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ABSTRACTIt is well acknowledged that ansamycins display immunosuppressive and anti-inflammatory properties in vitro and in vivo. Rifalazil, a new ansamycin derivative, has not been studied in the context of inflammation. In particular, there are no data on the possible interference of rifalazil with oxidant production by phagocytes. We have compared the antioxidant properties of rifalazil to those of rifampin, a drug well known in this context, by using cellular and acellular oxidant-generating systems. Oxidant production by polymorphonuclear neutrophils was measured in terms of cytochrome creduction, lucigenin-amplified chemiluminescence (Lu-ACL), and the 2′,7′-dichlorofluorescin diacetate H2(DCFDA-H2) technique (intracellular oxidant production). Rifalazil impaired O2−production in a concentration-dependent manner, with 50% inhibitory concentrations (IC50) (concentrations which inhibit 50% of the response) of 5.4 (30 and 60 min of incubation) and 6.4 (30 min) mg/liter, respectively, for phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation. In agreement with the published fMLP-like activity of rifampin, the inhibitory effect of rifampin was significantly greater for fMLP (IC50of 5.6 mg/liter) than for PMA (IC50of 58 mg/liter) stimulation. Alteration of intracellular oxidant production was also observed with IC50values similar to those obtained by the cytochrome assay. In addition, rifalazil and rifampin (≥25 mg/liter) scavenged O2−, as demonstrated by the acellular (hypoxanthine-xanthine oxidase) system. Interference with light detection systems was evidenced for both drugs by Lu-ACL. The clinical relevance of the antioxidant effect of rifalazil demonstrated in vitro, in particular its potential anti-inflammatory activity, requires further investigation.

AbstractInteractions between antibacterial agents and polymorphonuclear neutrophils (PMNs) are a major focus of investigation. Owing to the variable drug susceptibility of PMNs from different individuals, in vitrostudies require samples from large panels of healthy volunteers to reach statistical significance. Here, we used a phagocytic cell line, PLB-985, which can differentiate into mature PMNs in vitro, for the study of cellular interactions (drug uptake and antioxidant effects) of two macrolides (azithromycin and roxithromycin) and four ketolides [HMR 3004, HMR 3647 (telithromycin), HMR 3562 and HMR 3787]. The oxidative burst of differentiated (D) cells was inhibited by macrolides and ketolides. IC50%values (concentrations impairing the oxidative burst by 50%), determined after 30 min of incubation, were as follows for azithromycin, roxithromycin, HMR 3004, telithromycin, HMR 3562 and HMR 3787, respectively: 40, 39, 15, 23, 26, and 33 mg/l (fMLP stimulation) and 37, 86, 39, 43, 14, and 31 mg/l (PMA stimulation). These values were similar to those obtained with PMNs. Uptake of the two macrolides was significantly lower in non-differentiated (ND) cells than in D cells and PMNs. The cellular/extracellular (C/E) concentration ratios at 60 min for PMNs, D and ND PLB were respectively 67, 25 and 11 (roxithromycin) and 159, 137 and 48 (azithromycin). Ketolide uptake by ND-PLB was also significantly lower than that obtained with PMNs (C/E ratios at 60 min were about 75 versus 265 (HMR 3004), 36 vs 230 (telithromycin), 75 vs 235 (HMR 3562) and 20 vs 130 (HMR 3787). Although the active carrier system seemed to be present in ND cells, its activation pathway was not functional. Thus, the PLB-985 cell line is a good in vitromodel for studying drug-PMN interactions. The use of ND and D cells may shed light on the nature and activation pathways of macrolide transport systems present on the PMN membrane.

