The role of new antimicrobials for Gram-negative infections in daily clinical practice.

PURPOSE OF REVIEW: To discuss a possible clinical reasoning for treating resistant Gram-negative bacteria (GNB) infections in daily clinical practice, as well as developing a research agenda for the field. RECENT FINDINGS: Novel agents, both belonging to ß-lactams and to other classes of antimicrobials, have recently become available, likely replacing polymyxins or polymyxin-based combination regimens as the preferred choices for the first-line treatment of severe resistant GNB infections in the near future. SUMMARY: The peculiar characteristics of novel agents for severe resistant GNB infections have abruptly made the structure of previous therapeutic algorithms somewhat obsolete, in view of the differential activity of most of them against different classes of carbapenemases. Furthermore, other agents showing activity against resistant GNB are in late phase of clinical development. Optimizing the use of novel agents in order both to guarantee the best available treatment to patients and to delay the emergence and spread of resistance is an important task that cannot be postponed, especially considering the unavailability of well tolerated and fully efficacious options for treating resistant GNB infections that we faced in the last 15 years.

Antimicrobial activity and clinical effectiveness of sisomicin: an evaluation of the literature (1995-2011).

The authors sought to evaluate whether sisomicin has a place in the current therapeutic armamentarium. PubMed and Scopus databases were systematically searched. Ten cohort studies and 11 case reports and case series were included evaluating, in total, 383 Gram-positive and 83 Gram-negative isolates. Sisomicin was active in vitro against 41% of Enterococcus spp., 97% of Staphylococcus spp. and was the most active in vitro (74%) aminoglycoside against Stenotrophomonas maltophilia isolates in one study. Regarding clinical effectiveness, sisomicin topical cream was effective in all 290 patients with pyoderma in one study, while the intravenous formulation of sisomicin was effective as prophylaxis for the development of postoperative pneumonia in 91% of lung surgery patients in another. In conclusion, sisomicin may be useful against certain pathogens; however, clinical data are scarce. Further studies are needed and may shed additional light in this area.

[Antibiotics of the aminoglycoside group (gentamicin, sisomicin and amikacin) in the prevention and treatment of experimental plague]. / Antibiotiki gruppy aminoglikozidov (gentamitsin, sizomitsin, amikatsin) v profilaktike i lechenii éksperimental'noi chumnoi infektsii.

Activity of aminoglycosides such as gentamicin, sisomicin and amikacin against plague microbe strains of natural origin was studied in vitro. It was also studied in prophylaxis and treatment of experimental plague infection in albino mice. The MAC of gentamicin and sisomicin for 50 strains of the plague microbe was 0.2-1.6 micrograms/ml. For the majority of the strains it was 0.4 micrograms/ml. The amikacin MICs were 0.4-3.2 and 0.8 micrograms/ml, respectively. High efficacy of gentamicin, sisomicin and amikacin was shown in prophylaxis and treatment of experimental plague infection in albino mice. The optimal doses of the antibiotics were determined. Under definite conditions such as the use of short-term regimens and higher intervals, advantages of sisomicin over gentamicin and amikacin in prophylaxis of experimental plague infection were observed.

Failure of thiamphenicol in a penicillin-allergic patient with Listeria meningoencephalitis--delayed cure following penicillin desensitization.

A 27-year-old woman, without compromised immunodefenses, experienced a Listeria meningoencephalitis, with brainstem symptoms. The identified agent exhibited poor susceptibility to usual effective antibiotics, except for penicillins. Knowledge of past history of an allergic reaction to beta-lactam antibiotics lead to appropriate therapy after acute intravenous desensitization of the patient to amoxicillin. Treatment resulted in therapeutic administration rate over 24 h, and in rapid regression of clinical and biological disorders.

[Effectiveness of the new aminoglycoside sisomicin in surgery]. / Effektivnost' novogo aminoglikozida sizomitsina v khirurgii.

