Toxicologic and pharmacologic considerations in the choice of empiric parenteral antibiotics.

The last five years have produced an explosive development of new beta-lactam compounds with extended bacterial spectra to include most of the gram-positive cocci as well as the gram-negative bacilli. With the exception of activity against enterococci, there are now third-generation cephalosporins with a spectrum of activity similar to that of the aminoglycosides. In addition, beta-lactams retain a high level of activity against anaerobes and against aerobes surviving in anaerobic conditions, a capacity that is lacking with the aminoglycoside group of antibiotics. The beta-lactams in general and some specific compounds in particular (moxalactam, ceftriazone) have a good penetration into the cerebrospinal fluid, a capacity that is also lacking with the aminoglycosides. Since there is a wide range of different spectra of activity among penicillins and cephalosporins, it is also possible to choose an antibiotic with a spectrum restricted to the offending microorganisms. Finally, because the potential toxicity of beta-lactams is less than that of the aminoglycosides (with the possible exception of myelotoxicity), the first choice of antibiotic in a patient with suspected severe infection should be a beta-lactam. The addition of an aminoglycoside should be reserved for those situations in which a synergistic action between the beta-lactam and the aminoglycoside antibiotics is expected to increase the efficacy of the beta-lactam alone, e.g., enterococcal infections, Pseudomonas aeruginosa infections, infections in severely neutropenic patients, or bacterial endocarditis.

Inhibition of HSV-1 and vaccinia virus replication by cephalosporin derivatives.

Derivatives of beta-lactam antibiotics of the cephalosporin type at 0.02-1 mM concentrations interfered with in vitro replication of two DNA-containing viruses, herpes simplex I and vaccinia, but showed no effects on two RNA-viruses, lymphocytic choriomeningitis virus and vesicular stomatitis virus, or on cell viability. The exact structure of the active compounds remains unknown, but opening of the beta-lactam ring appears to be a prerequisite for their formation. Whereas cephalosporin derivatives were most active, no active products were obtained from penicillins and monobactams. The potential of these unexpected antiviral effects of widely used beta-lactam antibiotics remains subject of further study.

Misleading supine chest X-ray in complete detachment of a Starr-Edwards prosthetic aortic valve.

The authors report a case of total detachment of a Starr-Edwards aortic valve prosthesis occurring eleven years after implantation. The detached valve had embolized into the descending thoracic aorta. The prosthetic valve was projected into an apparently normal position on a supine chest X-ray. The correct diagnosis was thus delayed. The authors stress the importance of obtaining lateral views or performing fluoroscopy and/or echocardiography in the emergency room in patients with acute chest symptoms after heart valve replacement.

HIV-reverse transcriptase and human DNA polymerase alpha share amino acid sequence homologies to bacterial penicillin-binding proteins.

Penicillin-binding proteins are the specific targets for the beta-lactam antibiotics. Recently it was observed that beta-lactam antibiotics also have targets in proliferating eukaryotic cells (1), one of which most likely is the replicative DNA polymerase alpha. Here we show that HIV-reverse transcriptase and human DNA polymerase alpha share amino acid sequence homologies to five bacterial penicillin-binding proteins.

[Evaluation of hematologic side effects of anti-infective therapy: agranulocytosis caused by beta-lactam antibiotics, vancomycin and amodiaquine]. / Evaluation hämatologischer Nebenwirkungen der antiinfektiösen Therapie: Agranulozytose durch beta-Laktam-Antibiotika, Vancomycin und Amodiaquin.

Side effects in general and in particular to antiinfective therapy are obviously hardly predictable and a causal relationship is seldom firmly established. The handling of untoward reactions may be improved if a subpopulation which can be identified is at particular risk for a given reaction. A clear assessment of dose and time dependency of untoward reactions is important in this context. Agranulocytosis seen with (i) beta-Lactam-antibiotics, (ii) vancomycin and (iii) amodiaquine can exemplify how simultaneous investigations of epidemiological and experimental aspects lead to identification of a subpopulation at risk.

[Frequent problems of non-steroidal antirheumatic agents in old age]. / Häufige Probleme der nicht-steroidalen Antirheumatika (NSA) im Alter.

The relationship between nonsteroidal antiinflammatory drugs (NSAID) and peptic lesions in the upper gastrointestinal tract remains unclear in many respects. Nevertheless, there is increasing evidence that the risk in patients over 65 years of age and particularly in women is higher than in younger individuals. Data suggest that compounds with long elimination half life increase the risk further. In patients at risk it is therefore advisable to start treatment with the lowest potentially effective dosage and to avoid compounds with long half lives as first line treatment. NSAID are today the most frequent cause of drug induced renal damage. The renal function disturbances induced by NSAID are largely due to inhibition of renal prostaglandin synthesis. In patients with underlying risk factors NSAID can cause acute renal failure, salt and water retention and hyperkalemia. Because of a progressive decline in renal function and alterations in water and electrolyte homeostasis with aging, elderly patients taking NSAID are particularly at risk of developing renal disease.

Heat-induced radial segmentation of leucocyte nuclei: a non-specific phenomenon accompanying inflammatory and necrotizing diseases.

