Seven cases of agranulocytosis and two ofliver damage that were probably due to amodiaquine treatment were studied. In five cases agranulocytosis was combined with liver damage, and in one case of primary liver damage moderate neutropenia was present. Three patients died. High total doses or prolonged duration of treatment, or both, appear to favour the occurrence of these reactions.The clustering of five of the seven cases of agranulocytosis within six months in one medical centre indicates that the risk to benefit ratio of amodiaquine for malaria prophylaxis should be re-evaluated.

beta-Lactam antibiotics can induce severe neutropenia by a hitherto unknown mechanism. Fifty cases of beta-lactam antibiotic-induced neutropenia (less than 1,000 neutrophils/mm3) from 17 hospitals were analyzed and compared with 140 literature cases. The incidence of neutropenia was 5%-greater than 15% in patients treated for greater than or equal to 10 days with large doses of any beta-lactam antibiotic but less than 0.1% with shorter duration of therapy. In greater than 95% of cases recovery occurred between one to seven days after withdrawal of beta-lactam antibiotics. Bone marrow aspirates were characterized by a lack of well-differentiated myeloid elements in the presence of numerous immature granulocyte precursors. Nine penicillins and eight cephalosporins inhibited in vitro granulopoiesis in a dose-dependent manner. There was a good correlation between the inhibitory capacity of beta-lactam antibiotics in vitro and the doses inducing neutropenia in vivo. These observations may be relevant for therapy in the granulocytopenic patient.

The underlying mechanisms of reactive macrophage activation syndromes (rMAS) are not understood in detail, and there is no specific treatment. This observational study was prompted by intravenous immunoglobulin (IVIG), dramatically halting two distinct rMAS episodes in the same patient. We evaluated the potential benefits of IVIG administration in treating fulminant rMAS and the usefulness of monitoring serum ferritin levels as an indication for emergency treatment with IVIG. Ten females and 10 males experiencing 22 episodes of rMAS were recruited on the basis of serum ferritin levels ≥10,000 µg/l and/or direct evidence of haemophagocytosis in 11 intensive care units in secondary and tertiary care hospitals in Switzerland between October 1993 and May 2000. In individual patients, serially measured ferritin was closely related to disease activity. Abrupt increases of up to >100,000 µg/l could be observed within hours. Rapid and profound beneficial effects of emergency IVIG treatment were seen in 12 episodes of rMAS accompanied by a prompt decrease of serum ferritin. IVIG produced partial or delayed improvements in 5 patients. No apparent effects were seen in 5 patients. IVIG was only successful if started early during the ferritin run-up to peak values. In conclusion, IVIG is effective in at least a subgroup of adult rMAS when started at the beginning of the macrophage activation process. The monitoring of serum ferritin levels might be helpful in detecting macrophage activation in order to commence IVIG treatment early enough. Am. J. Hematol. 68:4-10, 2001.

In 3 of 15 consecutive patients receiving a human leukocyte antigen (HLA)-identical but major ABO incompatible bone marrow transplant (BMT), pure red cell aplasia (PRA) lasting 5 to 8 months was observed. Titers of the incompatible anti-A agglutinin before infusion of the red blood cell (RBC)-depleted BMT was very high in one, and in the usual range in two patients. Decrease of agglutinin titers during the first 4 weeks after BMT were comparable between PRA patients and those of ABO- incompatible BMT recipients with timely RBC recovery. However, in PRA patients, agglutinin titers rose again and remained elevated for 19 to 28 weeks. RBC engraftment and reticulocyte recovery ultimately occurred spontaneously and coincided with the decrease of agglutinin titers below 16. These observations indicate that PRA is antibody-dependent in this setting. Furthermore, it is conceivable that cyclosporine facilitates recipient-derived antibody synthesis after major ABO- incompatible BMT.

Antidrug IgG antibodies have been detected in some patients receiving amodiaquine (AQ). Antidrug antibodies were detected in 6/7 patients who experienced serious well-defined adverse drug reactions during malaria prophylaxis and in 7/22 patients who received comparable doses of the drug (at least 400 mg weekly ×6) but did not present with clinical adverse drug reactions. In contrast antidrug antibodies were not detected in 7 patients who received the drug for treatment (1.0–1.2 g total over 3 days). The specificity of the IgG response was defined by hapten inhibition experiments (IC₅₀ value for AQ ranged between 0.050 and 0.282 μM) which suggest that the antibody recognised the drug linked to cysteine residues in protein via the 4-hydroxyanilino side chain. The data show that AQ is immunogenic in man and are consistent with the hypothesis that idiosyncratic adverse reactions to the drug have an immunological aetiology.

