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Objective: To assess the effectiveness of combined therapy with azlocillin and amikacin in a group of neonates with sepsis caused by multiresistant staphylococci who were hospitalized in the neonatal intensive care unit of Hospital Ginecobstétrico "America Arias" in Havana, Cuba, from 1998 to 2000., Methods: A retrospective study was carried out of the clinical and laboratory results obtained in 15 patients with sepsis caused by multiresistant staphylococci who received combined therapy with azlocillin and amikacin, according to hospital guidelines on the use of antibiotics. We used a broth microdilution method to study the patterns of resistance shown by isolated strains to 10 of the antibiotics in use. In vitro synergy tests, specifically the checkerboard technique with microtitration plates, were used to observe the effects of treatment in 8 patients., Results: Twelve coagulase-negative staphylococci and three Staphylococcus aureus isolates showed five different patterns of resistance on the basis of their sensitivity to oxacillin, three aminoglycosides, and vancomycin. Six of the synergy tests showed a considerable synergistic effect, with an average three-fold reduction in the minimum inhibitory concentrations (MIC) of the two antibiotics used to treat the patients. No antagonistic effects were noted, and the combined antibiotics showed an overall clinical effectiveness of 91.7%., Conclusions: The test showed that the therapeutic combination used was effective, but further studies are needed before conclusive results are obtained.

The clinical efficacy and toxicity of once-daily compared with multiple-daily gentamicin dosing, in combination with azlocillin, were studied retrospectively in febrile neutropenic episodes following intensive chemotherapy. Fifty-two episodes were studied in 28 patients with acute myeloid leukaemia. Reasons for initiation of antibiotic therapy, dose, duration of treatment, organism isolation rates, response, cost comparison and toxicity were studied in the two treatment groups. The main indication for initiation of antibiotic therapy was neutropenic fever without a documented infection (80.8% of episodes). The response rate to once-daily gentamicin dosing and azlocillin was three times higher than to multiple-daily gentamicin dosing and azlocillin (P = 0.0112). The incidence of toxicity was low overall and was slightly but not significantly higher in the once-daily group. In this clinical context once-daily gentamicin at a dose of 7 mg/kg/day is more effective than a multiple-daily dosing regimen but may be more toxic.

Unlabelled: We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis., Study Design: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization., Results: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P =.034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P <.001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy., Conclusion: We conclude that the combination of a beta-lactam and an aminoglycoside produces a longer clinical remission than a beta-lactam alone and slightly better initial improvement.

Embryonated hens' eggs can be reliably infected by Pseudomonas aeruginosa in laboratory experiments. Therapy tests with the antibiotics azlocillin (CAS 37091-66-0) and gentamicin (CAS 13291-74-2) on this type of infected hens' eggs demonstrate that this test system offers a realistic alternative to septic experiments with small laboratory rodents. Chick embryos survive a lethal Pseudomonas infection when azlocillin or gentamicin in a relevant therapeutic dose are administered immediately after the infective agent. The use of Pseudomonas infected chick embryos in the screening for new antiinfectives allows, therefore, a considerable reduction of the number of laboratory rodents required.

We report a case of endocarditis caused by a ciprofloxacin-resistant strain of Serratia marcescens in a 50-year-old female neutropenic patient with non-Hodgkin's lymphoma which occurred while receiving ciprofloxacin prophylaxis. She made poor progress on first line therapy with azlocillin and gentamicin by bolus injection t.d.s. The infection was finally eliminated by a regimen of continuous infusion of azlocillin and once daily gentamicin.

Symptoms of bronchopneumonia developed over 4 months in a 63-year-old woman in previously good health. The symptoms worsened despite treatment with tetracycline (500 mg twice daily for 10 days). Middle-lobe pneumonia was diagnosed both clinically and radiologically, but monotherapy with ofloxacin (200 mg twice daily) was ineffective, as well as combined treatment with gentamycin (80 mg), oxacillin (1 g) and azlocillin (5 g), each three times daily intravenously. Bronchoscopy revealed obstruction of the lumen of the right middle lobe bronchus by viscous purulent secretion which contained a high count of Aspergillus fumigatus, previously found in several sputum samples. The inflammatory process regressed completely within 12 days on itraconazole (200 mg twice daily), combined with nystatin inhalation (100,000 IU five times daily). The only possible aetiologically significant risk factor in this immunocompetent woman could have been her frequent use of a bio-waste container.

