Ureidopenicillins and beta-lactam/beta-lactamase inhibitor combinations.

Although research and development of new penicillins have declined, penicillins continue to be essential antibiotics for the treatment and prophylaxis of infectious diseases. The most recent additions are the ureidopenicillins and beta-lactam/beta-lactamase inhibitor combinations. This article reviews the spectrum of activity, toxicity, pharmacokinetics, and clinical uses of the ureidopenicillins, and the beta-lactam/beta-lactamase inhibitor combination agents.

Scimitar-horned oryx (Oryx dammah) spermatozoa are functionally competent in a heterologous bovine in vitro fertilization system after cryopreservation on dry ice, in a dry shipper, or over liquid nitrogen vapor.

A heterologous bovine in vitro fertilization (IVF) system was used to study the functional competence of scimitar-horned oryx spermatozoa after cryopreservation. Four sperm-freezing methods were compared after dilution of ejaculates from six oryx with an equine semen extender: 1) dry ice, 2) dry shipper one-step, 3) dry shipper two-step, and 4) liquid nitrogen vapor. Post-thaw sperm motility, longevity, and acrosomal status were assessed and zona pellucida penetration, fertilization, and embryo cleavage were evaluated after coincubation of thawed oryx spermatozoa with in vitro-matured domestic cow oocytes. Sperm motility index (SMI) decreased (p < 0.05) over a 6-h period, but a high percentage (>/= 65%) of spermatozoa contained intact acrosomes in all treatments. Despite differences in sperm motility among methods, oocyte penetration, fertilization, and embryo cleavage did not differ (p >/= 0.05). However, cleavage success was < 50% across all treatments. There were positive correlations (p < 0.05; r = 0.81-0.97) between sample SMI at 3 and 6 h and fertilization, penetration, and cleavage, but no correlations (p >/= 0.05) between SMI at 0 or 1 h and IVF success. This study demonstrates that compatible heterologous gamete interaction allows thorough assessment of post-thaw sperm function in an endangered antelope. Scimitar-horned oryx spermatozoa appear relatively tolerant of varied cryopreservation methods, and preserved samples exhibit adequate post-thaw function to warrant use for assisted reproduction.

Heterologous in vitro fertilization and sperm capacitation in an endangered African antelope, the scimitar-horned oryx (Oryx dammah).

Scimitar-horned oryx sperm function was studied using protocols developed for domestic cattle. Objectives were to assess sperm 1) viability and motility in vitro over time, 2) capacitation in heparin- or calcium-supplemented medium, and 3) function in an in vitro fertilization system using heterologous (domestic cow) oocytes. Seminal aliquots were washed, and sperm were resuspended in 1) Talp with 5% fetal calf serum (TALP), 2) TALP + 10 microM heparin, 3) TALP + 20 microM heparin, and 4) TALP + 10 mM CaCl. At 0, 3, and 6 h, aliquots were evaluated for sperm motility, viability (using Hoechst 33258), and ability to acrosome-react when exposed to lysophosphatidylcholine (LC). Sperm function was assessed by evaluating fertilization and embryo development after coculture of in vitro-matured domestic cow oocytes with oryx sperm. Overall mean percentages of motile and viable sperm remained high at 6 h (> 60% and > 70%, respectively). Fewer (p < 0.05) sperm incubated in TALP + 10 microM heparin for 6 h contained intact acrosomes after exposure to LC, but there were no differences between LC and control samples after incubation in TALP without heparin. LC-treated sperm in TALP + 10 mM CaCl contained fewer (p < 0.05) intact acrosomes at 3 and 6 h (52.6% and 31.2%, respectively) than paired controls (83.6% and 70.0%, respectively). Oryx sperm from all males were capable of fertilizing cow oocytes (range 17 of 26 [65.4%] to 25 of 26 [96.2%]). Of the 55 2-cell embryos produced, 34 (61.8%) developed to > or = 8 cells. Of the 24 uncleaved oocytes, 7 (29.2%) were polyspermic. These data demonstrate that processed sperm from the endangered scimitar-horned oryx remain vigorous in vitro for at least 6 h. Capacitation can be induced using cattle sperm-processing techniques, with sperm appearing most responsive to elevated CaCl concentrations. Most interesting was the successful production and development of hybrid embryos after coincubation of oryx sperm with cow oocytes, suggesting that the two bovid species have similar fertilization mechanisms.

Newer penicillins and beta-lactamase inhibitors.

Penicillins continue to be essential antibiotics for the treatment and prophylaxis of many infectious diseases. Recent advances have resulted in compounds with favorable new antimicrobial and pharmacologic properties. This article reviews the spectrum of activity, toxicity, pharmacokinetics, and clinical uses of the extended spectrum penicillins and the beta-lactamase inhibitor combination agents.

Evaluation of initiating a hepatitis B vaccination schedule with one vaccine and completing it with another.

