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Biomedical subjects

S H Zinner

Publications and source records attributed to S H Zinner.

At least 73 records · Page 4Linked to original sources
PubMed1986

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.

Agranulocytosis↗
PubMed1986

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

Most conventional methods for in vitro testing of antibiotics involve exposure of a bacterial inoculum to a constant, static concentration of drug. The in vivo concentrations of antibiotics change continually according to their pharmacokinetics. When two drugs are used, the ratios of their concentrations also change with time. The usual checkerboard tests for combined activity of two or more antibiotics do not consider the pharmacokinetic properties. An in vitro two-compartment pharmacokinetic model has been developed that presents changing concentrations of one or two antibiotics to isolated bacterial inocula. This model simulates the treatment of a bacterial infection in the absence of host defenses and thus mimics infection in a neutropenic patient. This model has been used to study the synergistic activity of beta-lactam/aminoglycoside combinations compared with conventional checkerboard and time-kill methods. Also, in this model, the addition of azlocillin or ceftazidime to netilmicin prevented the selection of resistant subpopulations of Pseudomonas aeruginosa that occurred with the aminoglycoside alone. In vitro pharmacokinetic models add kinetic parameters to conventional susceptibility testing and may prove useful in the design of trials of the optimal dosing and administration of antibiotics for infected neutropenic patients.

Agranulocytosis↗
PubMed1986

Laboratory support for choosing and monitoring antimicrobial therapy in severely ill patients.

The microbiology laboratory plays an important role both in choosing initial antimicrobial therapy and in monitoring such therapy during the course of treatment. In septicemic patients who have few, if any, clinical findings suggesting a specific etiologic diagnosis, it is useful to know the antibiotic susceptibility patterns for the given hospital or community. This type of empiric approach to therapy might require a larger variety of antibiotics than that usually considered for treatment of infected neutropenic patients. In the absence of neutropenia, there is perhaps more latitude in the initial choice, and single-drug therapy often can be considered. While patients are receiving antibiotics that should be appropriate for an identified pathogen, several laboratory procedures can be used to monitor this treatment. Antibiotic synergism studies may be useful in neutropenic patients, as well as assays of serum bactericidal activity. The serum bactericidal activity may be useful also in monitoring therapy for bacterial endocarditis or for osteomyelitis, especially when oral or home therapy is considered. Similarly, drug levels may be measured by a variety of techniques to ensure appropriate serum concentrations and to minimize drug toxicity. In addition, the preclinical evaluation of antibiotics alone and in combination can be used in guiding the design of clinical studies of these drugs in certain patient groups, such as neutropenic patients.

Agranulocytosis↗
PubMed1986

In-vitro studies of antibiotic combinations with special emphasis on the evaluation of newly developed methods.

We have described an in-vitro pharmacokinetic model that mimics the serum and tissue concentrations of antibiotics during therapy of human patients, and thus presents a changing concentration of antibiotics to the bacterial inoculum. This pharmacokinetic model has been used to study antibiotic combinations that are used in the treatment of infections in granulocytopenic patients. In this model the addition of piperacillin to amikacin or of ceftazidime or azlocillin to another aminoglycoside prevented the regrowth of resistant subpopulations of Pseudomonas aeruginosa. The activities of several antibiotic combinations were studied in the in-vitro model, the conventional checker-board method and the time-kill method. Discrepant results were found with the model and the conventional tests in one-third of the combinations. The model may be useful in the preclinical study of antibiotic combinations and may be proved more predictive of clinical outcome than conventional tests.

Amikacin↗
PubMed1986

Bactericidal activity of ciprofloxacin alone and in combination with azlocillin in an in-vitro capillary model.

An in-vitro pharmacokinetic model was used to study the bactericidal activity of ciprofloxacin, alone and in combination with azlocillin. Ciprofloxacin alone produced excellent bactericidal activity against highly susceptible strains of Escherichia coli and Klebsiella pneumoniae. Against a strain of Pseudomonas aeruginosa, ciprofloxacin in clinically achievable dosing schedules produced a rapid bactericidal effect, but bacterial regrowth occurred. Azlocillin in combination with ciprofloxacin produced a rapid bacterial kill and regrowth was prevented. Further consideration of the clinical role of this combination is warranted.

Azlocillin↗
PubMed1986

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

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

Adolescent↗
PubMed1986

Influence of medium and method on the in vitro susceptibility of Pseudomonas aeruginosa and other bacteria to ciprofloxacin and enoxacin.

Ciprofloxacin and enoxacin were two- to fourfold less active against Pseudomonas aeruginosa in calcium- and magnesium-supplemented broth compared with unsupplemented broth regardless of inoculum size, presence of serum, or use of inhibitory or bactericidal endpoints (P less than 0.01). The effect of cation supplementation was less pronounced and less consistent for Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus.

