Metal-carbenicillin framework-based nanoantibiotics with enhanced penetration and highly efficient inhibition of MRSA.

The development of effective therapies to control methicillin-resistant Staphylococcus aureus (MRSA) infections is challenging because antibiotics can be degraded by the production of certain enzymes, for example, ß-lactamases. Additionally, the antibiotics themselves fail to penetrate the full depth of biofilms formed from extracellular polymers. Nanoparticle-based carriers can deliver antibiotics with better biofilm penetration, thus combating bacterial resistance. In this study, we describe a general approach for the construction of ß-lactam antibiotics and ß-lactamase inhibitors co-delivery of nanoantibiotics based on metal-carbenicillin framework-coated mesoporous silica nanoparticles (MSN) to overcome MRSA. Carbenicillin, a ß-lactam antibiotic, was used as an organic ligand that coordinates with Fe3+ to form a metal-carbenicillin framework to block the pores of the MSN. Furthermore, these ß-lactamase inhibitor-loaded nanoantibiotics were stable under physiological conditions and could synchronously release antibiotic molecules and inhibitors at the bacterial infection site to achieve a better elimination of antibiotic resistant bacterial strains and biofilms. We confirmed that these ß-lactamase inhibitor-loaded nanoantibiotics had better penetration depth into biofilms and an obvious effect on the inhibition of MRSA both in vitro and in vivo.

Randomized trial comparing oral ciprofloxacin plus penicillin V with amikacin plus carbenicillin or ceftazidime for empirical treatment of febrile neutropenic cancer patients.

Aminoglycoside-containing combination therapy has been the standard empirical approach for febrile neutropenic cancer patients. With the advent of the broad-spectrum oral fluoroquinolones, it is now possible to evaluate an initial empirical alternative therapy. A prospective randomized study was conducted comparing oral ciprofloxacin plus penicillin V (group A) with amikacin plus carbenicillin or ceftazidime (group B). Main criteria for eligibility were febrile patients with solid tumor or nonlymphoblastic lymphoma, a Zubrod PS equal to 1 or 2, no diarrhea, mucositis, or long-term central venous catheter. A total of 108 consecutive neutropenic febrile episodes were randomized (5 exclusions); 55 episodes were assigned to group A and 48 to group B. Most febrile episodes were of unknown origin. There were 10 microbiologically documented episodes with two cases of bacteremia. Both regimens were well tolerated. Oral regimen was substantially cheaper than parenteral regimen. Treatment success without regimen modification was 94.5% for group A and 93.8% for group B (p = .86; CI -0.08-0.10). Oral therapy with ciprofloxacin and penicillin V is a safe alternative to standard parenteral therapy in this low-risk group of neutropenic patients, with unquestionable cost containment.

[Sensitivity of pathogens of post-ventilation pneumonia in newborns to antibacterial drugs]. / Chuvstvitel'nost' vozbuditelei postventiliatsionnoi pnevmonii u novorozhdennykh detei k antibakterial'nym preparatam.

The majority of the enteric bacteria and aerobic and anaerobic cocci causing postventilation pneumonia in newborns were susceptible to gentamicin, carbenicillin, ampicillin and cephalosporins. The strains of Pseudomonas aeruginosa were mainly susceptible to gentamicin and carbenicillin. Bacteroides were susceptible to metronidazole, ceftazidime and lincomycin. 70.8 per cent of the causative agents of the pneumonia were polyresistant to at least 6 antibiotics.

Adverse reactions to prolonged treatment with high doses of carbenicillin and ureidopenicillins.

Charts were reviewed for 63 patients whose chronic pseudomonas osteomyelitis was treated with high doses of extended-spectrum penicillins for prolonged periods. The incidence of untoward drug reactions was significantly higher than expected. Carbenicillin evoked adverse reactions in 22.8% of patients. However, most of these reactions were mild, and a change of drug was required in only 5.7% of cases. No adverse drug reactions were observed with cumulative doses of less than 750 g. In contrast to carbenicillin, the ureidopenicillins were associated with adverse reactions in 67.7% of patients; most reactions were moderate to severe in intensity; a cumulative dose of greater than 250 g produced adverse reactions; and discontinuation or change of therapy was required in 51.6% of cases. The main adverse reactions to both carbenicillin and the ureidopenicillins included rash, drug fever, leukopenia, eosinophilia, thrombocytopenia, and hepatic damage.

In vitro models for the study of combination antibiotic therapy in neutropenic patients.