The in-vitro susceptibility pattern to newer beta lactams namely Ticer/Clav, Azlocillin, Piperacillin and Imipenem was determined with 50 clinical strains isolated from neutropenic patients with strains isolated from neutropenic patients with sepsis, with an objective of evolving a strategy for empirical antibiotic therapy for febrile neutropenic patients. The MIC90 value for Imipenem for the Gram negative bacilli tested, other than Pseudomonas was < 0.25 mcg/ml therapy revealing a high degree of susceptibility, while for Ps. aeruginosa and related species MIC50 and MIV90 values were 2.0 and 64.0 micrograms/ml respectively. A comparatively lower degree of susceptibility was found among Gram negative bacilli included in the study to ticar/clavu, azlocillin and piperacillin indicating a moderate degree of resistance to these antibiotics. The data from this study suggests that (i) Ureidopenicillins with an aminoglycoside should be effective therapy for proven Pseudomonas and other Gram negative sepsis in febrile neutropenic patients. (ii) Imipenem would be the antibiotic of choice in Gram negative bacterial sepsis in febrile neutropenic patients where the organism is resistant to cephalosporins and ureidopenicillins.

The therapeutic effect of azlocillin and its combinations with other antibiotics was studied in a model of experimental plague of albino mice. Azlocillin was shown to be efficient in the prophylaxis and treatment of the experimental plague infection. The optimal doses of azlocillin were determined. The protective action of the drug depended on the dose and the time of its administration. The therapeutic effect was mainly defined by the antibiotic dose. The use of azlocillin in not sufficiently active doses in combination with aminoglycosides (gentamicin, sisomicin and amikacin), rifampicin or doxycycline significantly increased the percentage of the animal survival by comparison with that after the use of every antibiotic alone. A synergistic effect was observed when azlocillin was used in combination with rifampicin or amikacin.

A prospective, randomized trial comparing monotherapy with high-dose ciprofloxacin versus a standard combination regimen of azlocillin and netilmicin in the empirical treatment of febrile episodes in neutropenic patients was performed. One hundred and forty-six patient episodes were randomized, but ten (seven ciprofloxacin and three azlocillin/netilmicin) were considered unevaluable for efficacy, and three episodes were withdrawn due to incorrect randomization or non-neutropenia. Of the remaining 133 episodes, infections resolved without modification of therapy in 25/66 (38%) versus 28/67 (42%) of ciprofloxacin and azlocillin/netilmicin treated groups respectively (P = 0.72). Considering all randomized episodes, therapy was modified in 46/73 (63%) episodes with ciprofloxacin and 39/70 (56%) with azlocillin/netilmicin (P = 0.40). Of 73 patient episodes randomized to ciprofloxacin, 25 (34%) received oral follow-on therapy after a median of three days of intravenous therapy. Infections were microbiologically documented in 31/73 (42%) ciprofloxacin and 32/70 (46%) azlocillin/netilmicin, of which 8/27 (30%) and 14/31 (45%) of evaluable episodes resolved without modification of therapy respectively (P = 0.28). Gram-positive organisms accounted for 78% of all organisms cultured with 36% coagulase-negative staphylococci. Bacteriological eradication was recorded in 18/24 (75%) and 26/29 (90%) evaluable patient episodes treated with ciprofloxacin and azlocillin/netilmicin respectively (P = 0.27). Superinfections were seen in 14% of episodes in both groups, and subsequent infections in 12% ciprofloxacin and 14% azlocillin/netilmicin treated patients. Two patients (one ciprofloxacin and one azlocillin/netilmicin) died within 48 h of randomization, and a further 13 patients (four ciprofloxacin and nine azlocillin/netilmicin) died before resolution of neutropenia. Adverse events were recorded in 9% and 15% of ciprofloxacin and azlocillin/netilmicin treated patients respectively, with skin rash (five ciprofloxacin and four azlocillin/netilmicin), nephrotoxicity (two azlocillin/netilmicin), abnormal liver function tests (two azlocillin/netilmicin), ototoxicity (one azlocillin/netilmicin) and nausea (one ciprofloxacin) being the major events recorded. It was concluded that monotherapy with ciprofloxacin at this dosage is a safe alternative to combination therapy with azlocillin/netilmicin, and has the advantages of twice daily administration, iv and oral presentations, no cross allergy in beta-lactam-hypersensitive patients, and no nephro- or oto-toxicity.