The purpose of this study was to determine if a hepatitis B vaccination schedule initiated with one recombinant DNA vaccine could be completed with another. Forty-eight adults on a hepatitis B vaccination schedule of 0, 1 and 6 months had received their first two doses with Merck Sharpe and Dohme's recombinant DNA (MSD rDNA) vaccine (Recombivax HB) at its adult dose of 10 micrograms. At month 6, the subjects were randomized to receive SmithKline Beecham's recombinant DNA (SB rDNA) vaccine (Engerix-B) at its adult dose of 20 micrograms or MSD rDNA vaccine. Just prior to the third dose of SB rDNA or MSD rDNA vaccine, the geometric mean anti-HBs titres (GMT) were 161 and 168 mIU ml-1 for the two groups, respectively. The GMT at month 7 were 4077 and 2654 mIU ml-1 for those who had received SB rDNA or MSD rDNA vaccine, respectively. This study demonstrates that a hepatitis B vaccination schedule initiated with MSD rDNA vaccine can be completed with SB rDNA vaccine.

Pneumococcal soft-tissue infections: possible association with connective tissue diseases.

Streptococcus pneumoniae is not a well-recognized cause of soft-tissue infections. In less than 4 years, 12 cases of pneumococcal soft-tissue infection were identified through discussions with infections disease subspecialists in the Philadelphia area. Principal sites of involvement included skin and fascia, tongue, epiglottis, thyroid, brain, and breast. Pneumococcal bacteremia was documented in six cases (50%); in three of these, pneumococci were also cultured from the involved soft tissues. In the cases in which bacteremia was not demonstrated, pneumococci were isolated from the infected sites. Six patients had connective tissue diseases, of which five were diagnosed as systemic lupus erythematosus. Four of these patients were receiving corticosteroids when their infections developed. Two additional patients were HIV-seropositive intravenous drug users. S. pneumoniae may be a more important cause of soft-tissue infections than previously appreciated, especially in patients with connective tissue diseases.

Pharmacodynamics of antimicrobial agents. Bactericidal and postantibiotic effects.

The effectiveness of antibiotic dosing regimens may be strongly influenced by the effects that drug concentrations at the site of infection have on bacterial population dynamics during the interval after a single dose and the cumulative effects after multiple, intermittent doses. These pharmacodynamic effects involve: (1) the rate and extent of bactericidal action and suppression of bacterial growth in tissues, and (2) persistent postantibiotic antibacterial effects. Antimicrobial agents may each exhibit unique pharmacodynamic effects that can vary with the site of infection and species of microorganism.

Newer penicillins and beta-lactamase inhibitors.

The penicillins continue to be important antibiotics for the treatment and prophylaxis of many infectious diseases. The emergence of resistant microorganism has led to the development of newer penicillin compounds that have extended spectrums of antimicrobial activity. Beta-lactamase production by many pathogenic bacteria is the most common and clinically relevant mechanism of antibiotic resistance. The addition of beta-lactamase inhibitors to penicillin antibiotics has proven to be successful in preventing the inactivation of the parent penicillin compound by the more commonly produced beta-lactamase enzymes.

In vitro postantibiotic effect of daptomycin (LY146032) against Enterococcus faecalis and methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains.

The suppression of bacterial growth that persists after brief exposure to antimicrobial agents has been termed the postantibiotic effect (PAE). This pharmacodynamic interaction varies for each microorganism-antimicrobial agent combination. Daptomycin (LY146032) is a new lipopeptide antibiotic with activity against gram-positive organisms. We studied the in vitro bactericidal activities and PAEs of the following drugs: daptomycin compared with penicillin G and vancomycin, without and with gentamicin against Enterococcus faecalis strains; daptomycin compared with nafcillin and vancomycin against methicillin-susceptible Staphylococcus aureus strains; and daptomycin compared with vancomycin against methicillin-resistant S. aureus strains. Daptomycin, alone and when used in combination with gentamicin, exhibited greater bactericidal activity and in general produced a longer PAE than standard effective regimens against the organism strains studied.

High-level penicillin resistance among isolates of enterococci. Implications for treatment of enterococcal infections.

STUDY OBJECTIVE: To determine the extent and clinical significance of high-level penicillin-resistant Enterococcus faecium at our institution. DESIGN: Surveillance of clinical enterococcal isolates, in-vitro susceptibility and timed survival studies, and determination of antibiotic efficacy in an experimental model of enterococcal endocarditis. MEASUREMENTS AND MAIN RESULTS: For a 6-month period, 14% of enterococcal isolates (30 of 212) were identified as E. faecium. One third of the isolates were highly resistant to penicillin G (minimum inhibitory concentration [MIC], greater than or equal to 200 micrograms/mL) but did not produce beta-lactamase. The findings from in-vitro survival studies showed that this high-level resistance resulted in the loss of bactericidal activity normally observed when an aminoglycoside antibiotic agent is combined with penicillin. An experimental rat model of endocarditis provided in-vivo data that confirmed our in-vitro observations. After the rats received therapy for 72 hours, penicillin G either alone or in combination with gentamicin did not significantly decrease the numbers of enterococci in vegetations on heart valves compared with untreated controls (P = 0.62 and P = 0.58, respectively). CONCLUSIONS: Enterococcus faecium accounts for a notable proportion of clinical enterococcal isolates. Many strains from patients at our institution, as well as from patients at other institutions throughout the country, are highly resistant to penicillin. Because high-level penicillin resistance has important therapeutic implications, periodic surveillance and MIC testing of significant enterococcal isolates, especially E. faecium, are suggested.

