Azlocillin can be the potential drug candidate against drug-tolerant Borrelia burgdorferi sensu stricto JLB31.

Lyme disease is one of most common vector-borne diseases, reporting more than 300,000 cases annually in the United States. Treating Lyme disease during its initial stages with traditional tetracycline antibiotics is effective. However, 10-20% of patients treated with antibiotic therapy still shows prolonged symptoms of fatigue, musculoskeletal pain, and perceived cognitive impairment. When these symptoms persists for more than 6 months to years after completing conventional antibiotics treatment are called post-treatment Lyme disease syndrome (PTLDS). Though the exact reason for the prolongation of post treatment symptoms are not known, the growing evidence from recent studies suggests it might be due to the existence of drug-tolerant persisters. In order to identify effective drug molecules that kill drug-tolerant borrelia we have tested two antibiotics, azlocillin and cefotaxime that were identified by us earlier. The in vitro efficacy studies of azlocillin and cefotaxime on drug-tolerant persisters were done by semisolid plating method. The results obtained were compared with one of the currently prescribed antibiotic doxycycline. We found that azlocillin completely kills late log phase and 7-10 days old stationary phase B. burgdorferi. Our results also demonstrate that azlocillin and cefotaxime can effectively kill in vitro doxycycline-tolerant B. burgdorferi. Moreover, the combination drug treatment of azlocillin and cefotaxime effectively killed doxycycline-tolerant B. burgdorferi. Furthermore, when tested in vivo, azlocillin has shown good efficacy against B. burgdorferi in mice model. These seminal findings strongly suggests that azlocillin can be effective in treating B. burgdorferi sensu stricto JLB31 infection and furthermore in depth research is necessary to evaluate its potential use for Lyme disease therapy.

A fast and simple FIA-chemiluminescence method for the evaluation of Roselle flowers as scavenger of the free radicals generated by UV irradiated antibiotics.

This work proposes a new method for the in vitro evaluation of the effect of UV irradiation on the production of free radicals and other reactive species during the photodecomposition of drugs. The method was based on the UV irradiation of antibiotics molecules to generate excited states that undergo to homolytic bond cleavages. These reactive species can be detected by their ability to oxidize the luminol, producing the electronically excited aminophtalate, which decays to the ground state releasing electromagnetic radiation in the visible zone of the spectrum. This method was applied to penicillin G, nafcillin, azlocillin and neomycin dissolved in water. It was found that the intensity of the luminol chemiluminescence emission (CL) was proportional to the concentration and dependent on the molecular structure of these drugs. Under the optimized conditions, it was found that penicillin and azlocillin were the most susceptible to photodegradation, while neomycin sulfate was the less affected by the UV light. It was observed that the addition to the antibiotics dissolutions of a hydro-alcoholic extract of petals of calyxes of Roselle reduced the CL intensity, indicating that the extract was able to scavenge the free radicals in the irradiated drugs. This result suggest that its addition to the antibiotics can help in the protection against the radicals formed during the exposition to solar light of patients treated with topic similar antibiotics.

[Azlocillin plus amikacin: an alternative therapy for sepsis caused by resistant staphylococci?]. / Azlocilina y amikacina: Una alternativa terapéutica para la septicemia por estafilococos resistentes?

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.

[Enhancement of treatment efficacy in experimental plague by the sequential administration of antibiotics]. / Povyshenie éffektivnosti lecheniia éksperimental'noi chumy putem posledovatel'nogo vvedeniia antibiotikov.

It was shown that the use of ampicillin, azlocillin or polymyxin 24 or 96 hours after the plague infection at the background of the every-day use of rifampicin in the doses protecting only 30 per cent of the animals from death provided 80-100-percent survival of the animals. With the every-day use of ampicillin, azlocillin or polymyxin in succession with rifampicin there was observed a 3-fold increases in the survival of the albino mice as compared to those exposed to an analogous dose of rifampicin alone. A decrease in the number of administrations of the above drugs and an increase in the intervals between the administration also resulted in a significant rise of the animal survival in comparison with that after the every-day use of a similar dose of rifampicin.

[A method of sequential administration of antibiotics in preventive treatment of experimental plague in albino mice]. / Metod posledovatel'nogo vvedeniia antibiotikov v predupreditel'nom lechenii éksperimental'noi chumy belykh myshei.