A combination of esterase electrophoretic typing and analysis of the restriction fragment length polymorphism of ribosomal DNA regions (ribotyping) was used to compare 27 Pseudomonas aeruginosa strains isolated before and after two-week courses of anti-pseudomonal treatment in seven cystic fibrosis patients. A total of 12 courses of therapy were studied in which ciprofloxacin, ceftazidime, azlocillin or imipenem were used alone or in combination with tobramycin. Isolates at a count of greater than or equal to 10(6) cfu/ml of sputum were collected when there was evidence of therapeutic failure on the basis of persistence of isolates whether or not they were resistant to the antibiotic used for therapy. Emergence of resistance was observed in ten cases and failure to eradicate sensitive strains in five cases. Among the 27 isolates, eight zymotypes and five ribotypes were identified. With this typing approach, resistant post-therapy isolates were found to be identical to pre-therapy isolates in all cases but one. However, in one case an additional resistant strain was isolated after therapy besides that initially present. In all five cases in which susceptibility was still observed after treatment, pre-therapy and post-therapy isolates were indistinguishable. Using this molecular typing approach, all the strains were typable. Thus combination of esterase typing and ribotyping should improve the analysis of therapeutic failure in cystic fibrosis patients.

The data on the efficacy of antibacterial drugs and their combinations in treatment of 150 three-month old infants with generalized infection due to Pseudomonas aeruginosa are presented. The clinical isolates of P. aeruginosa were found to be carriers of multiple drug resistance which markedly complicated the chemotherapy. Only combined antibacterial therapy of such infants proved to be rational. High activity of aminoglycosides, azlocillin and cefotaxime against P. aeruginosa and the synergistic action of their combinations observed in the patients permitted to recommend the use of combinations of the above drugs in the empirical chemotherapy.

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 a randomized multicentre study ciprofloxacin combined with azlocillin was compared with gentamicin and azlocillin for the treatment of febrile episodes in neutropenic patients. In 147 evaluable episodes in 108 patients, 80 patients received ciprofloxacin/azlocillin and 67 received gentamicin/azlocillin. The two treatment groups were comparable in terms of age, underlying diagnosis, and duration of neutropenia. Microbiologically documented infections were the cause of fever in 34 (42.5%) and 29 (43.3%) episodes in the ciprofloxacin/azlocillin and gentamicin/azlocillin groups respectively. At the end of therapy, 46 patients (57.5%) receiving ciprofloxacin/azlocillin showed complete resolution compared with 30 (44.7%) for the gentamicin/azlocillin group (P = 0.14). The clinical response rate for microbiologically documented episodes was 58.8% and 48.3% respectively (P = 0.45). Among the microbiologically documented infections with follow-up cultures available, 24 (92.3%) of 26 isolates from patients receiving ciprofloxacin/azlocillin were eradicated, in comparison with 19 (86.4%) of 22 in the gentamicin/azlocillin group (P = 0.65). There were five superinfections, all in the gentamicin/azlocillin group. Significant resistance to the study drugs was not seen. Of all evaluable patients, including those subsequently withdrawn because of early modification of therapy, there were 12 deaths within the study period; six (6.8%) of these occurred in 88 patients randomized to the ciprofloxacin/azlocillin group, compared with two of 80 (2.5%) in the gentamicin/azlocillin group. Both treatments were generally well-tolerated; one patient in the ciprofloxacin/azlocillin group developed convulsions, probably related to ciprofloxacin. The combination of ciprofloxacin and azlocillin is as effective as gentamicin plus azlocillin and offers a useful alternative for the empirical treatment of febrile neutropenic patients.

The value of ultra short antimicrobial prophylaxis using azlocillin in preventing postoperative wound infections was studied in a prospective clinical/bacteriological study in 41 orthognathic operations. Preoperatively the oral mucosa and pharyngeal flora of each patient was subjected to bacteriological identification with particular emphasis on anaerobes and sensitivity tests for organisms with established pathogenic potential. The results of a bacteriological examination of the redon drains on day 1 postoperatively indicated a contamination of the surgical wound. Clinically 31 patients showed moderate postoperative edema of the buccal soft tissues and 10 patients had hematomas or hemorrhages. In all patients the operation was followed by primary intraoral wound healing without any signs of an early infection.

Efficacy of the cephalosporin, ceftriaxone, was compared with that of the combination of the aminoglycoside, netilmicin, and the penicillin, azlocillin, in the treatment of febrile episodes in immunocompromised neutropenic children undergoing chemotherapy for neoplastic disease. During 100 separate febrile episodes, 40 strains of bacteria were isolated from the blood of 34 patients and a further 55 strains from other sites. Nine strains (four of which were staphylococci) to both netilmicin and azlocillin. There was no difference in clinical response between the two therapeutic regimens as assessed 4 and 7 days after treatment began. Ceftriaxone had the considerable practical advantages of once daily dosage without a need for blood monitoring. Ceftriaxone would appear to be effective as initial monotherapy in the treatment of bacterial infections in severely neutropenic children.

