Can Pharmacokinetic and Pharmacodynamic Principles Be Applied to the Treatment of Multidrug-Resistant Acinetobacter?

OBJECTIVE: To discuss treatment options that can be used for treatment of Acinetobac/erinfections. DATA SOURCES: A MEDLINE search (1966-November 2010) was conducted to identify English-language literature on pharmacotherapy of Acinetobacter and the bibliographies of pertinent articles. Programs and abstracts from infectious diseases meetings were also searched. Search terms included Acinetobacter, multidrug resistance, pharmacokinetics, pharmacodynamics, Monte Carlo simulation, nosocomial pneumonia, carbapenems, polymyxins, sulbactam, aminoglycosides, tetracyclines, tigecycline, rifampin, and fluoroquinolones. DATA SELECTION AND DATA EXTRACTION: All articles were critically evaluated and all pertinent information was included in this review. DATA SYNTHESIS: Multidrug resistant (MDR) Acinetobacter, defined as resistance to 3 or more antimicrobial classes, has increased over the past decade. The incidence of carbapenem-resistant Acinetobacter is also increasing, leading to an increased use of dose optimization techniques and/or alternative antimicrobials, which is driven by local susceptibility patterns. However, Acinetobacter infections that are resistant to all commercially available antibiotics have been reported. General principles are available to guide dose optimization of aminoglycosides, ß-lactams, fluoroquinolones, and tigecycline for infections due to gram-negative pathogens. Unfortunately, data specific to patients with Acinetobacter infections are limited. Recent pharmacokinetic-pharmacodynamic information has shed light on colistin dosing. The dilemma with colistin is its concentration-dependent killing, which makes once-daily dosing seem like an attractive option, but its short postantibiotic effect limits a clinician's ability to extend the dosing interval. Localized delivery of antimicrobials is also an attractive option due to the ability to increase drug concentration at the infection site while minimizing systemic adverse events, but more data are needed regarding this approach. CONCLUSIONS: Increased reliance on dosage optimization, combination therapy, and localized delivery of antimicrobials are methods to pursue positive clinical outcomes in MDR Acinetobacter infections since novel antimicrobials will not be available for several years. Well-designed clinical trials with MDR Acinetobacter are needed to define the best treatment options for these patients.

Structure and reactivity of a(n) and a(n) peptide fragments investigated using isotope labeling, tandem mass spectrometry, and density functional theory calculations.

Extensive (15)N labeling and multiple-stage tandem mass spectrometry were used to investigate the fragmentation pathways of the model peptide FGGFL during low-energy collision-induced-dissociation (CID) in an ion-trap mass spectrometer. Of particular interest was formation of a(4) from b(4) and a(4) (a(4)-NH(3)) from a(4) ions correspondingly, and apparent rearrangement and scrambling of peptide sequence during CID. It is suggested that the original FGGF(oxa)b(4) structure undergoes b-type scrambling to form GGFF(oxa). These two isomers fragment further by elimination of CO and (14)NH(3) or (15)NH(3) to form the corresponding a(4)and a(4) isomers, respectively. For ((15)N-F)GGFL and FGG((15)N-F)L the a(4) ion population appears as two distinct peaks separated by 1 mass unit. These two peaks could be separated and fragmented individually in subsequent CID stages to provide a useful tool for exploration of potential mechanisms along the a(4) --> a(4) pathway reported previously in the literature (Vachet et al. J. Am. Chem. Soc.1997, 119, 5481, and Cooper et al. J. Am. Soc. Mass Spectrom.2006, 17, 1654). These mechanisms result in formally the same a(4) structures but differ in the position of the expelled nitrogen atom. Detailed analysis of the observed fragmentation patterns for the separated light and heavy a(4) ion fractions of ((15)N-F)GGFL indicates that the mechanism proposed by Cooper et al. is consistent with the experimental findings, while the mechanism proposed by Vachet et al. cannot account for the labeling data. In addition, a new rearrangement pathway is presented for a(4)-CO ions that effectively transfers the former C-terminal amino acid residue to the N-terminus.

Current options in antifungal pharmacotherapy.