Daptomycin (LY146032) treatment of experimental enterococcal endocarditis.

This study compared daptomycin (LY146032) with penicillin G procaine and vancomycin without and with gentamicin for treatment of experimental enterococcal endocarditis. The strain of Streptococcus (Enterococcus) faecalis used in this study was killed by daptomycin in vitro in broth but not in serum. In rabbits treated for 3 days, daptomycin significantly reduced bacterial counts of vegetations compared with no therapy but was significantly less effective than penicillin G procaine or vancomycin. Daptomycin-gentamicin significantly reduced bacterial counts of vegetations compared with daptomycin alone but was significantly less effective than vancomycin plus gentamicin. The efficacy of daptomycin-gentamicin did not differ significantly from that of penicillin G procaine-gentamicin. The lack of enterococcal killing by daptomycin alone in serum and in experimental endocarditis is probably related to the high protein binding of the agent.

Antibiotic selection and pharmacokinetics in the critically ill.

In critically ill patients, a good outcome of an infection episode often requires early institution of appropriate antimicrobial therapy. The choice of one specific antimicrobial agent or combination of agents over another requires consideration of the nature of the etiologic organism, the host, and the drug(s).

Clinical efficacy of ciprofloxacin therapy for gram-negative bacillary osteomyelitis.

The efficacy and toxicity of ciprofloxacin, an orally administered fluoroquinolone, were evaluated in 24 infections in 23 patients with osteomyelitis caused by aerobic gram-negative bacilli. The diagnosis was confirmed by surgical findings and the results of bone biopsy and culture of bone or deep soft tissue. The aerobic gram-negative bacilli were Pseudomonas aeruginosa (15 isolates), Serratia marcescens (five isolates), Escherichia coli (three isolates), Enterobacter species (three isolates), Proteus mirabilis (one isolate), Pseudomonas fluorescens (one isolate), and Klebsiella pneumoniae (one isolate). Minimal bactericidal concentrations (MBCs) were 1.56 micrograms/ml or less for all but one isolate. Nine infections were polymicrobial, involving aerobic gram-positive cocci or anaerobes in addition to aerobic gram-negative bacilli. Additional antibiotics to which the aerobic gram-negative bacilli were resistant were given when the additional organisms were resistant to ciprofloxacin. Patients received 750 mg of ciprofloxacin twice daily for a mean of 62 days. Peak serum levels of ciprofloxacin were at least threefold higher than the MBCs in 20 of 24 patients. Twenty of 22 infections in which a full course of therapy was completed were without evidence of active disease at one to 17 months posttreatment. A sternotomy wound infection relapsed after eight weeks of therapy with a newly resistant S. marcescens strain, and an infection of a compound fracture relapsed two months posttreatment with a still sensitive P. aeruginosa strain. Toxicity was minimal in most patients: eosinophilia (six patients), nausea (eight patients), mild elevation in transaminase levels (three patients), pruritus (one patient), diarrhea (two patients), thrush (two patients), rash (two patients), and mild leukopenia (one patient). Two additional patients had severe side effects (vertigo in one and acute renal failure in another) that required discontinuation of ciprofloxacin therapy. Overall, ciprofloxacin is a promising agent for the oral treatment of gram-negative bacillary osteomyelitis.

The acid-base status of lions, Panthera leo, immobilized with four drug combinations.

Fifty-eight immobilizations were conducted using 21 lions (Panthera leo) and 4 drug combinations. The combinations used were ketamine-phencyclidine-promazine, xylazine-phencyclidine-promazine, xylazine-ketamine-phencyclidine-promazine, and tiletamine-zolazepam.

Physiologic measures of nonhuman primates during physical restraint and chemical immobilization.

The arterial acid-base balance and other selected physiologic measures of physically restrained and chemically immobilized nonhuman primates from the families Callithricidae, Cebidae, Cercopithecidae, and Pongidae were compared. The physically restrained primates had significantly lower pH, pCO2, and base excess values, but they had significantly higher pO2 values, rectal temperatures, and pulse and respiration rates. Of 56 physically restrained primates, 30 (54%) experienced severe metabolic acidosis, with pH values less than 7.2; 15 (27% of total) had pH values less than 7.1. Two types of behavior were observed during the physical restraint of golden marmosets. Some of the marmosets were excited during restraint, with a great deal of struggling and vocalizing. The other marmosets were quiet and calm, with minimal struggling. The excited group had significantly lower pH, pCO2, and base excess values, but significantly higher pO2 values, rectal temperatures, and pulse and respiration rates. Primates immobilized with ketamine or tiletaminezolazepam had a near normal acid-base balance and were handled more easily than the physically restrained animals.