Antimicrobial activity of sisomicin against causative agents of wound infections was studied. It was shown that by its antimicrobial activity and the rate of bactericidal effect attainment sisomicin is superior to other aminoglycosides, such as gentamicin and tobramycin. Individual variability of the pharmacokinetics of sisomicin on its intravenous and intramuscular injection to patients with wound infections was observed. For prediction of the treatment efficacy it is suggested that the drug be used under the control of its blood levels in comparison to the MTC for the isolated causative agent.

[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.

[Perioperative antibiotic therapy--clinical experiences with a combination of mezlocillin/sisomicin in accident surgery]. / Perioperative Antibiotikatherapie--Klinische Erfahrungen mit einer Kombination von Mezlocillin/Sisomicin in der Unfallchirurgie.

The clinical and bacteriological efficiency of the combination Mezlocillin and Sisomicin was studied in 25 patients from the Department of trauma. In 9 cases the combination of antibiotics was used for treatment of manifest infections. 16 patients received a prophylaxis before and after operation. Among them were patients with open fractures, with a large soft tissue damage, polytraumatized patients with multiple injuries or patients with pathological fractures. Dosage of Mezlocillin was 4 g every 8 h, and dosage of Sisomicin was 75 mg every 8 h. Mean duration of therapy was 6 days. In 24 cases the combination of antibiotics was successful. In one case occurred a postoperative haematoma without bacterial findings. In all infections (9 cases) isolated germs were achieved with the combination Mezlocillin and Sisomicin.

[Chemotherapeutic effectiveness of gentamycin, tobramycin and sisomycin in Pseudomonas aeruginosa pyelonephritis in rats compared with dioxidine]. / Izuchenie khimioterapevticheskoi éffektivnosti gentamitsina, tobramitsina i sizomitsina pri sinegnoinom pielonefrite u krys v sravnenii s dioksidinom.

The chemotherapeutic efficacy of gentamicin, tobramycin, sisomicin and dioxydin was studied and compared in rats with hematogenic obturation P. aeruginosa pyelonephritis. The drugs were injected intramuscularly in doses of 5, 8, 8 and 50 mg/kg, respectively for 7 days a day after infection. It was shown that on prolongation of the period of the treatment estimation from 24 hours to 7 days after discontinuation of the drug use a significant decrease was observed in the therapeutic efficacy of dioxydin, gentamicin and especially tobramycin. As for sisomicin, the decrease was insignificant. Dioxydin and gentamicin had a similar therapeutic effect at the early and late periods of their estimation after discontinuation of the treatment. They were inferior to tobramycin with respect to the early results and superior to it with respect to the late results. The chemotherapeutic efficacy of sisomycin in both the cases was higher than that of tobramycin, gentamicin and dioxydin.

The aminoglycosides. Streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, sisomicin.

Despite their toxicity, the aminoglycosides remain useful and are often the first choice in the treatment of serious infections due to gram-negative bacilli. Nephrotoxicity has restricted the indications for neomycin to topical and oral use. Emergence of resistant organisms has limited the use of streptomycin to a few specific conditions. Gentamicin, tobramycin, and amikacin are effective against a broad spectrum of gram-negative bacilli including Pseudomonas aeruginosa. Amikacin is the aminoglycoside of choice when gentamicin resistance is prevalent.

The combined action of azlocillin and sisomicin in a model simulating the in vivo serum kinetics.

The in vivo serum kinetics of azlocillin and sisomicin were simulated in a new in vitro test model. A strong synergistic effect against Pseudomonas aeruginosa resulted when both compounds were administered simultaneously and eliminated according to their individual half-life values, even when the decreasing drug concentrations exceeded the MICs for only a short period of time. When applied at intervals, neither pretreatment with azlocillin nor with sisomicin blocked the antibacterial activity of the combination partner.

[Experimental chemotherapeutic activity of sisomycin sulfate]. / Khimioterapevticheskaia aktivnost' sizomitsina sul'fata v éksperimente.

The chemotherapeutic activity of sisomicin was studied in comparison to that of gentamicin with respect to the experimental infection caused by grampositive and gram-negative organisms in albino mice. It was shown that sisomicin was 2-3 times more effective than gentamicin. The higher chemotherapeutic activity of sisomicin was confirmed by the data on the pathogen isolation from the animals.