Neutropenic patients are at risk of serious infection caused by gram-negative bacilli and staphylococci. The mortality rate associated with gram-negative bacteremia in these patients is extremely high, especially in those with persistent and profound granulocytopenia. In these latter patients, the best results have been obtained by administering combinations of antibiotics in which both agents are active and/or show in vitro synergism against the infecting organism. Most combinations include an aminoglycoside such as amikacin and a broad-spectrum beta-lactam antibiotic, such as azlocillin, mezlocillin, piperacillin, or ceftazidime. The International Antimicrobial Therapy Project Group of the European Organization for Research and Treatment of Cancer has completed several studies evaluating various antibiotic combinations in the empiric treatment of febrile neutropenic patients. These trials have evaluated cephalothin plus gentamicin, carbenicillin plus gentamicin, and cephalothin plus carbenicillin; carbenicillin plus amikacin and carbenicillin plus amikacin plus cefazolin; azlocillin plus amikacin, ticarcillin plus amikacin, and cefotaxime plus amikacin; and azlocillin plus amikacin versus ceftazidime plus long- or short-course amikacin. The preclinical evaluation of antibiotic combinations usually involves the in vitro testing of antibiotics alone and in combination by the checkerboard method or with the use of time-kill curves. However, these methods expose the bacterial culture to a static or constant concentration of the drugs. During the in vivo treatment of infections, bacteria are exposed to changing concentrations of antibiotics, which are contingent on the individual pharmacokinetics of these drugs. We have designed a two-compartment in vitro pharmacokinetic model that allows the simultaneous study of the activity of two antibiotics with similar or different half-lives against a number of bacteria. Amikacin and azlocillin have been studied alone and in combination in this model against Pseudomonas aeruginosa, a frequent cause of bacteremia in neutropenic patients. In pharmacologically relevant doses, amikacin alone produced rapid bacterial killing, followed by regrowth of resistant subpopulations. Azlocillin alone produced a more gradual reduction of the bacterial inoculum, with ultimate bacteriostasis. Amikacin plus azlocillin produced rapid and complete eradication of the organism. In vitro pharmacokinetic models may prove to be more predictive of clinical outcome than are traditional static in vitro methods used to study antibiotic combinations.

[Laboratory methods of controlling the effectiveness of antibacterial therapy]. / Laboratornye sposoby kontrolia éffektivnosti antibakterial'noi terapii.

The serum antibacterial activity (SAA) against causative agent isolated after the use of antibiotics was studied in 68 patients with pyoseptic diseases. The SAA ranged from 1:2 to 1:512 and depended on the antibiotic sensitivity of the causative agents. Antibiotic therapy was effective, when the SAA was equal to 1:8-1:512. With the use of monotherapy the adequacy of the regimens was controlled by the relation between the maximal blood level of the antibiotic and its MIC for the causative agent. The favourable clinical effect of the treatment with aminoglycosides and beta-lactams corresponded to the SAA exceeding 4.

Azlocillin compared with carbenicillin in the treatment of bronchopulmonary infection due to Pseudomonas aeruginosa in cystic fibrosis.

A randomised controlled open comparison of azlocillin and gentamicin versus carbenicillin and gentamicin was carried out in patients with cystic fibrosis who were chronically infected with Pseudomonas aeruginosa. The clinical response was assessed by measurements of pulmonary function and of the patients' feelings of wellbeing scored on a visual analogue scale. The sputum penetration of the antibiotics used was also studied. The two groups of 10 patients were similar in terms of age, sex, and pulmonary function at entry to the trial. Both regimens produced significant improvement in pulmonary function over 10 days. The mean FEV1 in the azlocillin group increased from 1206 to 1760 ml (p less than 0.001). In the carbenicillin group the mean FEV1 increased from 1116 to 1619 ml (p less than 0.001). Significant improvements in peak expiratory flow rate, forced vital capacity, and score on the visual analogue scale were also seen but there was no significant difference between the antibiotic regimens. Despite high serum concentrations the sputum penetration of the antibiotics was poor.

Comparative efficacy of piperacillin versus carbenicillin for complicated urinary tract infections.