Infections caused by yeasts and molds continue to be associated with high rates of morbidity and mortality in both immunocompromised and immunocompetent patients. Many antifungal drugs have been developed over the past 15 years to aid in the management of these infections. However, treatment is still not optimal, as the epidemiology of the fungal infections continues to change and the available antifungal agents have varying toxicities and drug-interaction potential. Several investigational antifungal drugs, as well as nonantifungal drugs, show promise for the management of these infections.

Part VII. Macrolides, azalides, ketolides, lincosamides, and streptogramins.

In this article we describe antimicrobials that are grouped by their similar mechanism of action, namely inhibition of protein synthesis at the bacterial 50S ribosomal subunit. Macrolides, azalides, and ketolides are primarily used to treat community acquired respiratory tract infections. A lincosamide antibiotic, clindamycin, is primarily used to treat anaerobic infections. A combination of streptogramins, quinupristin/dalfopristin, is used to treat infections due to multiple drug resistant Gram positive cocci.

Prospective comparison of methicillin-susceptible and methicillin-resistant community-associated Staphylococcus aureus infections in hospitalized patients.

BACKGROUND: We sought to determine the proportion of community-associated Staphylococcus aureus infections due to methicillin-resistant S. aureus (CA-MRSA) at a large county hospital. In addition, we sought to identify the demographic and clinical risk factors associated with CA-MRSA infection. METHODS: Patients were prospectively enrolled if they were admitted to Parkland Hospital and had a positive culture for S. aureus isolated within 72 h of admission. The patients were interviewed using a standardized data questionnaire. Data collected included patient demographics, clinical history, as well as health care and non-health care associated MRSA risk factors. Bacterial susceptibilities were verified through review of microbiology laboratory and pharmacy records. Isolates were tested for Panton-Valentine leukocidin (PVL) gene, SCCmec type, and for inducible clindamycin resistance. RESULTS: One hundred and ninety-eight patients were interviewed prospectively, of which eight had colonization without active infection. One hundred and nineteen patients were infected with MRSA and 71 patients were infected with methicillin-susceptible S. aureus (MSSA). Patients with MRSA were more likely to be African-American and unemployed. Patients with MRSA most commonly presented with a skin or soft tissue infection (SSTI): 69% versus 45%, p=0.0012, while patients with MSSA were more likely to have infection of the respiratory tract: 11% versus 3%, p=0.02. Patients with MRSA were more likely to have used antibiotics in the past six months, been homeless, have a history of incarceration, have abused alcohol and have a history of infection with MRSA. In multivariate analysis, African-American race, antibiotics in the past six months, and a history of being homeless were associated with MRSA infection. Only 11 of 119 (9%) MRSA patients did not have at least one of these risk factors. PVL gene was present in 72 of 74 (97%) MRSA isolates and SCCmec type IV was present in 63 of 75 (84%) MRSA isolates. CONCLUSIONS: The majority of patients hospitalized with community-associated S. aureus infections were due to MRSA, most of which involved an SSTI. African-American race, recent antibiotics and past homeless status predicted infection with MRSA; however, no clinical profile could reliably exclude MRSA. Clinicians should be aware of the increasing prevalence of CA-MRSA.

Collision-induced dissociation of protonated tetrapeptides containing beta-alanine, gamma-aminobutyric acid, epsilon-aminocaproic acid or 4-aminomethylbenzoic acid residues.

The influence of the presence and position of a single beta-alanine, gamma-aminobutyric acid, epsilon-aminocaproic acid or 4-aminomethylbenzoic acid residue on the tendency to form b(n)+ -and y(n)+ -type product ions was determined using a group of protonated tetrapeptides with general sequence XAAG, AXAG and AAXG (where X refers to the position of amino acid substitution). The hypothesis tested was that the 'alternative' amino acids would influence product ion signal intensities by inhibiting or suppressing either the nucleophilic attack or key proton transfer steps by forcing the adoption of large cyclic intermediates or blocking cyclization altogether. We found that specific b ions are diminished or eliminated completely when betaA, gammaAbu, Cap or 4AMBz residues are positioned such that they should interfere with the intramolecular nucleophilic attack step. In addition, differences in the relative proton affinities of the alternative amino acids influence the competition between complementary b(n) and y(n) ions. For both the AXAG and the XAAG series of peptides, collision-induced dissociation (CID) generated prominent b ions despite potential inhibition or suppression of intramolecular proton migration by the betaA, gammaAbu, Cap or 4AMBz residues. The prominent appearance of b ions from the AXAG and XAAG peptide is noteworthy, and suggests either that proton migration occurs through larger, 'whole' peptide cyclic intermediates or that fragmentation proceeds through a population of [M+H]+ isomers that are initially protonated at amide O atoms.