In the four EORTC International Antimicrobial Therapy Cooperative Group trials, the frequency of gram-positive isolates has increased significantly from 29% of single-organism bacteraemias in trial I (1973-1976) to 41% in trial IV (1983-1985). In trial IV febrile and neutropenic (less than 1000 polymorphonuclear lymphocytes per microliter) cancer patients were randomized prospectively to receive either azlocillin plus a long course (at least 9 days) of amikacin, or ceftazidime plus a short course (3 days) of amikacin, or ceftazidime plus a long course of amikacin. Without modification of the allocated antibiotics, the overall response rates for gram-positive bacteraemias were similar for all three regimens (19/37 [51%], 8/23 [35%] and 14/30 [47%]), respectively. However, in patients with prolonged and severe neutropenia, treatment with azlocillin plus amikacin was significantly more effective than with ceftazidime plus 3 days' amikacin (7/10 vs. 0/7). The overall response rate for these infections was significantly lower than that observed in trial I (46% vs. 74%), but this was not associated with increased mortality. The response to treatment was significantly influenced by the susceptibility of the infecting strain to the beta-lactam. Multivariate analysis revealed that increasing age, presence of a central venous catheter and resistance to beta-lactam adversely affected outcome. Future studies should be designed to improve the outcome of gram-positive bacteraemia in neutropenic patients with cancer.

The basic considerations for staging of malignant otitis are complimented by a case report. Azlocillin infusion was successful in the treatment of a 15 years old diabetic girl with early osteitis of the mastoid due to a pseudomonas infection of the external ear canal.

The ureidopenicillins (piperacillin, mezlocillin, and azlocillin), aztreonam, and thienamycin are new broad-spectrum beta-lactams with more potent antibacterial activity than the older cephalosporins and penicillins. However, therapy of severe infections with the ureidopenicillins alone is limited by the potential for emergence of resistant organisms, while monotherapy with aztreonam does not provide adequate coverage for Gram-positive aerobic organisms and anaerobes. In combination therapy with the aminoglycosides, the ureidopenicillins may be preferred to carbenicillin or ticarcillin in the treatment of Pseudomonas aeruginosa infections and in institutions with a high prevalence of carbenicillin or ticarcillin-resistant organisms. Double beta-lactam therapy with piperacillin plus either latamoxef (moxalactam) or ceftazidime may be advantageous in patients for whom aminoglycoside toxicity is a concern. Thienamycin is the most promising of the new beta-lactams for single-agent therapy of severe infections but may also be associated with the emergence of resistant P. aeruginosa during monotherapy. In febrile granulocytopenic patients or other severely ill patients at risk of severe P. aeruginosa infections, thienamycin or another antipseudomonal beta-lactam should be combined with an aminoglycoside.

The efficacy of azlocillin + amikacin was compared to ciprofloxacin (with and without amikacin) in 96 rabbits with right-sided endocarditis due to Pseudomonas aeruginosa. Animals received either: no therapy (controls); amikacin (15 mg/kg/day) + azlocillin (400 mg/kg/day); ciprofloxacin (80 mg/kg/day) or amikacin + ciprofloxacin (above dosages). All three antibiotic regimens were significantly more effective than no therapy in reducing mortality (p less than 0.0005), preventing pulmonary infarction (p less than 0.0005) and reducing mean vegetation titers of P. aeruginosa (p less than 0.0005). Also, the three therapy regimens were equivalent in preventing bacteriologic relapse after discontinuing therapy. No development of antibiotic resistance in vivo was observed.

Azlocillin is an important acylureido penicillin antibiotic for the management of complex gram-negative infections particularly those caused by Pseudomonas species. The current studies demonstrate that it manifests dose-dependent pharmacokinetics during the usual regimens of clinical dosing, that enterohepatic recirculation does not occur and that renal tubular secretion (maximum renal tubular secretory capacity 300 +/- 30 micrograms/min) and hepatic metabolism appear to be the dominant contributors to the dose-dependent nature of azlocillin. The possible therapeutic implications of azlocillin's dose dependency were evaluated by undertaking a six-day randomized, prospective, cross-over design study to evaluate the pharmacokinetic disposition of the drug during a 3-g q4h (typically used in adults) regimen versus a 5-g q8h regimen. By using the area under the serum-time concentration curve (AUC) as the major comparative parameter for these two regimens, the results demonstrate that both regimens provide approximately equal quantitative amounts of the drug systemically as a result of azlocillin's dose dependency. The AUC values, although not therapeutic end points, nonetheless correlate well with clinical response to antibiotic therapy. The 5-g q8h regimen was well tolerated. It is less disruptive for patients, requires half the number of intravenous administrations, 17% less drug, and is more cost effective than the 3-g q4h regimen.

