Third generation cephalosporins

The third generation cephalosporins demonstrate greater potency, broader antibacterial spectrum, and more favorable pharmacologic characteristics than other cephalosporins. The majority of strains of E. coli, Klebsiella pneumoniae, and Proteus are susceptible, including strains resistant to aminoglycosides, anti-Pseudomonas penicillins, and other cephalosporins. Pseudomonas aeruginosa is susceptible to a subgroup of third generation agents including ceftazidime, cefoperazone, and the experimental agents cefpirome and cefpiramide. Penetration into the cerebrospinal fluid is excellent especially for cefotaxime, ceftazidime, ceftriaxone, and ceftizoxime. These agents are safe, sharing most of the known toxicities of other beta-lactam compounds. Their greatest use is in the therapy of difficult to treat gram-negative bacterial infections, including meningitis, nosocomial infections, and infections caused by Pseudomonas aeruginosa.     

耐三代头孢菌素阴沟肠杆菌临床株中CTX-M型ESBLs与Ⅰ类整合子的相关性

目的研究CTX-M型超广谱β内酰胺酶（ESBLs）及Ⅰ类整合子在耐三代头孢菌素阴沟肠杆菌中的分布,进一步探讨Ⅰ类整合子与CTX-MM型ESBLs的关系.方法运用K-B法检测阴沟肠杆菌临床株的耐药表型,双纸片协同试验（DDST）初筛产ESBLs的菌株,聚合酶链反应（PCR）扩增确证产CTX-M型ESBLs和含有Ⅰ类整合子的临床菌株,套式PCR及序列测定寻找携带CTX-M型ESBLs基因盒的Ⅰ类整合子.结果37株耐药菌中,21株菌产生CTX-M型ESBLs;20株菌含有Ⅰ类整合子;在13株同时产生Ⅰ类整合子和CTX-M型ESBLs的临床株中,3株菌CH4、CH11和Q1的CTX-M型ESBLs基因盒分布在Ⅰ类整合子上.结论Ⅰ类整合子的存在增加了ESBLs在临床株中水平播散的危险,是造成多重耐药株在院内暴发流行的重要原因.     

In vitro activity of second and third generation cephalosporins against ampicillin susceptible and resistant haemophilus influenzae

Summary One hundred seventy-five clinical isolates ofHaemophilus influenzae (including 74 -lactamaseproducing strains) were examined for susceptibility to ampicillin, cefonicid, cefamandole, cefuroxime and cefotaxime. Cefonicid and cefamandole exhibited similar activity against ampicillin-susceptible strains (MIC₉₀ = 0.2 mg/l for both antibiotics); cefuroxime was slightly less active (MIC₉₀ = 0.01 mg/l). However, cefonicid, cefuroxime and cefotaxime were all more active against -lactamase-producingH. influenzae than cefamandole (MIC₉₀ = 1.0 mg/l for cefonicid, MIC₉₀ = 2.0 mg/l for cefuroxime, MIC₉₀ = 0.01 mg/l for cefotaxime, MIC₉₀ = 5.0 mg/l for cefamandole). One hundred twenty-five of the 175 isolates were also tested for susceptibility to cefonicid and cefamandole by disc diffusion technique and a plot of zone diameter vs. MIC was analyzed for the -lactamase-producing strains.

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In vitro-Aktivität von Cephalosporinen der zweiten und dritten Generation gegen Ampicillin-empfindliche und -resistente Stämme von Haemophilus influenzae

Zusammenfassung 175 klinische Isolate vonHaemophilus influenzae (einschließlich 74 -Laktamase bildenden Stämmen) wurden auf ihre Empfindlichkeit gegen Ampicillin, Cefonicid, Cefamandol, Cefuroxim und Cefotaxim untersucht. Die Aktivität gegen Ampicillin-empfindliche Stämme war bei Cefonicid und Cefamandol ähnlich (MHK für beide Antibiotika 0,2 mg/l); Cefuroxim zeigte etwas geringere Aktivität (MHK 1,0 mg/l); die Wirksamkeit von Cefotaxim war signifikant stärker (MHK₉₀ 0,01 mg/l). Gegen -Laktamase bildendeH. influenzae waren dagegen Cefonizid, Cefuroxim und Cefotaxim dem Cefamandol überlegen (MHK₉₀-Werte für Cefonizid 1,0 mg/l; für Cefuroxim 2,0 mg/l; für Cefotaxim 0,01 mg/l und für Cefamandol 5,0 mg/l). Bei 125 der 175 Isolate wurde die Empfindlichkeit gegen Cefonizid und Cefamandol auch im Blättchendiffusionstest bestimmt und für die -Laktamase-Bildner wurde die Kurve für die Hemmhofdurchmesser gegenüber den MHK-Werten analysiert.

