Ceftolozane-tazobactam activity against clinical isolates of Pseudomonas aeruginosa from ICU patients with pneumonia: United States, 2015-2018.

OBJECTIVES: To report on the activity of ceftolozane-tazobactam and comparators against Pseudomonas aeruginosa isolates collected from hospitalized patients with pneumonia in US intensive care units (ICUs) between 2015 and 2018. Activity against all P. aeruginosa and common resistant phenotypes are described to better inform decision-making and support antimicrobial stewardship efforts. METHODS: In total, 781 P. aeruginosa isolates were collected from 28 US hospitals. These isolates were tested for susceptibility to ceftolozane-tazobactam and comparators by Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology using CLSI (2020) breakpoints. Phenotypes analysed included piperacillin-tazobactam-non-susceptible (NS), cefepime-NS, ceftazidime-NS, meropenem-NS and difficult-to-treat resistance (DTR). RESULTS: Ceftolozane-tazobactam was the most potent agent tested (minimum inhibitory concentration to inhibit 50% and 90% of isolates of 0.5 and 2 mg/L, respectively, inhibiting 97.2% at the susceptible breakpoint of ≤4 mg/L). Traditional first-line antipseudomonal ß-lactam antibiotics (piperacillin-tazobactam, cefepime and ceftazidime) demonstrated <33% susceptibility when P. aeruginosa was NS to one or more agent. Although escalation of therapy to meropenem is commonly employed clinically, meropenem susceptibility ranged from 33.6% to 44.9% if P. aeruginosa was NS to any traditional first-line antipseudomonal ß-lactam agent. Conversely, ceftolozane-tazobactam remained active against isolates that were NS to other agents, inhibiting 88.4% of isolates NS to piperacillin-tazobactam, 85.0% of isolates NS to cefepime and ceftazidime, and 90.3% of isolates NS to meropenem. Ceftolozane-tazobactam also maintained activity against 73.0% of DTR isolates. CONCLUSIONS: Ceftolozane-tazobactam maintained high activity against P. aeruginosa isolated from hospitalized patients with pneumonia in US ICUs, and had the greatest activity against isolates NS to one or more antipseudomonal ß-lactams and DTR isolates.

Ceftaroline fosamil: a new cephalosporin active against resistant Gram-positive organisms including MRSA.

The growing prevalence of resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus continues to pose a dilemma to clinicians. With strains developing reduced susceptibility to vancomycin, effective and well-tolerated antibiotics to combat these resistant pathogens are needed. Ceftaroline is a new parenteral cephalosporin that has been available in the USA for almost 2 years. Similar to other cephalosporins, it is well tolerated with mostly mild adverse events; however, compared with existing parenteral cephalosporins, ceftaroline has the unique attribute of being bactericidal against resistant Gram-positive aerobes including both hospital- and community-acquired methicillin-resistant S. aureus, S. aureus strains with reduced susceptibility or complete resistance to vancomycin, and resistant Streptococcus pneumoniae including multidrug-resistant strains. Current indications in the USA and Europe include treatment of adults with complicated skin, skin-structure infections and community-acquired pneumonia. This paper will review the properties of ceftaroline, its spectrum of activity, clinical use, safety profile and future role.

In vitro activity of tigecycline and comparator agents against a global collection of Gram-negative and Gram-positive organisms: tigecycline Evaluation and Surveillance Trial 2004 to 2007.

The Tigecycline Evaluation and Surveillance Trial began in 2004 to monitor the in vitro activity of tigecycline and comparator agents against a global collection of Gram-negative and Gram-positive pathogens. Against Gram negatives (n = 63 699), tigecycline MIC(90)'s ranged from 0.25 to 2 mg/L for Escherichia coli, Haemophilus influenzae, Acinetobacter baumannii, Klebsiella oxytoca, Enterobacter cloacae, Klebsiella pneumoniae, and Serratia marcescens (but was > or =32 for Pseudomonas aeruginosa). Against Gram-positive organisms (n = 32 218), tigecycline MIC(90)'s were between 0.06 and 0.25 mg/L for Streptococcus pneumoniae, Enterococcus faecium, Streptococcus agalactiae, Staphylococcus aureus, and Enterococcus faecalis. The in vitro activity of tigecycline was maintained against resistant phenotypes, including multidrug-resistant A. baumannii (9.2% of isolates), extended-spectrum beta-lactamase-producing E. coli (7.0%) and K. pneumoniae (14.0%), beta-lactamase-producing H. influenzae (22.2%), methicillin-resistant S. aureus (44.5%), vancomycin-resistant E. faecium (45.9%) and E. faecalis (2.8%), and penicillin-resistant S. pneumoniae (13.8%). Tigecycline represents a welcome addition to the armamentarium against difficult to treat organisms.

In vitro activity of tigecycline against quinolone-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.