ABSTRACTHMR 3647 (telithromycin), a new ketolide, is active on intracellular pathogens. It was previously demonstrated that it inhibits superoxide anion production in a time- and concentration-dependent manner, at concentrations which inhibit 50% of the control response of about 55 μg/ml (5 min) to 30 μg/ml (30 min); these values are similar to those obtained with roxithromycin, a classical erythromycin A derivative. Here we investigated whether these drugs modified the bactericidal activity of human polymorphonuclear neutrophils (PMN) on four strains of Staphylococcus aureuswith different profiles of susceptibility to macrolides and ketolides. We found that the main factor involved in killing was the antibacterial potency of the drugs, although combinations of antibiotics with PMN were slightly more active than each component used alone against two of the four strains. In addition, high concentrations of the drugs, which impaired the PMN oxidative burst, did not impair PMN bactericidal activity. Likewise, some cytokines which enhance PMN oxidative metabolism did not modify PMN bactericidal activity in the presence or absence of macrolides or ketolides. These data suggest that oxygen-independent mechanisms contribute to the bactericidal activity of PMN on these strains of S. aureus. Both live and/or heat-killed bacteria impaired the uptake of telithromycin and roxithromycin (but not that of levofloxacin, a quinolone) in a concentration-dependent manner, owing to a modulation of PMN transductional systems involved in the activation of the macrolide carrier.

ABSTRACTWe analyzed the cellular accumulation of two new fluoroketolides, HMR 3562 and HMR 3787, by human polymorphonuclear neutrophils (PMN) in vitro. Both compounds were rapidly taken up by PMN, with a cellular-to-extracellular concentration ratio (C/E) of about 141 (HMR 3562) and 117 (HMR 3787) at 5 min, and this was followed by a plateau at 60 to 180 min, with a C/E of >300 at 180 min. Both ketolides were mainly located in PMN granules (about 75%) and egressed slowly from loaded cells (about 40% at 60 min), owing to avid reuptake. Uptake was moderately sensitive to external pH, and activation energy was also moderate (about 70 kJ/mol). As with other macrolides and ketolides, the existence of an active transport system was suggested by (i) the strong interindividual variability in uptake kinetics, suggesting variability in the number or activity of a transport protein; (ii) the saturation kinetics characteristic of a carrier-mediated transport system (Vmax, about 2,300 ng/2.5 × 106PMN/5 min; Km, about 50 μg/ml); (iii) the inhibitory effects of Ni2+(a blocker of the Na+-Ca2+exchanger), phorbol myristate acetate (a protein kinase C activator), and H89 (a protein kinase A inhibitor). Although these two ketolides are more related to HMR 3647 (telithromycin), it is interesting that the presence of a fluoride gave these molecules a cellular pharmacokinetics more like those of HMR 3004 than those of HMR 3647. The macrolide transport system has not been yet elucidated, but our data confirm that, despite variations in chemical structure, all erythromycin A derivatives share a transmembrane transport system.

ABSTRACTCytokines, the hallmarks of infectious and inflammatory diseases, modify phagocyte activities and thus may interfere with the immunomodulating properties of antibacterial agents. We have investigated whether various proinflammatory cytokines (interleukin 1 [IL-1], IL-6, IL-8, gamma interferon, tumor necrosis factor alpha [TNF-α], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) modify two macrolide properties, i.e., inhibition of oxidant production by polymorphonuclear neutrophils (PMN) and cellular uptake. Roxithromycin and two ketolides, HMR 3647 and HMR 3004, were chosen as the test agents. TNF-α and GM-CSF (but not the other cytokines) decreased the inhibitory effect of HMR 3647 only on oxidant production by PMN. Fifty percent inhibitory concentrations were, however, in the same range in control and cytokine-treated cells (about 60 to 70 μg/ml), suggesting that HMR 3647 acts downstream of the priming effect of cytokines. In contrast, the impairment of oxidant production by roxithromycin and HMR 3004 was unchanged (or increased) in cytokine-treated cells. This result suggests that HMR 3004 (the strongest inhibitory drug, likely owing to its quinoline side chain) and roxithromycin act on a cellular target upstream of cytokine action. In addition, TNF-α and GM-CSF significantly (albeit moderately) impaired (by about 20%) the uptake of the three molecules by PMN. The inhibitory effect of these two cytokines seems to be related to activation of the p38 mitogen-activated protein kinase. Our data also illuminate the mechanism underlying macrolide uptake: protein kinase A- and tyrosine kinase-dependent phosphorylation seems to be necessary for optimal uptake, while protein kinase C activation impairs it. The relevance of our data to the clinical setting requires further investigations, owing to the complexity of the cytokine cascade during infection and inflammation.