Anti-Bacterial Agents↗
PubMed1985

Review of amikacin usage in the EORTC trials.

Four trials have been conducted by the European Organization for Research and Treatment of Cancer's International Antimicrobial Therapy Project Group. These studies involve the randomized assignment of febrile neutropenic patients to receive various antibiotic combinations. The past three trials have utilized amikacin in combination with a variety of beta-lactam antibiotics to provide activity against the most commonly isolated pathogenic bacteria in this clinical setting. Amikacin in combination with expanded-spectrum beta-lactam agents is likely to remain useful in treating infections in granulocytopenic patients.

Agranulocytosis↗
PubMed1985

Two compartment kinetic model with multiple artificial capillary units.

A two compartment in-vitro model was designed to simulate human pharmacokinetics and to expose bacterial cultures to changing drug concentrations, thereby avoiding limitations of conventional antibiotic testing at constant drug levels. Serially placed bacterial compartments, representing extravascular infection sites, interface with a central compartment through artificial capillaries. Drug concentrations within the culture chambers closely mimic interstitial concentrations in vivo. Simultaneous first order elimination kinetics of two drugs with different half-lives were simulated to study antibacterial effects of drug combinations. This in-vitro model is an efficient tool for optimal dosage regimen design and the study of synergistic/antagonistic effects of antibiotic combinations.

Anti-Bacterial Agents↗
PubMed1985

Use of an in-vitro kinetic model to study antibiotic combinations.

A two compartment pharmacokinetic model was used to study combinations of piperacillin with N-formimidoyl thienamycin or amikacin, and azlocillin with netilmicin against strains of Pseudomonas aeruginosa. Antibiotic antagonism seen with in-vitro static tests of piperacillin and thienamycin did not occur with the kinetic model. Piperacillin plus amikacin showed enhanced activity, and azlocillin prevented bacterial regrowth seen with netilmicin alone during multiple dosing experiments at high bacterial inocula. This model is useful in the study of antibiotic combinations.

Anti-Bacterial Agents↗
PubMed1985

Infection with Chlamydia trachomatis in female college students.

Chlamydia trachomatis was isolated from genital specimens from 21 (4.9%) of 431 female college students. Antibody to C. trachomatis was found in the genital secretions of 52 (11.9%) of 437 women. Multiple logistic regression analysis showed race, number of sexual partners, and use of barrier methods of contraception to be predictive of infection with C. trachomatis. Logistic regression analysis found race, number of sexual partners, use of barrier methods of contraception, and presence of cervical erythema to be predictive of local chlamydial antibody. White participants were infected less often (12 of 388 (3.1%)) than black participants (9 of 43 (20.9%)) (p less than 0.001) and were less likely to have local chlamydial antibody. None of the sexually inexperienced women were infected or had local antibody. Among the sexually experienced women, chlamydial infection and local chlamydial antibody increased with increasing number of sexual partners only for women who were not using barrier methods of contraception. Sexually experienced women who used barrier methods of contraception (condom, diaphragm) were less likely to be infected (one of 105 (1.0%)) than were sexually experienced women who used other contraceptive measures or who did not use contraception (20 of 276 (7.2%)) (p = 0.031). Women who used barrier methods of contraception also were less likely to have local chlamydial antibody. Women with cervical erythema were more likely to have local chlamydial antibody (4 of 11 (36.4%)) than women without cervical erythema (48 of 426 (11.3%)). Vaginal colonization with other sexually transmitted microorganisms (Mycoplasma hominis, Ureaplasma urealyticum, Trichomonas vaginalis) was noted more often among women with chlamydial infection than among uninfected women.

Adult↗
PubMed1985

Efficacy of intermittent versus continuous administration of netilmicin in a two-compartment in vitro model.

Several aminoglycoside dosage regimens were studied in a kinetic in vitro model. Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus were exposed in serially placed artificial capillary units to netilmicin concentrations that changed based on human two-compartment pharmacokinetics. The same total dose per 24 h was administered as a continuous infusion (3.7 micrograms/ml) or in 1-h infusions given every 24 (24 micrograms/ml) or 8 h (8 micrograms/ml). The once daily administration showed the best response in terms of either faster killing of E. coli, K. pneumoniae, and S. aureus or greater reduction of the inocula of P. aeruginosa. After 28 h of treatment, however, all regimens reduced the nonpseudomonads by more than 99.99%, whereas all three P. aeruginosa strains regrew to greater than 10(8) CFU/ml due to selection of resistant subpopulations. In contrast to the bactericidal effect of the first dose, no killing occurred after subsequent doses if the ratio of peak drug concentration to MIC was low (less than or equal to 6). These results support the concept of administering high doses of aminoglycosides once every 24 h.