Combination of a betalactam antibiotic (ampicillin or azlocillin) or polymyxin B with rifampicin were studied with their administration in succession at various intervals in an experimental model of plague infection of albino mice. It was shown that when the administration of the betalactams or polymyxin B preceded the administration of rifampicin, the efficacy of the preventive therapy considerably increased. The time of the intervals was noted to be of importance and should be predetermined for every subsequent administration.

In vitro evaluation of newer beta-lactam antibiotics against gram negative bacilli isolated from neutropenic patients.

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.

A randomized trial of high-dose ciprofloxacin versus azlocillin and netilmicin in the empirical therapy of febrile neutropenic patients.

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.

Combination therapy with ciprofloxacin plus azlocillin against Pseudomonas aeruginosa: effect of simultaneous versus staggered administration in an in vitro model of infection.

The effect of dose scheduling on the pharmacodynamics of simulated human doses of ciprofloxacin (200 mg intravenously [iv] every 12 h) and azlocillin (4 g iv every 12 h) alone or in combination against Pseudomonas aeruginosa was studied in a two-compartment in vitro kinetic model of infection. Studies with the two drugs in combination were compared using simultaneous or staggered (first doses of each drug were administered 6 h apart) dosing schedules. Bacterial regrowth and resistance were prevented by all combination dosing schedules; however, the simultaneous regimen consistently provided the greatest extent of killing for all strains, particularly in those initially resistant to ciprofloxacin. These enhanced effects of the combination were corroborated by an increase in the peak and duration of bactericidal activity in the analogous "serum" compartment of the model. These data show the potential usefulness of simultaneous dosing of an antipseudomonal beta-lactam with ciprofloxacin against P. aeruginosa.

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.

[Cesarean section and postoperative infectious-inflammatory complications. II. A comparative evaluation of 2 methods for antibiotic prophylaxis in cesarean section]. / Sectio caesarea i sledoperativni infektsiozno-vuzpalitelni uslozhneniia. II. Sravnitelna otsenka na dva metoda na antibiotichna profilaktika [correction of diagnostika] pri sectio caesarea.

The authors compare two methods for antibiotic prophylaxis of infectious-inflammatory complications in cesarean section: 1. Widely distributed mass prophylaxis with penicillin and gentamicin and 2. selective prophylaxis with Azlocillin, performed after determination, of the degree of the risk. 233 cesarean section were included in the study, 122 of which were treated by the first method. 59 out of 11 cesarean sections were evaluated as such with high risk and respectively treated with Azlocillin, but 52 of the women with low risk were not treated with antibiotic. The results show the advantages and economic benefits of the selective antibiotic prophylaxis in cesarean section.

Evaluation of azlocillin-amikacin combination for empirical therapy of infection in febrile neutropenic patients.

We have evaluated the azlocillin-amikacin combination, given at a daily dose of 200 mg/kg and 15 mg/kg respectively, in the treatment of 62 consecutive febrile granulocytopenic patients (less than 500 PMN/microliters) affected by hematological disease. The effectiveness of the treatment was assessed in 60 patients, 44 (73%) of whom responded within 96 hours from the beginning. 36 of the responders showed microbiological and clinical infections, 2 had clinically documented pneumonia and 6 a possible infection. No improvement was obtained in 16 patients; 7 of whom suffered from clinical and microbiological infection, 2 from pulmonary mycosis, 4 from possible infection and 3 from doubtful infection. Seven of these patients subsequently responded to a proven antibiotic treatment, while only one of the remaining responded to a second-line empirical antibiotic schedule. These results suggest that the combination of azlocillin-amikacin was able to overcome about two-thirds of the infections, representing an effective remedy for the empiric treatment of febrile neutropenic patients.

Multicenter, randomized trial of ciprofloxacin plus azlocillin versus ceftazidime plus amikacin for empiric treatment of febrile neutropenic patients.