Summary The occurrence of antilymphocyte antibodies (AL-Ab) was investigated in the sera of 28 patients with scleroderma. By indirect immunofluorescence, we found these Ab in 53% of the sera. Inhibition of E rosette formation and lymphocytotoxicity revealed these Ab in 42% and 14% of the sera respectively. Most of the Ab (93%) reacted at 0°C. These AL-Ab can be separated into several groups depending on their inhibitory activity on the lymphocyte membrane. In some cases, the receptor seems similar to that of sheep red blood cells. The study of the clinical features of the patients showed few differences between the groups with and those without Al-Ab. It must be noted that all the patients with the CREST syndrome (6 cases) possessed Al-Ab.

The antimalarial drug quinine has been shown to impair human polymorphonuclear leukocyte (PMN) functions. To gain insight into the mechanism of this phenomenon, we investigated quinine uptake by PMN with a fluorometric assay based on the fluorescence properties of this drug. After 30 min of incubation at 37 degrees C in the presence of 1 and 10 micrograms of quinine per ml, PMN-associated quinine reached 90 +/- 6 and 780 +/- 150 ng/2.5 x 10(6) PMN, respectively, giving a cellular-to-extracellular concentration ratio of 140 to 150. A steady state was reached within 5 min. Uptake was partially dependent on temperature, cell viability, and extracellular pH. Fractionation studies showed that 30 to 40% of the PMN-associated quinine was located in the particulate fraction. The efflux of PMN-associated quinine was rapid and complete when the incubation mixture was replaced by drug-free medium. These data suggest that several mechanisms are involved in the uptake of quinine by PMN, including a viability- and energy-independent process possibly related to reversible association of quinine to cell structures (particularly the membrane). Other mechanisms could involve trapping by protonation and/or active PMN transport systems. Thus, most of the quinine taken up by resting PMN is found in the soluble fraction of disrupted cells. This may partly explain the depressive properties of quinine.

We have previously observed that the antimalarial drug amodiaquine impairs the human polymorphonuclear neutrophil (PMN) oxidative burst in vitro. However, the drug acted at a concentration of 100 micrograms/ml, far higher than that which is achievable therapeutically. Since amodiaquine is extensively metabolized into monodesethyl amodiaquine, we investigated whether the metabolite modified PMN functions at lower concentrations than amodiaquine does. Monodesethyl amodiaquine strongly depressed PMN chemotaxis and phagocytosis at concentrations as low as 10 micrograms/ml. This inhibition was reversed by washing out the drug. The PMN oxidative burst was markedly depressed by monodesethyl amodiaquine, whatever the assay technique (luminol-amplified chemiluminescence, lucigenin-amplified chemiluminescence, myeloperoxidase activity) or stimulus used (opsonized zymosan, phorbol myristate acetate, formylmethionyl leucyl phenylalanine). There were extreme interindividual variations in sensitivity to the depressive effect of monodesethyl amodiaquine when the PMN oxidative burst was assayed in terms of luminol-amplified chemiluminescence or lucigenin-amplified chemiluminescence. PMN samples were divided into two groups on the basis of the MIC of the drug: 60% of the samples were "highly sensitive," being strongly inhibited at concentrations as low as 0.1 micrograms/ml (obtained during therapy), whereas the "moderately sensitive" samples were inhibited at concentrations of 10 micrograms/ml and above. The difference between the two groups was highly significant. This PMN sensitivity to the inhibitory effect of the drug was not related to intrinsic oxidative metabolism. Our data indicate that monodesethyl amodiaquine, the main metabolite of amodiaquine, has a far stronger inhibitory effect on various PMN functions in vitro than the parent drug, warranting relevant in vivo studies.