     

In vitro activity of cefpirome compared with other third generation cephalosporins against nosocomial isolates in Argentina

Summary Thein vitro activity of cefpirome was evaluated against strains that showed conflicting results for third generation cephalosporins. Against isolates with derepressed inducible chromosomal cephalosporinase (n=40) cefpirome was the sole cephalosporin with an MIC₉₀ in the susceptible range;Klebsiella spp. with plasmid-mediated -lactamases (broad spectrum SHV-2 or SHV-2 type) (n=40) remained most susceptible to ceftizoxime and cefpirome; against aminoglycoside-resistantPseudomonas aeruginosa (n=50), cefpirome was as active as ceftazidime and cefoperazone; against oxacillin-susceptible and oxacillin-resistantStaphylococcus spp., (n=40 each) and againstEnterococcus spp., (n=20), cefpirome was more active than other third generation cephalosporins but killing was inadequate against both oxacillin-resistant staphylococci and enterococci.

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In-Vitro-Aktivität vom Cefpirom im Vergleich zu anderen Drittgenerations-Cephalosporinen gegen nosokomiale Isolate aus Argentinien

Zusammenfassung Cefpirom wurde auf seineIn-Vitro-Aktivität gegen Stämme untersucht, die sich in ihrer Empfindlichkeit gegen Drittgenerationscephalosporine widersprüchlich verhielten. Cefpirom wies als einziges Drittgenerationscephalosporin gegen 40 Isolate mit dereprimierter induzierbarer chromosomaler Cephalosporinase MHK₉₀-Werte im empfindlichen Bereich auf. Plasmid-vermittelte -Laktamase (Breitspektrum SHV-2 oder Typ SHV-2) bildendeKlebsiella spp. (n=40) verhielten sich gegen Ceftizoxim und Cefpirom am empfindlichsten. Cefpirom war gegen aminoglykosidresistente Stämme vonPseudomonas aeruginosa (n=50) ebenso wirksam wie Ceftazidim und Cefoperazon. Cefpirom war den anderen Drittgenerationscephalosporinen überlegen in seiner Aktivität gegen oxacillinempfindliche und oxacillinresistenteStaphylococcus spp. (je 40 Isolate) und gegenEnterococcus spp. (n=20); jedoch war die Abtötung oxacillinresistenter Staphylokokken wie auch der Enterokokken nicht adäquat.

     

Resistance to third-generation cephalosporins in adult gram-negative bacillary meningitis

Summary Ninety-three patients with gram-negative bacillary meningitis (GNBM) were identified at Kaohsiung Chang Gung Memorial Hospital, over a period of 12 years. Among them, eight showed resistance to third-generation cephalosporins, accounting for 9% of the total GNBM cases and 29% of the postneurosurgical GNBM cases. The resistant pathogens includedAcinetobacter baumannii, Klebsiella pneumoniae, Citrobacter freundii andMorganella morganii. These eight patients, six males and two females aged 18–61 years, all had nosocomially acquired meningitis associated with head trauma and/or postneurosurgical states. Six patients received imipenem/cilastatin treatment; five survived and one died. The other two expired because they did not receive appropriate antibiotic treatment. Although third-generation cephalosporin-resistant GNBM is rare, its incidence has been increasing over the past 5 years. In patients with nosocomially-acquired postneurosurgical GNBM, the presence of third-generation cephalosporin resistnace should therefore be highly suspected. The appropriate choice of antibiotic is essential for their survival.     