Tigecycline is a glycylcycline with promising broad-spectrum activity, including resistant Gram-positive organisms. This study characterizes in vitro activity of tigecycline against quinolone-resistant Streptococcus pneumoniae (QRSP), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). An in vitro pharmacodynamic model generated specific bacterial kill profiles for tigecycline against clinical isolates of QRSP, MRSA and VRE. Tigecycline produced a 6.6 log total reduction and cleared QRSP from the pharmacodynamic model by 18 h. Tigecycline and vancomycin were unable to achieve 3-log reductions in the MRSA and VRE isolates; log reductions in MRSA and VRE were 1.5 and 1.2 logs for tigecycline and 2.8 and zero for vancomycin, respectively. Area under the concentration time curve to minimum inhibitory concentration (AUC/MIC) values for tigecycline ranged from 79 to 158 microg h/mL and tigecycline concentrations remained above the MIC (T>MIC) throughout the simulated dosing interval. Tigecycline showed in vitro activity against the QRSP, MRSA and VRE isolates studied. Low MIC values, prolonged elimination half-life and the associated post-antibiotic effect (PAE) observed with tigecycline are desirable attributes that make it a potentially attractive option for treating resistant Gram-positive organisms.

Antibiotic selection and resistance issues with fluoroquinolones and doxycycline against bioterrorism agents.

Bacillus anthracis (anthrax), Yersinia pestis (plague), Francisella tularensis (tularemia), Coxiella burnetti (Q fever), and Brucella sp (brucellosis) are all potential bioterrorism agents. Their known virulence, potential lethality, and ability to develop resistance to known antibiotic treatments make these pathogens particularly dangerous. We reviewed the scientific literature by searching MEDLINE databases and published abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America from 1989-2005 for studies of each of these biologic agents with the specific aim of examining whether doxycycline or a fluoroquinolone should be stockpiled for mass-scale postexposure prophylaxis. An evidence-based approach was used to determine whether doxycycline or fluoroquinolones were efficacious (both in vitro and in vivo) against these biologic agents and to examine these drugs' respective susceptibility patterns and differences in cost, based on available data. Little published data are available on these pathogens, and much of the data are from studies that used older strains obtained from patient or animal sources in outbreaks decades ago. Doxycycline appears to show comparable minimum inhibitory concentrations to those of the fluoroquinolone class in most clinical and in vitro studies, perhaps with the exception of inhalation plague. Studies also suggest that development of antibiotic resistance is less likely to occur with doxycycline. Doxycycline is several-fold less expensive than most fluoroquinolones and appears to have similar efficacy in most scenarios based on clinical case studies and established Clinical and Laboratory Standards Institute (formerly known as the National Committee for Clinical Laboratory Standards) breakpoints for staphylococci. Therefore, doxycycline should be considered as a first-line antibiotic in the management of bioterrorism agents.

Pharmacodynamic assessment of the activity of high-dose (750 mg) levofloxacin, ciprofloxacin, and gatifloxacin against clinical strains of Pseudomonas aeruginosa.

The objective of this study was to comparatively evaluate specific bacterial killing ability of high-dose (750 mg) levofloxacin, ciprofloxacin, and gatifloxacin against 2 clinical isolates of Pseudomonas aeruginosa (PA-21 and PA-2105). An in vitro pharmacodynamic modeling apparatus was used to expose the P. aeruginosa isolates to total peak concentrations and elimination characteristics associated with each quinolone. All experiments were conducted over 24 h, and a subsequent dose of ciprofloxacin was given at 12 h to emulate twice-daily dosing. Respective 3-log reductions in PA-24 occurred after 0.6, 1.0, and 2.6 h for levofloxacin, ciprofloxacin, and gatifloxacin; regrowth was seen with all 3 agents, but was greatest with gatifloxacin. PA-2105 had 2- to 4-fold higher minimal inhibitory concentrations (MICs) than PA-24. Gatifloxacin failed to achieve a 3-log reduction. Levofloxacin and ciprofloxacin took roughly 3.5 h to decrease initial inoculum by 3 logs, but regrowth of PA-2105 followed. Simulated doses of levofloxacin and ciprofloxacin showed comparable activity against each study isolate; less activity was observed with gatifloxacin. Levofloxacin versus PA-24 was the only regimen that approached the desired AUC/MIC(0-24) ratio of greater than 100-125 and achieved the targeted peak/MIC ratio of > or =8. Although quinolones are typically used in combination with other antibiotics for P. aeruginosa, differences in activity favor the use of levofloxacin or ciprofloxacin for the study isolates. Use of gatifloxacin may contribute to the increased rate of quinolone-resistant P. aeruginosa.

Tigecycline: an investigational glycylcycline antimicrobial with activity against resistant gram-positive organisms.

