Eugénie Bergogne-Bérézin

Like all the disciplines involved in infectious diseases and antibiotic therapy, pharmacokinetics and pharmacodynamics (PK/PD) of antibiotics have evolved significantly. They include new investigation procedures like in vitro models and new animal models. There is a current trend towards better methods, newer definitions and improved quality of research in this particular field. The current evolution of pharmacology of antibiotics is mainly characterized by the development of pharmacodynamics (PD) which offers the advantage of including microbiology data. New PD parameters have been defined. It is recommended to working groups involved in PK/PD research to compare their results and tend to a consensus on the methods to be used. Benefiting from such progress, preclinical phases of PK/PD studies of new molecules as well as revision of older antibiotics permit a rigorous and clinical approach to the use of antibiotics.

In acute maxillary sinusitis, after an initial viral episode, bacterial infection can be demonstrated using specific investigations and bacterial isolation. In the vast majority of cases, however, the diagnosis is presumptive. Symptomatic treatments tend to reduce pain and inflammation for easier pus drainage. The decision for or against antibiotic therapy continues to be a matter of debate. Many antibiotics have been used but modern guidelines have established recommendations for the choice and duration of treatments, based on (i) knowledge of pathogens and of their resistance profiles; (ii) improved understanding of the pharmacology of antibiotics, guiding doses and administration routes; (iii) comparative double-blind studies, evaluating antibiotics versus placebo and beta-lactams versus macrolides. Use of newer drugs (fluoroquinolones, ketolides) must be discussed in terms of cost and efficacy.

Protein binding of antibacterials in plasma and tissues has long been considered a component of their pharmacokinetic parameters, playing a potential role in distribution, excretion and therapeutic effectiveness. Since the beginning of the ‘antibacterial era’, this factor has been extensively analysed for all antibacterial classes, showing that wide variations of the degree of protein binding occur even in the same antibacterial class, as with β-lactams. As the understanding of protein binding grew, the complexity of the binding system was increasingly perceived and its dynamic character described. Studies of protein binding of the fluoroquinolones have shown that the great majority of these drugs exhibit low protein binding, ranging from approximately 20 to 40% in plasma, and that they are bound predominantly to albumin. The potential role in pharmacokinetics-pharmacodynamics of binding of fluoroquinolones to plasma, tissue and intracellular proteins has been analysed, but it has not been established that protein binding has any significant direct or indirect impact on therapeutic effectiveness. Regarding the factors influencing the tissue distribution of antibacterials, physicochemical characteristics and the small molecular size of fluoroquinolones permit a rapid penetration into extravascular sites and intracellularly, with a rapid equilibrium being established between intravascular and extravascular compartments. The high concentrations of these drugs achieved in tissues, body fluids and intracellularly, in addition to their wide antibacterial spectrum, mean that fluoroquinolones have therapeutic effectiveness in a large variety of infections. The tolerability of quinolones has generally been reported as good, based upon long experience in using pefloxacin, ciprofloxacin and ofloxacin in clinical practice. Among more recently developed molecules, good tolerability has been reported for levofloxacin, moxifloxacin and gatifloxacin, but certain other new compounds have been removed from the market because of renal, hepatic and cardiac toxicity. To what extent the protein binding of fluoroquinolones can play a role in their tolerability is unclear. In terms of drug-drug interactions, the role of protein binding is questionable: several drug combinations can be responsible for toxicity, such as with β-lactams, metronidazole, theophylline, nonsteroidal anti-inflammatory agents or a series of drugs used for cardiac diseases, but protein binding does not seem to be involved in these interactions. In conclusion, protein binding of fluoroquinolones appears to be a complex phenomenon, but has no clear role in therapeutic effectiveness or toxicity.

Among gram-negative organisms playing a significant role in nosocomial infections, Acinetobacter species have attracted increasing attention in intensive care units during the past two decades. Acinetobacter species are implicated in a wide spectrum of infections (eg, bacteremia, nosocomial pneumonia, urinary tract infections, secondary meningitis, superinfections in burn patients). One of the most striking features of Acinetobacter species is their extraordinary ability to develop multiple resistance mechanisms against major antibiotic classes. They have become resistant to broad-spectrum β-lactams (third-generation cephalosporins, carboxypenicillins, and increasingly to carbapenems); they produce a wide range of aminoglycoside-inactivating enzymes; and most strains are resistant to fluoroquinolones. In Acinetobacter nosocomial infections, the major problems confronting clinicians in intensive care units are related to the severity of Acinetobacter nosocomial infections and to resistance to major antibiotic classes of these organisms.