In a multicenter, randomized clinical trial, the efficacy of ciprofloxacin plus azlocillin was compared with that of a standard regimen of ceftazidime plus amikacin for the initial empiric treatment of fever in neutropenic cancer patients. In addition, the efficacy of early conversion from intravenous therapy to orally administered ciprofloxacin was compared with that of continued ceftazidime plus amikacin. Seventy-one oncology patients with 79 episodes of fever and neutropenia were randomly assigned to receive initial empiric antibiotic therapy with either intravenously administered ciprofloxacin and azlocillin followed by orally administered ciprofloxacin (regimen 1, 25 episodes); ceftazidime and amikacin (regimen 2, 30 episodes); or ceftazidime and amikacin followed by oral ciprofloxacin (regimen 3, 24 episodes). Microbiologically documented infections were the cause of fever in 10 (40 percent), seven (23 percent), and nine (38 percent) episodes in regimens 1, 2, and 3, respectively, including six, five, and four episodes of bacteremia. Patient survival was 90 to 92 percent in each regimen; however, some modification of antimicrobial therapy occurred in 65, 44, and 41 percent of surviving patients in regimens 1, 2, and 3, respectively. The rate of clearance of initial bacteremia was 67 percent (four of six) in regimen 1, 100 percent (five of five) in regimen 2 and 50 percent (two of four) in regimen 3. Patients in regimens 1 and 3 were able to convert to orally administered ciprofloxacin in 32 (65 percent) of 49 episodes after a mean of six days of intravenous therapy. Superinfections occurred in 24, 10, and 12 percent of patients receiving regimens 1, 2, and 3, respectively, and occurred similarly for patients receiving orally administered ciprofloxacin, 12 percent (four of 32), and intravenous therapy, 17 percent (eight of 47). Parenteral ciprofloxacin was generally well tolerated. One (4 percent) of 25 patients receiving regimen 1 experienced oto- or nephrotoxicity, compared with eight (15 percent) of 54 patients receiving regimens 1, 2, and 3 (p = 0.15), including three patients who required premature termination of aminoglycoside therapy. Our data suggest that the combination of ciprofloxacin and azlocillin is an effective alternative to ceftazidime and amikacin for the initial empiric therapy of febrile neutropenic patients, is generally well tolerated, and avoids the oto- and nephrotoxicity associated with aminoglycoside use. In addition, a majority of patients could change to orally administered ciprofloxacin alone after six days of parenteral therapy.

A randomised trial of empirical antibiotic therapy in febrile neutropenic patients with hematological disorders: ceftazidime versus azlocillin plus amikacin.

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.

[Azlocillin in the treatment of pulmonary infections in patients with cystic fibrosis: plasma concentrations and therapeutic indications]. / L'azlocillina nel trattamento delle infezioni polmonari dei pazienti affetti da fibrosi cistica: concentrazioni plasmatiche e indicazioni terapeutiche.

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.

Once-daily versus thrice-daily administration of netilmicin in combination therapy of Pseudomonas aeruginosa infection in a man-adapted neutropenic animal model.

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.

Treatment of neonatal sepsis with ceftriaxone/gentamicin and with azlocillin/gentamicin: a clinical comparison of efficacy and tolerability.

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.

Ceftazidime combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia.

To determine whether combination antibiotic therapy including a short course of an aminoglycoside was as effective and less toxic than a conventional long course of the combination for the empirical therapy of gram-negative bacteremia in patients with cancer and granulocytopenia, we conducted a randomized multicenter trial comparing ceftazidime plus a short course (three days) of amikacin, ceftazidime plus a long course (nine days) of amikacin, and azlocillin plus a long course (nine days) of amikacin. Single-organism gram-negative bacteremia occurred in 129 of 872 evaluable patients. Without a change in antibiotics, the response rates were 81 percent with ceftazidime and long-course amikacin, 48 percent with ceftazidime and short-course amikacin (P = 0.002), and 40 percent with azlocillin and long-course amikacin (P less than 0.001). Among patients with fewer than 100 granulocytes per cubic millimeter throughout therapy, the response rates were 6 percent with ceftazidime and short-course amikacin and 50 percent with ceftazidime and long-course amikacin (P = 0.03). Linear logistic-regression analysis showed that therapy with ceftazidime and long-course amikacin was the most favorable prognostic factor of the response to infection, whereas the presence of leukemia or shock was the least favorable. We conclude that ceftazidime should be given in combination with a conventional full course of an aminoglycoside (amikacin) when used for the empirical treatment of gram-negative bacteremia in cancer patients with granulocytopenia.