Cefepime, a broad-spectrum, fourth-generation cephalosporin, showed excellent CSF penetration with levels ranging between 10 and 16 mg/L after two intravenous injections (100 mg/kg). The bactericidal activity of cefepime (-0.60 +/- 0.28 Deltalog(10) cfu/mL/h) was superior to that of ceftriaxone (-0.34 +/- 0.23 Deltalog(10) cfu/mL/h, P < 0.05) and vancomycin (-0.39 +/- 0.19 Deltalog(10) cfu/mL/h, P < 0.05) in the treatment of rabbits with meningitis caused by an isolate highly resistant to penicillin (MIC of penicillin G: 4 mg/L). The addition of vancomycin to both cephalosporins did not significantly increase the killing rate compared with monotherapies (P > 0.05). Similar results were obtained in time-killing experiments in vitro.

The bactericidal activities of monotherapy with trovafloxacin (؊0.37 ؎ 0.15 ⌬log 10 CFU/ml ⅐ h), vancomycin (؊0.32 ؎ 0.12 ⌬log 10 CFU/ml ⅐ h), and ceftriaxone (؊0.36 ؎ 0.19 ⌬log 10 CFU/ml ⅐ h) for the treatment of experimental meningitis in rabbits due to a clinical penicillin-resistant pneumococcal strain (MIC, 4 mg/liter) were similar. The combination of ceftriaxone with trovafloxacin considerably improved the killing rates (؊0.67 ؎ 0.16 ⌬log 10 CFU/ml ⅐ h) and was slightly superior to ceftriaxone with vancomycin (killing rate, ؊0.53 ؎ 0.22 ⌬log 10 CFU/ml ⅐ h), the regimen most commonly used in clinical practice. In vitro, synergy was demonstrated between ceftriaxone and trovafloxacin by the checkerboard method (fractional inhibitory concentration index, 0.5) and by time-killing assays over 8 h.The treatment of pneumococcal infections has been jeopardized lately by the worldwide increase in the spread of resistant pneumococci (2). Among recently developed compounds, new quinolones are promising candidates, especially due to their activity against many gram-positive microorganisms, including penicillin-resistant pneumococci. Trovafloxacin showed dosedependent bactericidal activity against penicillin-resistant pneumococci in an experimental model of meningitis in rabbits (10). However, at doses (15 mg/kg of body weight) that lead to levels achievable in humans, its activity was only moderate (14). These data raise the possibility that trovafloxacin in combination with other antibiotics might play a role in the enhancement of bactericidal activity. We have recently shown that the addition of vancomycin to the trovafloxacin treatment regimen significantly improved the rate of killing of penicillinresistant pneumococci by trovafloxacin in an experimental model of meningitis and in vitro (14). Little is known about possible interactions between ␤-lactam antibiotics, e.g., ceftriaxone, and quinolones against penicillin-resistant pneumococci in an experimental model of meningitis. The aim of this study was to test the activity of trovafloxacin (15 mg/kg) in combination with ceftriaxone against penicillin-resistant pneumococci. Ceftriaxone, trovafloxacin, and vancomycin monotherapies and ceftriaxone in combination with vancomycin served as comparison regimens.Rabbit meningitis model. The meningitis model, originally described by Dacey and Sande (3), was slightly modified. Briefly, young New Zealand White rabbits that weighed between 2 and 2.5 kg were anesthetized by intramuscular injections of ketamine (30 mg/kg) and xylazine (15 mg/kg) and were immobilized in stereotactic frames for induction of meningitis and sampling of cerebrospinal fluid (CSF). An inoculum that contained approximately 10 5 CFU of penicillin-resistant pneumococci serotype 6 was directly injected into the cisterna magna. The pneumococcal strain had originally been isolated from a patient with pneumonia at the University Hospital of Bern, Bern, Switzerland. The MICs were as follows: penicillin, 4 mg/liter; ceftriaxone, 0.5 mg/liter; vancomycin, 0.12 ...

cMultidrug resistance in Gram-negative bacteria has become so threatening to human health that new antibacterial platforms are desperately needed to combat these deadly infections. The concept of siderophore conjugation, which facilitates compound uptake across the outer membrane by hijacking bacterial iron acquisition systems, has received significant attention in recent years. While standard in vitro MIC and resistance frequency methods demonstrate that these compounds are potent, broad-spectrum antibacterial agents whose activity should not be threatened by unacceptably high spontaneous resistance rates, recapitulation of these results in animal models can prove unreliable, partially because of the differences in iron availability in these different methods. Here, we describe the characterization of MB-1, a novel siderophore-conjugated monobactam that demonstrates excellent in vitro activity against Pseudomonas aeruginosa when tested using standard assay conditions. Unfortunately, the in vitro findings did not correlate with the in vivo results we obtained, as multiple strains were not effectively treated by MB-1 despite having low MICs. To address this, we also describe the development of new in vitro assays that were predictive of efficacy in mouse models, and we provide evidence that competition with native siderophores could contribute to the recalcitrance of some P. aeruginosa isolates in vivo.