Examining blood level values and urinary concentrations taken from pregnant and nonpregnant women, the pharmacokinetic dates of azlocillin have been evaluated. We used a computer program based on the two-compartment model. The evaluation of azlocillin concentrations in serum and urine has been realized with the two following methods: polarography and agar diffusion test. We found nearly equal values of serum concentrations when using both methods. There are no statistical differences between pharmacokinetic dates of pregnant and nonpregnant women. Therefore we state: It is not necessary to change the dosage and the application interval of azlocillin during pregnancy.

The article reports on the incidence, the conditions of occurrence, possibilities and successes of treatment with certain (combinations of) antibiotics, in dealing with cases of pseudomonas meningitis. The various possible substances used for treatment are discussed. Rates of penetration and CSF concentrations of azlocillin and cefsulodin are stated. Alternative possibilities for treatment are pointed out.

The in vivo activity of ciprofloxacin against Pseudomonas aeruginosa was studied in a septicemia model in neutropenic mice and compared to that of other antibiotics with established activity against P. aeruginosa. When given as a single agent, ciprofloxacin proved to be as effective as imipenem/cilastatin, whereas azlocillin and tobramycin were rather ineffective. After infection with higher challenge inocula, combinations of two (synergistic) antibiotics were more effective than single agent therapy in most instances. The combination of ciprofloxacin with azlocillin was at least as effective as that of imipenem/cilastatin with tobramycin. Selection of mutants with decreased sensitivity to ciprofloxacin occurred during therapy, however, post-therapy MICs of ciprofloxacin did not exceed a level of 1 mg/l and rises of MICs did not detrimentally influence treatment outcome. Taken together with the results of earlier studies, our data encourage the use of ciprofloxacin in gram-negative septicemia in neutropenic patients.

In a still ongoing open, randomized prospective trial the preliminary data of 50 intensive care patients on artificial ventilation were analysed. The evaluation included clinical and bacteriological efficacy and tolerance of ceftazidime alone or in combination with tobramycin versus azlocillin plus tobramycin. Artificially ventilated patients who had been treated in an intensive care unit for at least five days were selected to enter the study because of a high probability of colonisation with gram-negative bacteria. 16 patients were treated for bronchopulmonary infection with ceftazidime alone, and 17 each were treated with ceftazidime plus tobramycin or with azlocillin plus tobramycin. In the ceftazidime group nine patients were cured and three were improved (75% clinical success). Of the patients treated with ceftazidime plus tobramycin, 11 were cured and one was improved (75% clinical success); one patient died from very severe multiple trauma. In the azlocillin-tobramycin group, six patients were cured and two were improved (57% clinical success). Two patients from this group died from their underlying disease and another died from multiple organ failure due to septicemia.

Nine adult patients with cystic fibrosis, nearly a quarter of the 38 patients with this disease who were treated with piperacillin (59 courses in all) during 1981-3 at the Brompton Hospital, developed a swinging pyrexia after a mean of 13.5 days' treatment with this antibiotic. The fever resolved shortly after the piperacillin treatment was stopped, as did the widespread rashes in the two patients who developed them. Three of four patients who had probable reactions to azlocillin may have been sensitised by piperacillin. As piperacillin does not appear to be any more effective than other antipseudomonal penicillins in cystic fibrosis, it is no longer used at the hospital for treating bronchopulmonary exacerbations in such patients.

In a randomized trial ceftazidime plus piperacillin or azlocillin, and netilmicin plus piperacillin or azlocillin were used as initial empirical therapy in 202 febrile neutropenic episodes. Netilmicin plus azlocillin was the most effective combination with a clinical response rate of 81% in clinically and microbiologically documented infections compared with 63% for ceftazidime plus piperacillin. All of the episodes of Gram-negative bacteraemia treated with azlocillin responded compared with 43% of those treated with piperacillin. Gram-positive organisms accounted for 52% of all bacteriologically documented infections and 40% of the febrile episodes were treated with vancomycin for presumptive or documented Gram-positive infection. Patients treated with netilmicin had significantly more nephrotoxicity than those given the double beta-lactam combinations (14.8% vs 3.5%; P less than 0.05). However, this difference was not shown in those patients who did not receive concurrent vancomycin or amphotericin. The double beta-lactam combinations were associated with more hypokalaemia (58.2% vs. 37.7%; P less than 0.05) and more colonization with yeasts (24% vs. 10.4%; P less than 0.05) but there was no evidence that their use was associated with prolongation of neutropenia. These results indicate that ceftazidime plus a ureidopenicillin would be adequate empirical therapy in situations where the concomitant use of nephrotoxic agents precludes the use of aminoglycoside containing combinations.