Evaluation of therapeutic efficacy of ureidopenicillins in comparison to sisomicin and cephalotin in experimental infections of rabbits.

The therapeutic efficacy of azlocillin, mezlocillin, cephalotin, and sisomicin was evaluated by experimental infection in rabbits. After one hour following infection with Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa, antibiotics were applied intramuscularly. Colony-forming units were counted before the infection and every day thereafter. Leukocytosis was determined before infection and 3 and 7 days after initiation of therapy. Therapy with antibiotics was continued for seven days, rabbits sacrificed and CFU/g tissue determined. It was shown that in experimental infection caused by E. coli or K. pneumoniae in rabbits, sisomicin was most effective, followed by mezlocillin, azlocillin, and cephalotin. Efficacy of therapy against P. aeruginosa was as follows: sisomicin, azlocillin, mezlocillin.

[Treatment of severe febrile neutropenia (author's transl)]. / Zur Behandlung der schweren febrilen Neutropenie.

Random allocation of 22 patients with benign and malignant diseases with neutrophil counts of up to 1 X 10(9)/l blood and probably infection-caused fever of more than 38 degrees C to intravenous treatment with one of the following antibiotic combinations was performed: carbenicillin (6 g/m(2) . 6 h) plus sisomicin (45 g/m2 . 6 h) or mezlocillin (3 g/m2 . 6 h) plus sisomicin (45 g/m2 . 6 h). Both combinations were tolerated equally well. Patients became afebrile in 16 out of 23 treatment periods. Seven out of 11 patients responded to carbenicillin - sisomicin, and 9 out of 12 to mezlocillin - sisomicin. Mezlocillin thus leads to equal success of treatment in febrile neutropenia as the double dose of carbenicillin when both antibiotics are combined with the same aminoglycoside.

Experimental osteomyelitis caused by Pseudomonas aeruginosa.

An experimental model of chronic osteomyelitis caused by Pseudomonas aeruginosa was established with use of techniques identical to those employed previously with Staphylococcus. Infection of bone was consistently produced, but the disease was less severe than that seen with Staphylococcus. There were lower mortality, decreased severity of infection as demonstrated by X ray, and less evidence of sequestrum formation with P. aeruginosa than with Staphylococcus. Carbenicillin was used alone and in combination with sisomicin in the treatment of experimental pseudomonas osteomyelitis. The combination, when administered for four weeks, was significantly more effective than either agent alone.

[Clinical and bacteriological evaluation of sisomicin in sixteen cases of severe bronchopulmonary infection (author's transl)]. / Evaluation clinique et bactériologique de la sisomicine dans seize cas d'infections broncho-pulmonaires sévères.

Sisomicin, an aminoglycoside antibiotic, was used as sole bactericidal therapy in sixteen cases of severe bronchopulmonary infection for an average of 11,5 days (range 7 to 14) with a dose of 3,5 mg/kg per day in three intramuscular injections. Fifteen of these hospitalized patients presented with chronic airway obstruction which resulted in lowered O2 saturation (SaO2 congruent to 86,1%, range 74 to 93) and, in twelve patients, hypercapnia (PaCO2 = 55,7 torr, range 33--73). Two of these patients were under continuous assisted ventilation. Two patients had a lower lobe infiltrate and a lung abscess respectively. Proteus (n = 3), Pseudomonas (n = 9), K. pneumoniae (n = 2), E. Coli (n = 1), Enterobacter (n = 1), S. aureus (n = 1) and D. pneumoniae (n = 1) were the dominant organisms in the bronchial secretions isolated by Mulder's method; P. aeruginosa was associated with K. pneumoniae, P. rettgeri and E. coli respectively in three cases. In thirteen cases, either a clinical cure (n = 2) or a definite improvement was observed (sputum volume and purulence, auscultatory signs, temperature). However, among these patients were three cases of superinfection/colonization and two cases of persistent organisms. In addition, in two of the three cases showing no improvement colonization occured. The favorable results of this study appear to be due to vigorous antibiotic therapy combined with intensive adjunct therapy. No adverse local or systemic reactions clearly attributable to the drug were observed.