The sera of 322 patients with various connective tissue diseases were checked by immunofluorescence (IF) on rat tissue sections. Twelve sera containing ribosomal antibodies were selected by this procedure and their antigenic specificities were studied. It was possible to divide the sera into two groups: R sera, the IF pattern of which disappeared after RNase treatment of the tissue sections and the DR sera, still detectable after RNase treatment. In immunodiffusion (ID) these two groups were antigenically distinct but in each group complete identity of the precipitin lines was observed. The diversity of the ribosomal antigens involved was shown. The prognostic value of these antibodies is discussed.

Macrolide antibiotics are taken up and concentrated by host cells, particularly phagocytes, and are likely candidates to modify cell functions. In this study, we extended our previous work concerning the effect of three 14-membered-ring macrolides (dirithromycin, erythromycin and erythromycylamine) on human neutrophil exocytosis, and found that three other erythromycin A derivatives (roxithromycin, clarithromycin and the azalide, azithromycin) also triggered neutrophil degranulation in a time- and concentration-dependent manner. After 30 min of incubation, the correlation coefficients for concentration-dependence for roxithromycin were 0.885, 0.739 and 0.750 (P < 0.005) and for clarithromycin were 0.795, 0.599, 0.733 (P < 0.02), respectively, for lysozyme, beta-glucuronidase and lactoferrin release. Although the underlying mechanism was not elucidated, these and previous data suggest that intracellular accumulation is a prerequisite. Furthermore, comparison of the characteristics of macrolide-induced exocytosis with those of exocytosis triggered by the synthetic chemotactic stimulus FMLP suggested that different mechanisms are involved. In keeping with this possibility, we showed that combined treatment (macrolides plus FMLP) resulted in totally additive exocytosis of azurophilic but not specific granules. The clinical relevance of our data remains to be ascertained.

We analyzed the uptake of RU 64004 by human neutrophils (polymorphonuclear leukocytes [PMNs]) relative to those of azithromycin and roxithromycin. RU 64004 was strongly and rapidly accumulated by PMNs, with a cellular concentration/extracellular concentration ratio (C/E) of greater than 200 in the first 5 min, and this was followed by a plateau at 120 to 180 min, with a C/E of 461 +/- 14.8 (10 experiments) at 180 min. RU 64004 uptake was moderately sensitive to external pH, and activation energy was also moderate (63 +/- 3.8 kJ/mol). RU 64004 was mainly located in PMN granules (about 70%) and egressed slowly from loaded cells, owing to avid reuptake. The possibility that PMN uptake of RU 64004 and other macrolides occurs through a carrier-mediated system was suggested by three key results. First, there existed a strong interindividual variability in uptake kinetics, suggesting variability in the numbers or activity of a transport protein. Second, macrolide uptake displayed saturation kinetics characteristic of that of a carrier-mediated transport system: RU 64004 had the highest Vmax value (3,846 ng/2.5 x 10(6) PMNs/5 min) and the lowest Km value (about 28 microM), indicating a high affinity for the transporter. Third, as observed previously with other erythromycin A derivatives, Ni2+ (a blocker of the Na+/Ca2+ exchanger which mediates Ca2+ influx in resting neutrophils) impaired RU 64004 uptake by PMNs, with a 50% inhibitory concentration of about 3.5 mM. In addition, we found that an active process is also involved in macrolide efflux, because verapamil significantly potentiated the release of all three macrolides tested. This effect of verapamil does not seem to be related to an inhibition of Ca2+ influx, because neither EGTA [ethylene glycol-bis (beta-aminoethyl ether)-N,N',N'-tetraacetic acid] nor Ni2+ modified macrolide efflux. The nature and characteristics of the entry- and efflux-mediating carrier systems are under investigation.