Large amounts of free granulocyte elastase (GE), an enzyme capable of mediating airway damage, have been found in bronchial secretions of patients with cystic fibrosis who are infected with Pseudomonas aeruginosa. This finding indicates an imbalance between GE and its antiproteases, alpha 1-proteinase inhibitor (alpha 1-PI) and bronchial mucosal inhibitor (BMI), in the airways of these individuals. The effect of intravenous antimicrobial treatment against P. aeruginosa on activity and concentration of GE, BMI, and alpha 1-PI was evaluated in 30 treatment courses of 20 patients with cystic fibrosis. Although sputum volume and level of immunoreactive GE decreased and concentrations of alpha 1-PI and BMI increased significantly (P less than .05), a high level of free GE persisted. No active alpha 1-PI and BMI were detectable after treatment. High levels of GE correlated with a poor pulmonary condition (rs = .98, P less than .001). In vitro, elastolytic activity of bronchial secretions from patients with cystic fibrosis was significantly inhibited by eglin C and an oxidation-resistant variant of alpha 1-PI, both compounds currently produced by recombinant DNA technology.

Ten patients with cystic fibrosis received 19 therapeutic courses of ciprofloxacin at a dose of 750 mg orally twice daily. The length of therapy ranged from two to five weeks except for one patient who was treated for six weeks. The mean peak serum concentration of ciprofloxacin was 3.41 mg/l and the mean trough level was 1.11 mg/l. For comparison nine patients were treated with the combination of azlocillin at a dose of 350 mg/kg/day in four divided doses and tobramycin at an initial dose of 9 mg/kg/day in three divided doses. All patients were infected with Pseudomonas aeruginosa except for one patient in whom P. cepacia grew in the sputum cultures; the MICs of ciprofloxacin ranged from 0.05 to 1.56 mg/l. The results obtained with these two therapeutic regimens were comparable. The patient treated for P. cepacia infection developed resistance to ciprofloxacin (MIC greater than 6.24 mg/l) during the course of treatment. Ciprofloxacin appears to be an alternative treatment to the use of an aminoglycoside and a penicillin in cystic fibrosis patients.

In a prospective controlled clinical study interactions between nondepolarizing muscle relaxants and acylaminopenicillins were investigated electromyographically. Six patients in each group received either apalcillin, azlocillin, mezlocillin or piperacillin during the operation. Muscle relaxation was maintained using the short acting nondepolarizing relaxant vecuronium, which shows no cumulative effect within clinical dosages. The intra-individual comparison with the control period (100%) showed a significant prolongation of the duration of action after a fixed dose of vecuronium. The mean increase was +26% following apalcillin, +46% after piperacillin, +38% following mezlocillin and +55% following azlocillin. The shortest time of the control periods was 8.6 min and the maximum time was 32.6 min. We also found a significant depression of the EMG-response. No significant differences could be detected between the four antibiotics. The method described here has proven to be sensitive enough to detect clinically relevant interactions with muscle relaxants. As a result of our study, caution seems to be necessary if acylaminopenicillins are administered in the early postoperative period.

The therapeutic efficacy and safety of ciprofloxacin was studied in 30 patients with Pseudomonas aeruginosa infections. In 20 patients ciprofloxacin was given alone and in 10 patients (including 8 compromised hosts) in combination with an aminoglycoside (9) or azlocillin (1). Ciprofloxacin was given in doses of 500 mg orally or 200-300 mg i.v. every 12 h. In patients receiving only ciprofloxacin clinical cure with eradication of bacteria was obtained in 15 patients (75%) with infections of bone and joint (6), skin and soft tissue (4), lung (2), middle ear (2) and CSF (1). Two patients with lymphoma and Pseudomonas aeruginosa pneumonia died. In patients receiving combination therapy a definite therapeutic success was achieved in four (40%). Three patients with Pseudomonas aeruginosa septicemia died. In seven patients nine bacterial strains with decreasing susceptibility of ciprofloxacin (increase in MIC from less than or equal to 0.5 micrograms/ml to 2-16 micrograms/ml) were selected (6 Pseudomonas aeruginosa, 1 Enterobacter cloacae, 1 Serratia marcescens, 1 Staphylococcus aureus). Ciprofloxacin was well tolerated. This new quinolone seems to be suitable for single drug treatment of Pseudomonas aeruginosa infections in patients with normal host defense mechanisms, while its therapeutic potential in compromised hosts requires further evaluation.