Perspectives of beta-lactamases inhibitors in therapy of infections caused by Escherichia coli or Klebsiella with plasmidic resistance to third generation cephalosporins

Summary New plasmidic -lactamases inactivating so far stable cephalosporins, aztreonam and cephamycins restrict the use of these antibiotics in therapy of infections, e.g., byEscherichia coli and Klebsiella. Thus, combinations of -lactamase inhibitors and -lactam antibiotics were investigatedin vitro with regard to their therapeutic perspectives. Minimal inhibitory concentrations and the kinetics of killing in a pharmacodynamic model were determined. Extended broad spectrum betalactamases (EBS--lactamases) representative both for the TEM- and SHV-type were included. None of the available fixed combinations of penicillins and -lactamase inhibitors appears useful for therapy of infections caused by producers of EBS--lactamases. In contrast, combinations of piperacillin and tazobactam or sulbactam plus cephalosporins (cefoperazone, cefotaxime, ceftazidime) or aztreonam are highly active (both by their MICs and bactericidal activity) against TEM-type EBS--lactamases, but less promising for the SHV-type EBS--lactamases, and plasmidic cephamycinase. Of the -lactams available, the monobactam carumonam and the carbapenems (imipenem, meropenem) remain safe in infections caused byE. coli and Klebsiella EBSBase producers.

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Therapeutische Perspektiven von -Laktamase-Inhibitoren bei Infektionen durch Escherichia coli oder Klebsiella mit plasmid-determinierter Resistenz gegenüber Drittgenerationscephalosporinen

Zusammenfassung Neue plasmid-kodierte -Laktamasen inaktivieren bisher stabile Cephalosporine, Aztreonam und Cephamycine. Sie schränken damit die therapeutische Sicherheit dieser Antibiotika bei Infektionen zum Beispiel durchEscherichia coli oder Klebsiellaarten ein. Deshalb wurden die therapeutischen Perspektiven von Kombinationen aus -Laktamase-Inhibitoren und -Laktam-Antibiotikain vitro analysiert. Die minimalen Hemmkonzentrationen (MHK) wurden gemessen. Zu einem pharmakokinetischen Modell wurde die Abtötungskinetik bestimmt. Einbezogen wurden Enzyme sowohl aus der TEM- als auch der SHV-Reihe. Keine der beiden zugelassenen festen Kombinationen aus Penicillinen und -Laktamase-Inhibitoren erwies sich als erfolgversprechend für die Therapie von Infektionen durch Stämme, welche -Laktamasen mit erweitertem Spektrum produzieren. Demgegenüber waren Kombinationen aus Piperacillin und Tazobactam oder Sulbactam mit Cephalosporinen (Cefoperazon, Cefotaxim, Ceftazidim) oder Aztreonam sowohl aufgrund ihrer MHK-Werte als auch ihrer bakteriziden Aktivität im pharmakodynamischen Modell hochaktiv gegenüber TEM--Laktamasen mit erweitertem Spektrum, jedoch weniger wirksam bei Stämmen mit neuen Enzymen der SHV-Reihe und plasmid-kodierter Cephamycinasen. Unter den derzeit vorhandenen -Laktam-Antibiotika kommt anhand ihrerIn-vitro-Aktivität dem Monobactam Carumonam sowie den Carbapenemen (Impipenem, Meropenem) auch ohne -Laktamase-Inhibitor die größte therapeutische Sicherheit bei Infektionen durchE. coli und Klebsiella-Stämme mit der Fähigkeit zur Synthese von -Laktamasen mit erweitertem Spektrum zu.

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Symposium 2nd Biennial Conference on Chemotherapy of Infectious Diseases and Malignancies, Montreux, March 5^th–8^th, 1989.

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Supported by Pfizer GmbH, Karlsruhe, FR Germany.     

Resistance to penicillin derivatives inducible by cephalosporins in Enterobacteriaceae and Pseudomonadaceae

Summary Antagonistic effects of cephalosporins on penicillin derivatives were observed in 52 strains (9.3%) of a total of 558Enterobacteriaceae andPseudomonadaceae strains (Enterobacteriaceae: 7.6%,Pseudomonadaceae: 21.4%). Development of resistance was most frequently induced by cefoxitin — namely in 83% of the strains. Proof of this antagonism was obtained by a simple screening test in an agar diffusion test, and for confirmation purposes, by the checker-board technique. There was a four to 32-fold titer increase in the minimum inhibitory concentration of azlocillin and mezlocillin when cefoxitin was exposed simultaneously to the bacterial suspension. Possible effects of a combined use of cephalosporins and ureidopenicillins are discussed with regard to therapeutic efficacy.