We compared the uptakes and intracellular locations of four 14-membered-ring macrolides (roxithromycin, dirithromycin, erythromycin, and erythromycylamine) in human polymorphonuclear neutrophils (PMNs) in vitro. Intracellular location was assessed by cell fractionation and uptake kinetics in cytoplasts (granule-poor PMNs). Trapping of dirithromycin within PMN granules (up to 80% at 30 min) was significantly more marked than the intracellular trapping of the other drugs (erythromycylamine, 45% +/- 5.1%; erythromycin, 42% +/- 3.7%; roxithromycin, 35% +/- 3.0%). A new finding was that, in the absence of extracellular calcium, the uptakes of all of the macrolides by PMNs and cytoplasts were significantly impaired, by about 50% (PMN) and 90% (cytoplasts). Furthermore, inorganic Ca2+ channel blockers inhibited macrolide uptake in a concentration-dependent manner, with 50% inhibitory concentrations of 1.6 to 2.0 mM and 29 to 35 microM, respectively, for Ni2+ and La3+. The intracellular distributions of the drugs were unchanged in the presence of Ni2+ and La3+ and in Ca(2+)-free medium supplemented with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. The organic Ca2+ channel blocker nifedipine had no effect on macrolide uptake, whereas verapamil inhibited it in a time- and concentration-dependent manner. These data show the importance of extracellular Ca2+ in macrolide uptake by phagocytes and suggest a link with Ca2+ channels or a Ca2+ channel-operated mechanism.

Dirithromycin and, to a lesser extent, erythromycylamine and erythromycin directly induced the release of three intragranular enzymes (lysozyme, lactoferrin, and beta-glucuronidase) from unstimulated human neutrophils. Macrolide-induced enzyme release was dependent upon the incubation time (30 to 180 min) and drug concentration. Dirithromycin was the most effective. At 120 min, release of lysozyme, beta-glucuronidase, and lactoferrin by macrolide (100 micrograms/ml)-treated cells, expressed as a percentage of total enzyme content, was, respectively, 58% +/- 8.3%, 52% +/- 10.7%, and 35% +/- 5.1% (dirithromycin); 42% +/- 3.9%, 28% +/- 5.8%, and 10% +/- 2.2% (erythromycylamine); and 35% +/- 4.0%, 19% +/- 4.3%, and 10% +/- 5.2% (erythromycin) (mean +/- standard error of the mean of three to eight experiments). The lowest macrolide concentrations which induced significant enzyme release were 10, 100, and 25 micrograms/ml, respectively, for dirithromycin, erythromycylamine, and erythromycin. Furthermore, we obtained evidence of a link between the prodegranulation effects of dirithromycin and erythromycylamine and the intragranular location of these drugs. Indeed, cell-associated drug levels increased for up to 60 min and then plateaued and declined substantially. Increasing the pH from 7 to 9 resulted in a parallel increase in drug uptake and the prodegranulation effect. Finally, when macrolide-treated neutrophils were disrupted by sonication and centrifuged, a correlation was found between lysozyme and beta-glucuronidase activities (both granule markers) and pellet-associated macrolide levels. Taken together, our results suggest that dirithromycin and erythromycylamine concentrate within neutrophil granules and then induce degranulation.

This study concerns the in vitro interaction with human polymorphonuclear neutrophils (PMNs) of amodiaquine, chloroquine, and mefloquine, three antimalarial drugs currently in use for the treatment and prophylaxis of malaria. It was found that mefloquine (100 and 50 micrograms/ml) significantly altered PMN viability while the other two drugs did not. Neutrophil chemotaxis was impaired by chloroquine (100 micrograms/ml) and mefloquine (greater than 10 micrograms/ml) but not by amodiaquine. Phagocytosis was decreased by about 50% in the presence of chloroquine (100 micrograms/ml) or mefloquine (10 micrograms/ml). The three antimalarial drugs altered neutrophil oxidative metabolism as assessed by luminol-amplified chemiluminescence. The strongest effect was observed with mefloquine, which abolished almost completely the neutrophil burst at concentrations of greater than 10 micrograms/ml whatever the stimulus used. This effect was not reversed by washing. Chloroquine and amodiaquine also impaired this PMN response by approximately 80 and 50%, respectively, but only at the highest concentration used (100 micrograms/ml). In the case of amodiaquine, the neutrophil response was restored by washing, except for stimulation with opsonized particles. After washing, the depressive effect of chloroquine was reversed completely in the case of phorbol myristate acetate stimulation and partly in the case of opsonized particle stimulation, but the formylmethionyl-leucyl-phenylalanine-induced response was not restored. These data show that although they are structurally related, amodiaquine and chloroquine exhibit qualitatively and quantitatively different depressive effects on PMN function and probably interfere at different points of cell activation, although the precise mechanisms are as yet unresolved.