Azlocillin plasma concentrations have been studied in 10 cystic fibrosis patients suffering from chronic pulmonary infections with Pseudomonas aeruginosa. Patients were given single i.v. doses of 100 e 200 mg/kg body weight as intravenous infusion over 30 minutes. Azlocillin plasma levels have been assayed by a rapid, sensitive and precise high performance liquid chromatographic method. After the dose of 100 mg/kg body weight concentrations of azlocillin decreased below the therapeutic concentrations after three hours; dose of 200 mg/kg was followed by plasma concentrations in the therapeutically desirable range during the 6-8 hours study period. The pharmacokinetic analysis offers further evidence of the dose-dependent nature of azlocillin elimination. Higher dosage of 200 mg/kg body weight and monitoring of plasma drug levels are recommended in the therapy of patients with cystic fibrosis.

A granulocytopenic mouse model was used to elucidate the impact of dose spacing on the activity of netilmicin against Pseudomonas aeruginosa. A thigh infection was produced and then treated with netilmicin combined with azlocillin. Netilmicin was injected subcutaneously at decreasing doses every 20 min to result in plasma-concentration-time curves similar to those observed in patients on intravenous netilmicin treatment. A once-daily regimen was simulated and compared to a simulated conventional schedule of every 8 h. Identical total amounts of drug were used in both groups of comparatively treated mice. Therapeutic efficacy was quantitated by repeated determinations of surviving organisms in thigh homogenates. Combination therapy was significantly more effective than azlocillin treatment alone. In combination regimens the simulated once-daily netilmicin schedule killed the target organisms faster than the simulated thrice-daily regimen and was significantly more efficacious by 24 and 32 h in two out of three strains of Pseudomonas aeruginosa tested. It is concluded that the results of combination therapy of severe Pseudomonas aeruginosa infections in the immunocompromised host might be improved by choosing an aminoglycoside dosage interval of 24 h instead of the conventional 8 h.

One hundred and two patients with neutropenia (less than 1 x 10(9)/L) secondary to primary hematological disorders or chemotherapy for hematological malignancies were prospectively randomised, upon the development of fever or other signs of infection, to receive empirical antibiotic treatment with either ceftazidime (+/- flucloxacillin) (n = 52) or azlocillin plus amikacin (+/- flucloxacillin) (A&A, n = 50). The two groups were equivalent with respect to clinical and laboratory parameters prior to antibiotic therapy and flucloxacillin was added to approximately 25% of the patients in each group on the clinical suspicion of Gram positive infection. When assessed at 96 hours, the complete response rates were 59.6% for the ceftazidime treated patients and 44% for A&A treated patients. Partial response rates were 17% and 20% respectively. This difference was not statistically significant. Eight patients died whilst on the trial, three of those initially randomised to ceftazidime and five initially randomised to A&A. Moderate to severe hypokalemia was encountered significantly less often in the ceftazidime treated group (p less than 0.01), whilst other parameters of toxicity were equivalent. No primary or acquired resistance to ceftazidime was encountered. Separate analysis of those patients who did not receive flucloxacillin yielded identical results. We conclude that ceftazidime (+/- flucloxacillin) is as efficacious as azlocillin plus amikacin (+/- flucloxacillin) in the empirical antibiotic management of such patients and is associated with a lower incidence of moderate to severe hypokalemia.

To evaluate the impact of parenteral azlocillin therapy on human colon microflora, faecal specimens were taken from 6 patients before, during and after therapy for analysis of the microflora. In 2 patients major changes took place. Thus the numbers of streptococci, Escherichia coli, anaerobic cocci, lactobacilli, clostridia and bacteroides decreased markedly during therapy. One of these patients was colonized with azlocillin-resistant Enterobacter cloacae. The other 4 patients had only minor changes in the microflora. Variations between patients seem to exist. Pronounced alterations in the colonic flora may have clinical implications.