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Durch Cephalosporine induzierbare Resistenz gegen Penicillinabkömmlinge bei Enterobacteriaceae und Pseudomonadaceae

Zusammenfassung Es wurden bei der Untersuchung von insgesamt 558Enterobacteriaceae undPseudomonadaceae bei 52 Stämmen (9,3%) antagonistische Effekte von Cephalosporinen gegen Penicillin-Abkömmlinge beobachtet (Enterobacteriaceae: 7,6%,Pseudomonadaceae: 21,4%). Dabei wurde die Resistenzentwicklung am häufigsten — nämlich in 83% der Stämme — durch Cefoxitin induziert. Der Nachweis dieses Antagonismus wurde als einfacher Screening-Test im Agar-Diffusionstest sowie zur Bestätigung in der Checkerboard-Technik geführt. Hier traten 4- bis 32fache Titeranstiege in der Minimalen Hemmkonzentration (MHK) von Azlocillin und Mezlocillin auf, wenn gleichzeitig Cefoxitin auf die Bakteriensuspension einwirkte. Mögliche Auswirkungen einer kombinierten Anwendung von Cephalosporinen und Ureidopenicillinen werden im Hinblick auf den therapeutischen Effekt diskutiert.

     

The third generation Carpentier-Edwards bioprosthesis: early results

The current status of valve replacement was reviewed by analyzing six groups of 100 consecutive patients, each receiving the standard Carpentier-Edwards bioprosthesis, the Starr-Edwards valve or the Bj?rk-Shiley valve in the mitral or aortic position and operated on by the same surgeons in the same institution during an identical time frame. Data were evaluated for valve failure, reoperation, thromboembolism and valve-related deaths. Long-term results up to 9 years showed the superiority of bioprostheses over mechanical valves in terms of valve-related deaths and thromboembolic and anticoagulant complications for a similar rate of valve failure. Persistent drawbacks associated with valvular bioprostheses, namely, transvalvular gradients, limited durability and tissue calcification in young patients, led to continual improvements in valve design and preservation techniques and the development of the third generation Carpentier-Edwards bioprosthesis: the supraanular porcine valve and pericardial valve. The supraanular porcine valve was designed with the aim of decreasing the transvalvular gradient, decreasing turbulence, increasing longevity and decreasing calcification. The pericardial valve was designed with the aim of improving hemodynamics in small-sized orifices, improving mounting techniques to avoid fixation sutures at the commissures, achieving a flexible stent and improving preservation. Between July 1980 and October 1984, there were 391 supraanular porcine and 61 pericardial valves implanted. The supraanular valves were used for three purposes: isolated aortic, isolated mitral and mitral valve replacement associated with tricuspid anuloplasty. The pericardial valves were used for isolated aortic valve replacement. Short-term results (1 to 4 years) are presented concerning the clinical use of these third generation bioprostheses.     

亚临床疾病的现状与思考

近年来在内分泌代谢领域中提出的"亚临床疾病"或"亚临床状态"或"疾病前期"是大家比较关注的问题,对它的诊断和治疗也存在着争议,特别是近年来对多种疾病谱的诊断时间提前,并对各种疾病的后果进行早期预防和干预,更使"亚临床疾病"或"亚临床状态"成为不仅是内分泌代谢学科,而且是其他多个学科在不同方面或在疾病的不同阶段的研究热点.     

A new method to study the efficiency of third generation blood filters

Summary. In order to study the efficiency of third generation blood filters we have devised a new method using 3 μm pore size polycarbonate filter membranes and a filtration chamber to trap leucocytes passing through the blood filter. The method has enabled us to make two important observations: (1) The filters function very efficiently at the start but the efficiency diminishes progressively with time. (2) When the blood flow through the filter is retarded, due to defective priming and/or filter malfunction, the filters fail even at the outset of the transfusion.