The in vitro effects of RU 28965 (roxithromycin), a new semisynthetic macrolide, on human neutrophil activity were compared with those of erythromycin. RU 28965, at a concentration as low as 0.1 microgram/ml, significantly enhanced the phagocytosis and killing of Staphylococcus aureus by neutrophils. Erythromycin displayed a less stimulating effect in a dose-dependent manner. Phagocytosis of Klebsiella pneumoniae was also increased after incubation of neutrophils with RU 28965, but killing was not altered. Neutrophil chemotaxis, myeloperoxidase activity, and O2 consumption were unchanged in the presence of RU 28965.

Polymorphonuclear neutrophils play a crucial role in host defences against infectious diseases. New trends in anti-infectious therapy require knowledge of the possible interactions between the drugs and the natural defence system. This overview summarizes some of the in vitro data on the effects of anti-infectious agents on neutrophils. The relevance for the clinical situation is discussed.

ABSTRACTHMR 3647, a new ketolide, is active upon intracellular pathogens. We previously demonstrated that HMR 3004 (RU 64004), another ketolide, is highly concentrated by human polymorphonuclear neutrophils (PMNs). This prompted us to evaluate whether the presence of a 3-keto group instead of an l-cladinose, a neutral sugar characteristic of erythromycin A derivatives, confers peculiar pharmacokinetic properties with regard to cellular accumulation and efflux. After incubation with the radiolabelled drug, HMR 3647 uptake was determined by a velocity gradient centrifugation technique. HMR 3647 was avidly concentrated by PMNs, without saturation, over a 3-h incubation period, with cellular-to-extracellular concentration ratios of 31 ± 4.2 at 5 min and up to 348 ± 27.1 at 180 min. About 60% of HMR 3647 was located in the granular compartment; less than 6% was associated with the membranes. HMR 3647 gradually egressed from loaded cells placed in drug-free medium. Uptake was dependent on environmental temperature (activation energy, 128 ± 9.4 kJ/mol) but not on extracellular pH. HMR 3647 displayed Michaelis-Menten saturation kinetics with a mean Vmax of 2315 ng/2.5 × 106PMNs/5 min and a mean Kmof 117 mg/liter (144 μM). As already observed with erythromycin A-derived macrolides, extracellular Ca2+was necessary for optimal uptake of HMR 3647. Interestingly, verapamil increased the uptake of HMR 3647 at 5 min, but this was followed by gradual inhibition at later incubation times, a phenomenon probably related to stimulation of drug efflux. The impact of intracellular accumulation of HMR 3647 on PMN functions was also investigated. In contrast to other erythromycin A derivatives, HMR 3647 only weakly triggered granule exocytosis, but it inhibited superoxide anion production in a time- and concentration-dependent manner, with concentrations which inhibited 50% of control response of 55 (67 μM) (5 min) and 30 (36 μM) (30 min) mg/liter for formyl-methionyl-leucyl-phenylalanine stimulation and 117 (143 μM) (5 min) and 44 (54 μM) (30 min) mg/liter for phorbol myristate acetate stimulation.

Summary The immunomodulatory properties of cefodizime, a new aminothiazolyl cephalosporin, are reviewed. Cefodizime displaysin vitro andex vivo stimulatory effects on phagocyte bactericidal function. It also increases certain lymphocyte responses, including delayed type hypersensitivity and antibody production. In addition, it restores various immune functions in immunocompromised animals and humans. The immunomodulating activity of this drug is further supported by itsin vivo efficacy in experimental models of infections using cefodizime-sensitive or-resistant pathogens. Cefodizime appears to be a promising molecule, exhibiting potent antimicrobial activity and exerting potentially beneficial effects on the immune system.