Proteinuria and enzymuria were measured in 27 patients with Cystic Fibrosis before and after tobramycin therapy. Prior to treatment, kidney function was normal in 23 patients. Four patients showed a pathological proteinuria and two haematuria. Renal biopsy in one patient showed segmental basement membrane alterations on electron microscopy; there were no immunoglobulin deposits. During intravenous therapy with tobramycin (10 mg/kg per day) and azlocillin (100 mg/kg per day) mean urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion rose six-fold and mean urinary alaninaminopeptidase excretion increased ten-fold. After cessation of therapy, enzymuria rapidly returned to pretreatment values in all 14 patients. Aerosol tobramycin therapy in four patients did not affect urinary excretion of NAG. It can be concluded that tobramycin did not cause persistent renal damage in our patients, whether given intravenously or as an aerosol.

Of the pathogens causing septicaemia due to Gram-negative bacteria at Zentrum der Inneren Medizin, Frankfurt, over a 7-year period (1974-80), 16.8 per cent were due to P. aeruginosa. Analysis of all septicaemias over this period, however, shows a decrease from 13 per cent in the 3-year period 1974-76 to 8 per cent in 1977-79 and 5 per cent P. aeruginosa septicaemia in 1980. The overall mortality rate was 66 per cent, most of the patients dying within 24 hours. Azlocillin and Piperacillin are at present the drugs of choice for systemic therapy of pseudomonas infections, preferably in combination with an aminoglycoside.

The efficacy of ciprofloxacin alone and in combination with azlocillin was compared with that of azlocillin plus tobramycin in a rat model of aortic valve endocarditis due to Pseudomonas aeruginosa. MICs against the infecting strain of ciprofloxacin, azlocillin and tobramycin were 0.125, 8, and 0.5 mg/l, respectively. Antimicrobials were administered 24 h after bacterial challenge and for six days. Mean peak/trough serum levels for ciprofloxacin (50 mg/kg i.v. q 12 h), azlocillin (500 mg/kg i.v. q 12 h) and tobramycin (6.5 mg/kg i.v. q 12 h) were: 10.5/0.2, 386/less than 16, and 6.2/less than 0.6 mg/l, respectively. Ciprofloxacin alone was more effective than the combination azlocillin-tobramycin in increasing survival (p less than 0.05), sterilizing blood (p less than 0.05) and valves (p less than 0.001), and in reducing bacterial titers in vegetations (p less than 0.001). Ciprofloxacin-azlocillin combination was not more effective than ciprofloxacin alone. Drug resistance was not encountered in post-treatment isolates with any therapy regimen.

The two antibiotic combinations ceftriaxone (Rocephin)/gentamicin and azlocillin/gentamicin were compared in a randomized study in a total of 49 premature and full-term neonates with the clinical symptoms of sepsis. In both groups, equally good efficacy and reliability and very good tolerability were observed.

The antibacterial activity of azlocillin VUFB and gentamicin was tested in vivo. To mice with Pseudomonas sepsis the test substances were injected either alone or combined, and the mortality was assessed. The test substances were freeze dried injectable azlocillin and gentamicin (Pharmachim). Azlocillin was injected into mice either intravenously or intramuscularly in graduated doses of 50-500 mg/kg once daily. The therapeutic effect was assessed on the basis of survival of the treated mice. Our expectation of a potentiated effect of the azlocillin-gentamicin combination was confirmed. After intramuscular administration of azlocillin plus gentamicin 90% of the mice survived, in comparison with 40% only after either azlocillin or gentamicin alone.

Closed-space neutropenic infection sites were simulated in rabbits by subcutaneous semipermeable chambers that were inoculated with 5 X 10(4) CFU/ml of various strains of Streptococcus pneumoniae, Streptococcus faecalis, and Streptococcus avium. Four hours after inoculation, treatment was begun with ciprofloxacin, 10 or 30 mg/kg, azlocillin, 100 mg/kg, amikacin, 15 mg/kg, procaine penicillin G, 300 U/dose, or gentamicin, 2 mg/kg, alone and in two-drug combinations. Antimicrobials were given intramuscularly every 6 hr for 16 doses. Extravascular chambers were sampled throughout the treatment course for bacterial counts and antimicrobial concentration. In vivo results were compared to in vitro tests of inhibition, killing, and synergism. Ciprofloxacin alone had little effect on the animal infection sites. Azlocillin alone reduced, in vivo, eight of 12 isolates greater than or equal to 5 log10 CFU/ml by 92 hr as compared to control. Azlocillin plus ciprofloxacin reduced all 12 isolates greater than or equal to 5 log10 CFU/ml by 92 hr, whereas amikacin plus azlocillin reduced only three and penicillin plus gentamicin only one of the six group D streptococcal isolates greater than or equal to 5 log10 CFU/ml.