A study of the elimination of water from lithium-cationized tripeptide methyl esters by means of tandem mass spectrometry and isotope labeling.

Extensive isotope labeling (2H, 13C and 15N), collision-induced dissociation (CID) and multiple-stage tandem mass spectrometry were used to investigate the elimination of H2O from a series of model, metal-cationized tripeptide methyl esters. The present results corroborate our earlier suggestion that loss of water from lithiated peptides is initiated by a nucleophilic attack from the N-terminal side upon an amide carbonyl carbon atom to form a five-membered ring as an intermediate followed by 1,2-elimination of water. We show that the nucleophilic atom is the oxygen atom of the N-terminal amide group in the fragmentation of [AcGGGOMe+Li]+ as well as [GGGOMe+Li]+. However, the subsequent fragmentation is markedly different in the two cases as a result of the absence and presence of a free amino group. In particular, extensive scrambling of protons in the alpha-positions of GGGOMe is observed, presumably as a consequence of intervention of the basic amino group.

Isotope labeling and theoretical study of the formation of a3* ions from protonated tetraglycine.

Extensive 13C, 15N, and 2H labeling of tetraglycine was used to investigate the b3+ --> a3* reaction during low-energy collision-induced dissociation (CID) in a quadrupole ion-trap mass spectrometer. The patterns observed with respect to the retention or elimination of the isotope labels demonstrate that the reaction pathway involves elimination of CO and NH3. The ammonia molecule includes 2 H atoms from amide or amino positions, and one from an alpha-carbon position. The loss of NH3 does not involve elimination of the N-terminal amino group but, instead, the N atom of the presumed oxazolone ring in the b3+ ion. The CO molecule eliminated is the carbonyl group of the same oxazolone ring, and the alpha-carbon H atom is transferred from the amino acid adjacent to the oxazolone ring. Quantum chemical calculations indicate a multistep reaction cascade involving CO loss on the b3 --> a3 pathway and loss of NH=CH2 from the a3 ion to form b2. In the postreaction complex of b2 and NH=CH2, the latter can be attacked by the N-terminal amino group of the former. The product of this attack, an isomerized a3 ion, can eliminate NH3 from its N-terminus to form a3*. Calculations suggest that the ammonia and a3* species can form various ion-molecule complexes, and NH3 can initiate relay-type mobilization of the oxazolone H atoms from alpha-carbon positions to form a new oxazolone isomer. This multiple-step reaction scheme clearly explains the isotope labeling results, including unexpected scrambling of H atoms from alpha-carbon positions.

Novel fragmentation pathway for CID of (b(n) - 1 + Cat)+ ions from model, metal cationized peptides.

We report a new fragmentation pathway for the CID of (b3 - 1 + Cat)+ product ions derived from the model peptide AXAG, where X = beta-alanine, gamma-aminobutyric acid, epsilon-amino-n-caproic acid, or 4-aminomethylbenzoic acid. By changing the amino acid to the C-terminal side of the amino acid X, and incorporating 15N and 13C labeled residues at the same position, we conclude that the dissociation pathway most likely leads to a metal cationized nitrile. With respect to the various amino acids at position X, the putative nitrile product becomes more prominent, relative to the conventional (a3 - 1 + Cat)+ species, in the order beta-alanine < gamma-aminobutyric acid < epsilon-aminocaproic acid < 4-aminomethylbenzoic acid. The pathway is not observed for peptides with alpha-amino acids at position X. The product ion is observed most prominently during the CID of Li+ and Na+ cationized peptides, only to a small extent for Ag+ cationized peptides, and not at all from protonated analogues.