In this controlled, randomized clinical trial we compared piperacillin and carbenicillin in the treatment of complicated urinary tract infections. 24 patients received piperacillin 150 mg/kg/day for 7.2 +/- 2.75 days and 17 patients received carbenicillin 200 mg/kg/day for 7.5 +/- 2.90 days. Patients were evaluated for clinical and bacteriologic responses and tolerance to therapy. Although the clinical cure rate significantly favored carbenicillin treatment (p less than 0.01), the sum of the percentages of cases with clinical cure and clinical improvement were similar between groups: 91.6% for piperacillin and 88.2% for carbenicillin. The bacteriologic cure rates for piperacillin and carbenicillin patients (54.1 and 47.0%, respectively) were not significantly different (p greater than 0.05). The low cure rates in our study were probably the result of uncorrected/uncorrectable genitourinary tract abnormalities. Superinfections developed in 12.5 and 17.6% of piperacillin and carbenicillin patients, respectively, and were due to Klebsiella pneumonia, Proteus mirabilis, Citrobacter diversus, and Pseudomonas aeruginosa. Overall, side effects were mild, reversible, and did not require discontinuation of treatment. However, carbenicillin caused elevations in liver enzymes more frequently than piperacillin (p less than 0.05). Based on our data, we recommend reserving piperacillin monotherapy for patients who are poor candidates for aminoglycosides, or are on severe sodium restriction, and have serious complicated urinary tract infections due to susceptible organisms. We do not recommend piperacillin alone for empiric treatment of complicated urinary tract infections.

Comparative efficacy and tolerance study of azlocillin and carbenicillin in patients with cystic fibrosis: a double blind study.

Azlocillin, a new acylureidopenicillin, has been compared to carbenicillin in a controlled, double-blind study for acute exacerbations of pulmonary infections in 29 patients with cystic fibrosis. Twenty-six patients were valid for final analysis of their therapeutic results; 12 treated with azlocillin (group I) at mean dosage of 252 mg/kg/day for a mean duration of 13.2 days of treatment, and 14 treated with carbenicillin (group II) at mean dosage of 505 mg/kg/day for a median duration of 12.6 days. Except for one patient of group I who had Staphylococcus aureus in sputum culture, the remaining patients all had Pseudomonas aeruginosa of mucoid colonial morphology with or without the same organism of rough variety in their sputum culture. Therapeutic efficacy was evaluated according to our scoring system of ten clinical factors, five radiological and five pulmonary function factors with 5 points each and 100 points total if perfect. The percentage of patients who improved by 20% or greater in clinical scores was found in 91.7% of patients in group I and 64.3% of patients in group II, which was statistically significantly different. The percentage of patients who improved by 20% or greater in total scores was found in 80% of group I and 45.5% of group II patients, which was less significant than the evaluation of clinical scores alone. Azlocillin was well tolerated and safe in the dosage employed. Its optimal dosage for patients with cystic fibrosis should be established.

Piperacillin v Carbenicillin in the therapy for serious infections.

One hundred seven patients were treated with either piperacillin (56) or carbenicillin (51) in an open randomized trial of hospitalized patients with pleuropulmonary (40), urinary tract (26), gynecologic (21), skin and soft-tissue (eight), joint (five), bone (three), and miscellaneous other infections (four). Patients with urinary tract infections were given 150 mg/kg/day of piperacillin sodium or 200 mg/kg/day or carbenicillin sodium in divided doses every six hours intravenously. Patients with other infections were given 250 mg/kg/day of piperacillin sodium and 450 mg/kg/day of carbenicillin sodium; 53/56 (95%) patients treated with piperacillin and 45/51 (88%) patients treated with carbenicillin were cured clinically. In general, the drugs were well tolerated. There were, however, more adverse experiences in the groups taking carbenicillin. Of special interest was the finding of liver function test abnormalities in 17/78 (21%) carbenicillin recipients (evaluative and nonevaluative cases). We concluded that piperacillin was effective and safe. It has potential for use in a great variety of infections.

Preliminary report comparing piperacillin and carbenicillin for complicated urinary tract infections.

Piperacillin is a new semisynthetic penicillin with a broad spectrum of in vitro activity against common gram-negative urinary tract pathogens. We compared the efficacy and safety of piperacillin versus carbenicillin in patients with complicated urinary tract infection. A total of 56 adult patients (mean age 55 years) in stable medical condition with 1 or more structural genitourinary abnormalities entered the study. Of these patients 27 were evaluated for antibiotic efficacy. There were 20 lower tract and 7 upper tract infections, of which 17 were acute and 10 were chronic. Patients were randomized into 2 groups: 17 patients with 18 organisms received single agent treatment with 181 mg. per kg. intravenous piperacillin daily for 6 days and 10 patients with 11 organisms received 270 mg. per kg. intravenous carbenicillin daily for 6 days. Infecting organisms were Escherichia coli 45 per cent, Proteus mirabilis 14 per cent, Klebsiella pneumoniae 14 per cent. Enterobacter species 10 per cent, Pseudomonas aeruginosa 7 per cent and so forth. Antimicrobial susceptibility assessed by measurement of minimal inhibitory concentration and disk diffusion zone size demonstrated superior activity of piperacillin over carbenicillin for most micro-organisms tested. All patients responded clinically. The bacteriologic cure rate was 72 per cent at 5 to 9 days after therapy in both groups. Three patients who received piperacillin had urosepsis and were cured. No resistance emerged during therapy. Superinfections developed in 5 patients on carbenicillin (50 per cent) and in 4 patients on piperacillin (24 per cent), and none was resistant to piperacillin. Superinfections were attributed to catheterization and structural genitourinary abnormalities. The over-all incidence of adverse effects in patients on piperacillin was less than that of those on carbenicillin, 31 and 51 per cent respectively. Side effects in both groups were mild and did not require discontinuation of therapy. There were no significant alterations in fluid and electrolyte balance, or hematologic or renal function.