Polymorphonuclear neutrophils (PMN) play a prominent role in the host response to infectious diseases. One major bactericidal mechanism used by these cells is the production of reactive oxygen species during what is referred to as the oxidative burst. However, excessive oxidant generation can also be involved in cell and tissue damage associated with severe inflammatory reactions. Macrolide antibiotics are able to penetrate and concentrate within phagocytes and have been successfully used to treat infections due to facultative intracellular pathogens. However, intracellular accumulation of macrolides with possible alkalinization of cellular compartments may interfere with normal cell function. In-vitro and ex-vivo data suggest that macrolides affect various phagocytic functions. This paper presents an overview of the published data concerning the modulation of neutrophil function by macrolides. Preliminary data concerning the in-vitro modulation of the neutrophil oxidative burst by dirithromydn and its metabolite, erythromycylamine, are also discussed.

Immunomodulation by antibacterial agents shows promise as a novel strategy in the treatment of infectious diseases. Cefodizime, a new oxi-imino-amino-2-thiazolyl cephalosporin, is a particularly good candidate in this context. In-vivo models of experimental infections show that prophylactic administration of cefodizime increases the survival of some strains of mice after challenge with Toxoplasma gondii or Candida albicans; its curative effect in infections due to members of the Enterobacteriaceae is better than that expected from in-vitro MIC determinations relative to other third-generation cephalosporins; this effect is even more marked in immuno-compromised animals. Data obtained both in vivo and ex vivo show that cefodizime enhances various immune parameters such as phagocyte function, B lymphocyte responsiveness and delayed hypersensitivity; it may restore natural killer (NK) and phagocyte activity, as well as interleukin 1 (IL-1) and interferon production, in immunocompromised patients and animals. The in-vitro effects of this drug include enhancement of phagocyte bactericidal activity and alteration of bacterial virulence factors. The chemical basis for these various immunomodulatory properties is related to the thio-thiazolyl side-chain at position 3 of the cephem nucleus. To date, the mechanisms underlying the immunomodulatory properties of cefodizime have not been identified clearly, but it is likely that it interferes at different levels of specific and non-specific immune defences.

Cefodizime, a 2-amino-thiazolyl cephalosporin, is reported to display in-vitro, ex-vivo and in-vivo immunomodulatory properties; in particular, it enhances the survival of mice infected with cefodizime-resistant pathogens. We have used an in-vitro model to assess the indirect effect of this drug (compared with other cephalosporins) on the neutrophil (PMN) oxidative response. Pseudomonas aeruginosa was employed as the bacterial target for cefodizime and cefotaxime (MICs > 128 mg/l), cefsulodin (MIC 16 mg/l) and ceftazidime (MIC 32 mg/l). After overnight growth in the presence of subinhibitory concentrations of each drug (10 mg/l), the altered filamentousP. aeruginosa induced a stronger oxidative response of PMN than untreated control bacteria. For all cephalosporins this was related to alterations of bacterial structure leading to increased deposits of antibodies and/or complement. Furthermore, increased non-opsonin dependent stimulation of the PMN oxidative burst was obtained; the strongest response was observed with cefodizime-treated P. aeruginosa in the case of low responder PMN, which displayed a deficient response after stimulation by control bacteria. The possibility that cefodizime could enhance this PMN function in opsonin-deficient patients requires further investigation.

Cefodizime is a 2-aminothiazolyl cephalosporin for parenteral use. Cefodizime has a bisubstituted thiothiazole moiety in position 3 of the cephem nucleus. The presence of this moiety does not alter the in-vitro antibacterial activity, or safety in animal studies, which are similar to those of cefotaxime, but results in an apparent long elimination half-life in rodents and dogs, and in novel immunological properties.