Bacteria↗
PubMed1985

Impact of netilmicin regimens on the activities of ceftazidime-netilmicin combinations against Pseudomonas aeruginosa in an in vitro pharmacokinetic model.

The antibacterial activities of ceftazidime and netilmicin were studied in a two-compartment in vitro model. Pseudomonas aeruginosa cultures were exposed to changing drug concentrations that mimic human pharmacokinetics. Netilmicin alone reduced the numbers of organisms in cultures of the susceptible strains by more than 99% within 4 h; however, regrowth occurred after 8 h. Although ceftazidime alone killed more slowly than netilmicin, only one of the five strains regrew within 28 h. When both drugs were combined, rapid initial killing occurred without subsequent regrowth. Studied after 24 h in combination with ceftazidime, netilmicin was as effective when given as a single daily dose as when administered in three daily doses that provided 50% more aminoglycoside per day. Decreased bacterial susceptibility was seen after ceftazidime exposure for one strain and after netilmicin exposure for all originally netilmicin-susceptible strains. No such reduction in susceptibility was observed during exposure to the combination. The results of standard in vitro checkerboard tests for synergism were predictive of the initial (4 to 8 h) but not the final (24 to 28 h) assessment of drug interaction in the pharmacokinetic model.

Ceftazidime↗
PubMed1984

Comparison of tube dilution and microtitre methods for the detection of antibiotic tolerance in strains of Staphylococcus aureus.

Comparison of the MICs and MBCs of oxacillin for ten isolates of Staphylococcus aureus determined by tube dilution with those by microtitre dilution tests demonstrated that, whereas the MICs did not differ, the mean MBC by tube dilution was significantly higher (P less than 0.05) than that by microtitre after both 24 and 48 h of incubation. In addition, tolerance (MBC/MIC ratio greater than 32) was seen in four of ten strains with the tube dilution method but in only one strain with the microtitre technique after 24 h of incubation. These results and the poor correlation (r = 0.33) between MBCs by these methods indicate the importance of technical factors in the quantitation of MBCs and resulting identification of tolerance in Staph. aureus, and the need for a reference procedure in determination of MBCs.

Anti-Bacterial Agents↗
PubMed1983

Inability of counterimmunoelectrophoresis to detect echovirus in cerebrospinal fluid.

Methods for rapid detection of viral antigens in cerebrospinal fluid (CSF) are needed to aid in the differentiation of viral from bacterial meningitis. The formation of precipitin bands in patients with suspect viral meningitis utilizing viral antisera in a counterimmunoelectrophoresis (CIE) system has been described. To investigate further the possible value of CIE in the diagnosis of viral meningitis, the specificity of the CSF precipitin bands was studied. Precipitin bands were formed between commercially available type-specific antisera and cell culture supernatant fluids. Precipitin bands were also formed when control CSF was used as an antigen. Using type-specific antisera produced against purified virus, enteroviral antigens were not detected in CSF from patients from whom CSF viruses had been isolated. CIE lacks sufficient sensitivity for the detection of echovirus 11 antigens in CSF.

Antigens, Viral↗
PubMed1983

Prophylaxis of bacterial infections with oral antibiotics in neutropenic patients. Lessons from the last two EORTC trials and prospects for the future.

It is well known that patients with granulocytopenia due either to bone marrow failure, acute leukemia or its treatment, or as a result of other intensive chemotherapy are at enhanced risk of serious infection. Several approaches have been designed to minimize the risk of infection in these patients by means of suppression of gastrointestinal flora. A retrospective review of infection in febrile neutropenic patients revealed a significant decrease in bacteremia in patients who had received some oral antimicrobial regimen compared with those who did not. In one large series, infection due to the four most common infecting organisms in neutropenic patients (Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Klebsiella species) occurred in 28% of 380 patients receiving some oral antibiotic regimen compared with 44% of 426 receiving no oral prophylaxis. Aminoglycosides alone or in combination with vancomycin or polymyxin and bacitracin and other agents have been utilized in gut decontaminating regimens. More recently, selective decontamination with a variety of oral agents including nalidixic acid, cotrimoxazole, colistin, etc. have been shown to be effective in some trials. Although cotrimoxazole initially was thought to be beneficial in reducing infection and bacteremia in neutropenic patients, the recently completed EORTC trial did not show a significant difference in incidence of infection or bacteremia in acute leukemia patients attendant upon the use of oral trimethoprim-sulfamethoxazole. There was a significant reduction in infections and bacteremia in patients with malignancies other than acute non-lymphocytic leukemia. Thus, there is a need for infection prevention in neutropenic patients but the optimal method for achieving this goal remains to be determined.

Administration, Oral↗