance to the combination antibiotic. Of specific interest, all 14 isolates of Staphylococcus aureus were susceptible to ticarcillin plus clavulanic acid, whereas only 2 of the 14 isolates were susceptible to ticarcillin alone. Adverse reactions to the study drug were minimal; eosinophilia, unaccompanied by other allergic phenomena, and oral candidiasis were most frequent. Overall, the combination of ticarcillin with the beta-lactamase inhibitor, clavulanic acid, appears to be a safe and effective drug for the treatment of infections caused by susceptible organisms.

In vitro studies of investigational beta-lactams as possible therapy for Pseudomonas aeruginosa endocarditis.

The inadequacy of the present medical therapy of Pseudomonas aeruginosa endocarditis prompted an investigation of the in vitro activities of aztreonam, cefsulodin, and imipenem compared with that of ticarcillin against 37 strains of P. aeruginosa isolated from patients with endocarditis. Inhibitory and bactericidal activities were studied for each beta-lactam alone and in combination with tobramycin. All agents showed excellent inhibitory activity. Imipenem was the most inhibitory beta-lactam yet lacked inhibitory synergy against 95% of the strains and bactericidal synergy against 62%. Tolerance to imipenem was seen in six strains. Aztreonam alone was bactericidal against 46% of the strains (at 16 micrograms/ml) and showed bactericidal synergy in 70%. Cefsulodin alone was even less active but similar to aztreonam synergistically. Ticarcillin and tobramycin inhibited all strains as single agents and showed universal bactericidal synergy in combination. None of the new beta-lactams showed consistent superiority to the presently used agent, ticarcillin.