Heat-induced radial segmentation (RS) of leucocyte nuclei in vitro (2 h at 41 degrees C) is a heretofore unknown phenomenon, accompanying inflammatory and necrotizing diseases. This phenomenon appears to be identical with the known oxalate-induced radial segmentation and is caused by contractile microfilaments and microtubuli radiating from the centriole. Preincubation of washed leucocytes from healthy donors with plasma of patients showing the phenomenon of RS did not induce RS and preincubation of washed RS-leucocytes with normal plasma did not suppress RS. RS, however, could be induced by intravenous endotoxin injection in a healthy volunteer and could be prevented in part by addition of Vincristine to the blood samples. The phenomenon corresponds to an incomplete, heat-inducible amitosis. The cause of the thermolability of the mitotic apparatus in various diseases remains unclear.

Simultaneous primary infection with HIV and CMV leading to severe pancytopenia, hepatitis, nephritis, perimyocarditis, myositis, and alopecia totalis.

Simultaneous primary infection with HIV and CMV in an 18-year-old woman led to an acute cytotoxic reaction, manifesting as pancytopenia, hepatitis, nephritis, perimyocarditis, and myositis. Within 14 days parameters indicating acute cell damage reverted to normal. Two weeks later transient alopecia totalis developed. Initially, HIV-antigen but no HIV antibodies were present. Within 3 weeks HIV-IgG antibodies appeared while HIV antigen disappeared. Anti-CMV-IgM was clearly and anti-CMV-IgG questionably positive; IgM persisted further, while IgG remained definitely undetectable. We speculate that a particular HIV-induced imbalance of the immune system led to a generalized severe cytotoxic reaction to a simultaneous infection with CMV.

Atenolol and pindolol interfere with urinary 5-hydroxyindole-3-acetic acid.

Oral beta-blockade with atenolol and pindolol was found to increase urinary 5-hydroxyindoleacetic acid (5-HIAA). In addition pindolol and perhaps some of its metabolites but not atenolol do interfere with chemical analysis of 5-HIAA. This may be due to structural similarities.

Different effects of selective and nonselective beta adrenoceptor blockade on urinary catecholamine and creatinine excretion in stress.

We tested the hypothesis that (1) beta 1-selective and nonselective beta adrenoceptor blockades have a different influence on stress-induced catecholamine overshoot, and (2) beta 1-selective blockade shifts the epinephrine/norepinephrine ratio in favor of norepinephrine. Seven violinists were investigated; each performed four times in public after ingesting different beta blockers. A significantly greater urinary norepinephrine/creatinine excretion was found with selective beta blockade than with nonselective. In addition during selective beta blockade creatinine excretion decreased significantly in comparison with nonselective blockade. This might be due to a higher concentration of circulating norepinephrine, stimulating alpha receptors in the renal vasculature.

Heat induced radial segmentation of leukocyte nuclei in patients with polymyalgia rheumatica and other inflammatory diseases.

Heat induced radial segmentation of leukocyte nuclei is an in vitro phenomenon accompanying inflammatory diseases. We studied 62 patients with suspected polymyalgia rheumatica (PMR) to determine, whether heat induced radial segmentation can help in discriminating PMR from other conditions. At the initial presentation patients with PMR had more radial segmentation formation than patients with other inflammatory conditions. Prednisone induced a rapid and marked decrease in radial segmentation formation in patients with PMR. This latter finding was much less marked in patients with other inflammatory conditions. We conclude that heat induced radial segmentation at the initial presentation and during prednisone treatment can help in discriminating PMR from other inflammatory conditions.

Amoxicillin-induced immune hemolysis.

Severe hemolysis occurred in a 51-year-old female after a 17-day course of intravenous amoxicillin. A strongly positive direct antiglobulin test (anti-IgG titer 1:2,000) ensued which disappeared after withdrawal of the drug. Both the patient's serum and eluate obtained from the patient's red cells contained an IgG antibody which reacted with red blood cells coated in vitro with amoxicillin, but not with uncoated cells. In addition, high-titer antipenicillin, antiampicillin and antiamoxicillin IgG antibodies could be demonstrated in her serum by a RAST-based solid-phase radioimmunoassay. The patient's hemolysis gradually subsided within 1 week after discontinuing the drug. This is the first report of amoxicillin-induced immune hemolytic anemia.

Inhibition of granulopoiesis in vivo and in vitro by beta-lactam antibiotics.

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.

[Radioimmunologic detection of IgE and IgG antibodies against drugs. Conclusions after experience with over 1200 patients]. / Radioimmunologische Erfassung von IgEund IgG-Antikörpern gegen Medikamente. Standortbestimmung nach Erfahrungen mit über 1200 Patienten.