Severe infections (SIs) in Intensive Care Units (ICUs) constitute difficult therapeutic problems confronting clinicians who deal with severely ill patients. Some SIs are opportunistic infections acquired either in the community or in hospitals, particularly in immunodepressed patients. The great majority of ICU infections are of nosocomial origin. Resistant organisms have led to changing antibiotic therapy in ICU infections. Before microbiology is available, empiric therapy is based on: (i) proper identification of bacterial risks in each infection site; (ii) local surveillance of frequent nosocomial organisms/susceptibility patterns in the ICU; (iii) identification of environmental risk factors and the patient's underlying condition. In documented infection, antibiotic therapy must take into account gram-positive vs gram-negative bacteria or mixed infections, pharmacokinetics/pharmacodynamic parameters of chosen antibiotic(s) and concentrations at the infection site, in order to prevent selection of resistant mutants and to provide the most efficient antibiotic therapy. With increasingly sophisticated intensive care measures, invasive exploratory procedures, and surgical procedures, evolving profiles of hospital infections require updated Guidelines for treatment of severe infections in ICUs. Preventive and therapeutic strategies include control of antibiotic use, and suitable antibacterial treatments which result in shortened hospital stay, improved outcome of hospital infections and significant cost savings.

INJECTABLE SPECTROGRAMIN: Combination regimens using quinupristin/dafopristin with either gentamicin or vancomycin have powerful bactericidal activities (even against quinupristin-resistant strains) against methicillin-resistant Staphylococcus aureus (MRSA) in a model of experimental endocarditis in the rabbit. In clinical trials, quinupristin/dalfopristin is becoming a therapeutic alternative to consider after failure of conventional antistaphylococcal treatments. NEW GENERATION CEPHALOSPORINS: These new cephalosporins, particularly C-3 pyridinium-thiomethyl-cephalosporins, new (3-dithiocarbamoyl) cephalosporins, and a series of new compounds with high affinity for MRSA PLP2a, are particularly active against MRSA and are unaffected by beta-lactamases. A NEW CARBAPENEM: This new antibiotic has a wide bactericidal effect against Gram-positive organisms and is active against MRSA as well as penicillin-resistant S. pneumoniae. NEW FLUOROQUINOLONE DERIVATIVES: In vitro, these new derivatives have been found to be active against MRSA, pneumococci non-sensitive to ciprofloxacin, and Bacteroides fragilis, Mycobacterium tuberculosis, Chlamydia pneumoniae.

ANTI-PNEUMOCOCCAL DRUGS: New fluoroquinolones with different targets than earlier compounds have been found to be active in certain cases of respiratory tract pneumococcal infections. Moxifloxacin, levofloxacin and gatifloxacin have been particularly effective. These new antibiotics can be classed in a new category of "respiratory quinolones". EFFLUX PUMP INHIBITORS: The bacterial efflux systems are complex resistance mechanisms allowing the bacteria to expulse certain antibiotics belonging to several drug families and thus to develop multiple resistance capacities. A new series of efflux pump inhibitors has been recently synthesized. Associated with an antibiotic (levofloxacin, macrolide) these inhibitors significantly increase antibacterial activity. BACTERIAL WALL INHIBITORS: These compounds target the biosynthesis units of the bacterial walls, inhibiting for example bacterial enzyme Mur A. CYCLIC LIPOPEPTIDES: These include daptomycin which acts on peptidoglycan synthesis in the bacterial wall via a mechanism different from that of glycopeptides. NEW BETA-LACTAMS: Faropenem is a new member of the penem family. Ceftidoren is an oral cephalosporin that gives 64 to 70% cure after 7 to 10 days in cases of acute maxillary sinusitis and 81 to 83% in exacerbations of acute bronchial infections. In streptococcal pharyngitis in adults, ceftidoren produces better eradication (90%) of S. pyogenes than penicillin V (83%) at treatment end.