BACKGROUND: Bacterial resistance to currently available antimicrobials is an increasing concern, particularly among various gram-positive organisms such as drug-resistant pneumococci, methicillin-resistant staphylococci, and drug-resistant enterococci. Tigecycline is an investigational glycylcycline antibiotic that shows promising activity against these resistant gram-positive organisms. OBJECTIVE: : This paper reviews the pharmacology, pharmacokinetic and pharmacodynamic properties, in vitro and in vivo activity, safety profile, and potential role of tigecycline in the management of gram-positive infections involving resistant microbes. METHODS: Articles included in this review were identified through a search of MEDLINE from 1998 through 2004 using the terms tigecycline and GAR-936. Abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy from 1998 to 2003 were searched using the same terms. The reference lists of identified articles were also reviewed for pertinent publications. RESULTS: Whereas resistance has developed with many of the earlier tetracycline derivatives, tigecycline appears to have a reduced potential for resistance. Several reports have evaluated the in vitro activity of this agent against a number of organisms. It has exhibited pronounced activity against most gram-positive microbes, including resistant strains (eg, drug-resistant pneumococci, methicillin-resistant staphylococci, resistant enterococci). Tigecycline has also shown useful activity against many clinically important gram-negative microbes. In vivo studies of tigecycline are limited. Only 2 clinical trials have been reported to date, one in patients with complicated skin and skin-structure infections and the other in patients with complicated intra-abdominal infections. In these studies, tigecycline therapy resulted in clinical cures in more than two thirds of evaluable patients. Tigecycline was well tolerated in both studies; nausea and vomiting were the most common adverse events. CONCLUSIONS: Although published clinical trials involving tigecycline are limited and additional trials are needed, preliminary reports on its use in the treatment of gram-positive infections are encouraging. Tigecycline has favorable pharmacokinetic properties and, apart from gastrointestinal adverse events, appears to be well tolerated.

Comparative antimicrobial activity of levofloxacin and ciprofloxacin against Streptococcus pneumoniae.

OBJECTIVES: Levofloxacin has good coverage against both Gram-positive and Gram-negative pathogens. Recent reports demonstrate enhanced activity associated with a higher 750 mg dosage of levofloxacin. The objective of this study was to comparatively evaluate the activity of common regimens of levofloxacin (500 mg) and ciprofloxacin (500 mg), and a higher 750 mg levofloxacin regimen against penicillin susceptible and non-susceptible strains of S. pneumoniae. MATERIALS AND METHODS: An in vitro pharmacodynamic modelling apparatus (PDMA) characterized specific bacterial kill profiles for simulated regimens of levofloxacin and ciprofloxacin against four strains of S. pneumoniae. Total log reduction, time for 3-log reduction and AUC/MIC were determined. RESULTS: Ciprofloxacin was less effective than the levofloxacin regimens against all four study isolates. Ciprofloxacin produced 3-log reduction in only one isolate compared with all four isolates with the levofloxacin regimens. Bacterial regrowth did not occur over 12 h with levofloxacin; however, three of four isolates demonstrated bacterial regrowth with ciprofloxacin. None of the isolates were cleared from the PDMA by ciprofloxacin. The 500 mg levofloxacin regimen cleared two of four isolates and the 750 mg dose of levofloxacin cleared all study isolates. Respective AUC/MIC values for levofloxacin (500 and 750 mg) and ciprofloxacin were 44-89, 63-126 and < or =13, which correlated well with bacterial kill data. CONCLUSIONS: Both levofloxacin regimens were more effective than ciprofloxacin against the study isolates tested. The 750 mg levofloxacin regimen generated more favourable bacterial killing compared with the 500 mg levofloxacin regimen. In addition to using the 750 mg levofloxacin dose for nosocomial infections, this dose may also prove useful for the management of resistant pneumococcal infections.

In vitro pharmacodynamic activity of gatifloxacin, gemifloxacin, moxifloxacin and levofloxacin against Streptococcus pneumoniae containing specific mutations in DNA gyrase and topoisomerase IV.

An in vitro pharmacodynatnic modeling apparatus (PDMA) generated specific bacterial kill profiles for single-dose regimens of gatifloxacin (GT), gemifloxacin (GM), moxifloxacin (MX) and levofloxacin (LV) against isolates of Streptococcus pneumoniae with specific QRDR profiles: SP-WT (no modifications); SP-C (changes in parC); and SP-AC (changes in both parC and gyrA). No differences in 3-log reduction time or total log reduction were observed among the four agents for SP-WT; however, LV failed to achieve a 3-log reduction in SP-C and SP-AC, and total log reduction after 12 hrs was minimal compared to the other agents. GM and MX required less time for 3-log reduction of SP-AC compared to GT, but total log reductions in SP-AC were similar among the three newer quinolone agents (GM > MX > GT). The study isolates with QRDR modifications greatly reduced LV activity. GM and MX maintained the greatest degree of activity against all study isolates and their activity was not adversely influenced by the genetic modifications in SP-C and SP-AC. The dual targeting characteristic of GM was also assessed, but did not offer significant advantages relative to MX and GT.

New potential in pneumococcal immunization. Conjugate vaccine may improve disease protection, health of infants and young children.

Since 2000, a new pneumococcal conjugate vaccine has been on the US market, offering immunization against seven serotypes. Its use has the potential to dramatically reduce the incidence of pneumococcal disease and its sequelae in children. Here, the authors review the efficacy, safety, and cost of the new pneumococcal vaccine and offer guidelines on how to incorporate this newer vaccine into today's immunization regimens.