[Clinical experience of mezlocillin in France (author's transl)]. / Expérience clinique de la mezlocilline chez l'adulte. Etudes réalisées en France.

The acylureidopenicillin mezlocillin -- the first penicillin with activity against both ampicillin -- and carbenicillin-resistant micro-organisms--has been clinically tested on a world-wide scale on more than 4000 patients. The present study summarizes the results of clinical trials conducted in France on 580 patients, most of whom had urinary tract or respiratory tract infection, as well as septicaemia, meningitis and various post-operative infections. The daily dosage ranged from 100 to 250 mg/kg (6 to 15 g) divided into three 8-hourly intravenous bolus injections or infusions, or 2 to 3 g doses administered intramuscularly. Eighty-two p. cent of the organisms isolated were completely eradicated, and the incidence of relapses was only 5 %. Therapeutic results were satisfactory in about 90 % of the cases. The best results were obtained in upper and lower UTIs, respiratory infections meningitis, biliary tract infections, peritonitis and septicaemia. Side-effects were those common to all penicillins, i.e. allergic or digestive disorders : they seldom occurred and were always reversible. This, together with the lack of renal or hepatic disturbances, should encourage the use of mezlocillin in extremely or moderately severe infections caused by sensitive organisms. The antibiotic appears to be particularly valuable in patients with impaired renal function or immunodepressed.

[Effectiveness of the combined use of tobramycin with carbenicillin or cephalosporins in experimental infection in mice caused by Providencia stuartii]. / Effektivnost' kombinirovannogo primeneniia tobramitsina s karbenitsillinom ili tsefalosporinami pri éksperimental'noi infektsii u myshei, vyzvannoi Providencia stuartii.

Antibacterial activity of tobramycin in combination with carbenicillin or cephalosporins against 20 strains of Providencia stuartii was studied. The combinations of tobramycin with carbenicillin (1 : 2.5) or cephaloridine (1 : 1) were most active. The MIC of tobramycin used in combination with carbenicillin or cephaloridine decreased 3-30 times. In treatment of albino mice with sepsis caused by Providencia stuartii it was possible to lower 2-8 times the dose of tobramycin used in combination with carbenicillin or cefazolin.

Mezlocillin and carbenicillin: a clinical comparison of serious systemic infections in surgical patients.

Eighty patients suffering from severe cases of systemic surgical infections were enrolled in a prospective, controlled randomized study to compare mezlocillin and carbenicillin. The daily dosage was chosen according to international recommendation, i.e. 4 g mezlocillin 6-hourly and 5 g carbenicillin 4-hourly. A clinical, bacteriological and combined "overall" evaluation was made. There was a distinct trend in favour of the mezlocillin group which was not statistically significant. The treatment was well tolerated; no side-effects were observed.

[Comparison of effect and tolerance of mezlocillin with carbenicillin in the treatment of bacterial infections]. / Vergleich der Wirkung und Verträglichkeit von Mezlocillin mit Carbenicillin bei der Behandlung bakterieller Infektionen.

Of 60 patients who were suffering from bacterial infections, 30 were treated with mezlocillin and 30 with carbenicillin in a randomized study. The patients received the recommended daily doses of 16 g and 30 g, respectively. Clinical efficacy was found in all patients. Mezlocillin eliminated the strains more reliably than carbenicillin. The bacteriological success rate was 27/30 and 16/30, respectively. We should also take into account the fact that the six patients with cholecystitis who were treated with carbenicillin could not be controlled after treatment.

Mezlocillin in serious surgical infections caused by carbenicillin-resistant bacteria.

Fifty-eight surgical patients suffering from severe bacterial infections caused by mezlocillin-sensitive, carbenicillin and/or gentamicin-resistant bacteria were treated with mezlocillin in 1980. At the end of therapy, the infection had been eliminated in 52 patients; they were cured. The remaining six did not need any additional antibacterial treatment. Sixty-two of the bacterial strains isolated had been eliminated, seven markedly reduced in number and three persisted. No development of resistance or side-effects was observed. A randomized comparative study was conducted at the same time.