Inhibition of lymphoma growth in vivo by combined treatment with hydroxyethyl starch deferoxamine conjugate and IgG monoclonal antibodies against the transferrin receptor.

Synergistic inhibition of hematopoietic tumor growth can be observed in vitro when the iron chelator deferoxamine (DFO) is used in combination with an IgG mAb against the anti-transferrin receptor antibody (ATRA). Our goal was to ascertain whether similar findings could be seen in vivo. A high molecular weight conjugate of deferoxamine, known as hydroxyethyl starch (HES) DFO or HES-DFO, was tested in conjunction with C2, a well-defined rat antimouse transferrin receptor mAb, against the 38C13 tumor in C3H/HeN mice. It was shown that while neither HES-DFO alone nor C2 alone produced consistent, significant inhibition of tumor growth, the combination of HES-DFO and C2 produced virtually complete inhibition of initial tumor outgrowth. The latter combination failed, however, to inhibit the growth of established tumors. It was then found that when C2 was used in conjunction with RL34, another IgG ATRA, the two ATRAS were themselves capable of causing synergistic inhibition of the growth of 38C13 in vitro. When the two IgG ATRAS were used together in vivo, regressions of established tumors were observed. Moreover, the addition of HES-DFO to the IgG ATRA pair then caused more frequent regressions. Although there was never any obvious toxicity seen with a single IgG ATRA, the use of the IgG ATRA pair was associated with sporadic mortality. In addition, although HES-DFO by itself was also not associated with any obvious toxicity, combined treatment with HES-DFO and a single ATRA resulted in death due to bacterial infection in about half of the mice after 10-15 days. Combined treatment with HES-DFO and the ATRA pair resulted in death attributed to infection in nearly all of the mice after 6 days. Thus, an iron deprivation treatment protocol with HES-DFO and IgG ATRAS produced both a significant antitumor effect and an increased risk of infection in a murine model system.

Prevalence of important pathogens and antimicrobial activity of parenteral drugs at numerous medical centers in the United States, I. Study on the threat of emerging resistances: real or perceived? Fluoroquinolone Resistance Surveillance Group.

Forty-three medical centers participated in a national (United States) surveillance study of parenteral antimicrobial agents as empiric therapy of pathogens isolated from blood, skin wounds, respiratory tract, and urine (> 8500 strains, 200 per laboratory). All laboratories tested each organism by the same reagent disks and/or Etest (AB Biodisk, Solna, Sweden) strips. Quality control results validated all laboratories for analyses. The most common isolates were Escherichia coli (1648), Staphylococcus aureus (1408), Pseudomonas aeruginosa (1003), Klebsiella species (792), and the enterococci (684). Among the tested drugs the percent susceptible rates observed were ofloxacin (83.4%), ciprofloxacin (82.0%), and cefuroxime (62.9%) tested against all organisms; cefazolin (54.7%) and ceftazidime (76.7%) tested against all nonfastidious aerobes; gentamicin (91.2%), imipenem (95.3%), ticarcillin-clavulanate (78.2%), and ceftriaxone (66.2%) tested against Gram-negative organisms only; and vancomycin (97.9%) and erythromycin (49.2%) tested against Gram-positive aerobes. Several drug-resistant species appear to be emerging or increasing in the United States: (a) vancomycin-resistant enterococci (7.9%, mostly Enterococcus faecium); (b) oxacillin-resistant S. aureus (21.0%); (c) third-generation cephalosporin-resistant Enterobacteriaceae, including E. coli and Klebsiella species with extended-spectrum beta-lactamases (approximately 1.3%-8.6%); (d) penicillin-resistant Streptococcus pneumoniae (17.8%); and (e) ciprofloxacin-resistant P. aeruginosa (14.9%). Fluoroquinolone resistance among the enteric bacilli was confirmed in 60 of 66 referred strains (0.8% of total strains), and cross-resistance was high among ciprofloxacin, ofloxacin, lomefloxacin, fleroxacin, and norfloxacin (98.3%-100%). Seventeen strains of fluoroquinolone-resistant enteric bacilli (0.2% of total) also harbored an ESBL and resistance to aminoglycosides. Clonal spread within medical centers was observed with the ESBL-producing Klebsiella pneumoniae. This national clinical isolate data base continues to demonstrate broad fluoroquinolone efficacy (ofloxacin > ciprofloxacin) against hospital-based pathogens and many strains of emerging resistant bacteria. Continued US surveillance studies are urged to monitor emerging antimicrobial resistance and to guide interventions to minimize its occurrence.