Based on the radioallergosorbent test (RAST), the authors have developed a series of assays to detect IgE and IgG antibodies against a number of frequently used drugs. In this system drugs bound covalently to cellulose paper are incubated with serum and washed; the hapten-specific IgE and IgG antibodies are then qualified and quantified by means of 125I-labelled anti-human IgE and IgG respectively. Thus far the sera of 1,228 patients have been analyzed following therapy with betalactam antibiotics, co-trimoxazole, salicylates, pyrazolones, flavonoids and tetrahydroisoquinoline. The induction of IgG antibodies is a frequent occurrence and that of IgE rare. Isolated high titers of IgE are associated mainly with anaphylactic reactions; in the presence of simultaneously raised IgG titers such side reactions are often absent. Highest IgG titers were found in patients with immune hemolysis after betalactam antibiotics, flavonoids and tetrahydroisoquinoline. In the other types of side reaction specific IgG titers were not significantly higher than in patients without side reactions. The estimation of circulating antibodies against drugs cannot yet be utilized diagnostically except in the rare cases of anaphylactic side reactions. However, the method described permits specific and sensitive detection of sensitization and is suited for scientific purposes.

Suppressive effects of B-lactam-antibiotics on in vitro generation of cytotoxic T-cells.

The in vitro effect of several compounds containing the B-lactam structure (including 6-aminopenicillanic acid, piperacillin, 7-aminocephalosporanic acid, ceftazidime and clavulanic acid) on the generation of cytotoxic lymphocytes was investigated in two different in vitro systems: (1) generation of virus specific cytotoxic T-cells and (2) proliferation of lymphocytes were assessed in secondary in vitro anti-viral immune responses. Both activities were suppressed by B-lactams in a dose-dependent manner. In these experiments, as found previously with human in vitro granulopoesis and proliferation of the human erythroleukaemic cell line K-562, cephalosporins and clavulanic acid were five to twenty times more suppressive than penicillins. Since concentrations that were effective in vitro are being achieved, particularly with cephalosporins, in the serum of patients, the possible clinical consequences of our findings may have to be taken into consideration.

Betalactam antibiotics interfere with eukaryotic DNA-replication by inhibiting DNA polymerase alpha.

Betalactam antibiotics (BLA) are the most widely used antibacterial drugs in practical medicine. Recent experiments suggested that BLA, especially after "aging" in aqueous solutions, have an inhibitory effect on the growth of a variety of cultured human cells by interfering with DNA synthesis (Neftel et al. Cell Biol. Toxicol. 2, 513-521, 1986). Our initial observation that the replicative DNA polymerase alpha might be the target of the action of betalactam compounds (Hübscher et al. Cell Biol Toxicol. 2, 541-548, 1986) is now substantiated due to the following experimental data: (i) extractable DNA polymerase alpha is greatly reduced in cells that had been treated with BLA; (ii) the relative cellular distribution of thymidine and of its phosphorylated derivatives is not affected by BLA; (iii) BLA inhibit crude and highly purified mammalian DNA polymerase alpha; (iv) the inhibitory effect appears to be of the mixed type with a slight deviation from purely non-competitive behaviour towards the four deoxyribonucleoside triphosphates and; (v) the inhibition is evident in aphidicolin sensitive DNA polymerases from mammalian tissues and in DNA polymerases from DNA viruses such as Herpes simplex and Vaccinia. In sum, the results suggest that one of the most commonly used class of drugs has a target within eukaryotic cells being most likely the replicative DNA polymerase alpha.

Measurement of specific IgG antibody levels in serum of patients on regimes comprising high total dose beta-lactam therapy.

Sera from 125 patients receiving mean total doses of beta-lactam therapy of 215 g over a mean of 14 days were assayed by radioimmunoassay. Titres of anti-penicilloyl antibodies, expressed in arbitrary units of specific IgG per microliter of serum (u/microliter), ranged from undetectable (less than 3 u/microliter) to 1,650 u/microliter. There was a higher prevalence of elevated IgG levels in patients who developed haemolytic anaemia or neutropenia compared with patients with no adverse reactions but only in those patients who developed haemolytic anaemia were the antibody titres significantly higher. A subsidiary finding was that a correlation was established between mean total dose and prevalence of positive IgG titres, on a patient group basis (r = 0.87).

[Livedo reticularis and multiple vascular occlusions in a patient with HLA-B27-negative spondyloarthrosis and antiphospholipid antibodies]. / Livedo reticularis und multiple Gefässverschlüsse bei einem Patienten mit HLA-B27-negativer Spondylarthropathie und Antiphospholipid-Antikörpern.

We report the case of a 74-year-old patient with HLA-B27 negative spondylarthropathy presenting with acute disseminated vascular occlusions. The presence of livedo reticularis prompted a search for antiphospholipid antibodies which were found to be markedly elevated. Histopathological examination revealed noninflammatory vascular obstruction. The clinical evolution was rapidly fatal in spite of corticosteroid treatment. Livedo reticularis can be an important diagnostic clue to various types of underlying disease. Increased levels of antiphospholipid antibodies have been associated with thrombosis and thromboembolism, especially in the context of autoimmune diseases such as systemic lupus erythematosus. This paper reports antiphospholipid antibody-associated noninflammatory vascular occlusions in a patient with HLA-B27 negative spondylarthropathy. The pathogenetic mechanism of antiphospholipid antibody-mediated vascular occlusions is not completely understood and optimal therapy remains to be defined.