Guest guest Posted June 11, 2000 Report Share Posted June 11, 2000 To All, FYI. Larry NV Medscape Home Site Map Marketplace My Medscape CME Center Feedback Help Desk NOTE: To view the article with Web enhancements, go to: http://www.medscape.com/thieme/SRCCM/2000/v21.n01/rcm2101.01.owen/rcm2101.01 ..owen-01.html. ---------------------------------------------------------------------------- ---- New Antibiotics in Pulmonary and Critical Care Medicine: Focus on Advanced Generation Quinolones and Cephalosporins G. Ambrose, Pharm.D. * and C. Owens, Jr., Pharm.D. ? [sem Resp Crit Care Med 21(1):19-32, 2000. © 2000 Thieme Medical Publishers, Inc.] Abstract The primary goal in the treatment of respiratory tract infections is to provide the best possible clinical outcome for the patients. In order for this to occur, one must consider and synthesize a tremendous amount of data, much of it changing continually. Important considerations include the pharmacokinetics of the selected agent, its microbiological potency when used alone and in combination with various other agents, and the susceptibilities of the target organisms. Gram-negative bacilli remain among the most frequent cause of bacterial infection in the intensive care unit and in debilitated populations. They also have the ability to resist the best therapies. Among the topics to be discussed here are the important pharmacodynamic concepts and their role in the determination of clinical efficacy, the newer quinolone agents, newly emerging mechanisms of resistance, and recent countermeasures that have been added to the therapeutic armamentarium. In addition, specific strategies designed to combat current resistance trends supported by several recent publications will be reviewed. Pharmacodynamic Concepts Since the dawn of penicillin therapy in the 1940s, controversy has existed as to the most appropriate method to administer antibiotics to maximize the killing of microorganisms while minimizing toxicity. Almost 50 years ago, Eagle et al [1-3] demonstrated that in the syphilitic infection of rabbits and streptococcal infection in mice and rabbits the total dose of penicillin G could be less if it were administered continuously, rather than intermittently. Additionally, it was observed that maximal bacterial killing plateaus when penicillin concentrations were three times the minimum inhibitory concentration (MIC) for the microorganism.[1] These data contrasted sharply with observations made about aminoglycosides, in which the magnitude of the concentration rather than the duration that effective concentrations were maintained was found to be the determinant of efficacy.[1] Contemporary scientific data have emerged over the past decade that have confirmed and expanded on Eagle's original observations. Today, data from animal models of infection and toxicity, in vitro pharmacodynamic studies, and human trials enable us to establish the best mode of antibiotic administration to maximize clinical efficacy while minimizing toxicity. Mathematically, bacterial killing may be described as a function of drug concentration (Cp max ) and time of exposure. The product of these two pharmacokinetic measures is the correlated parameter, the area under the concentration-time curve (AUC). Over clinically obtainable drug concentrations, simplifying assumptions can be made so that either drug concentration or time of drug exposure is of primary importance. When these assumptions cannot be made, however, both concentration and time of drug exposure must be considered (e.g., the AUC). Like penicillin, all ß-lactam (e.g., cephalo-sporin, cephamycin, carbapenem, monobactam) glycopeptide, and macrolide antibiotics kill bacteria in a similar time-dependent fashion.[4] Once the concentration exceeds two to four times above the MIC for a given organism, killing occurs at a zero order rate, and increasing drug concentration does not change the microbial death rate.[5] Under these conditions, there is little correlation between peak serum concentration and the rate or extent of bacterial killing. In brief, these antibiotics exhibit time-dependent or concentration-independent killing over the usual therapeutic concentration range. Consequently, the duration of the concentration of these drugs above their MIC for the microorganism is the best predictor of clinical outcome. On the other hand, aminoglycosides, fluoro-quinolones, metronidazole, and amphotericin B kill most rapidly when their concentrations are appreciably above the MIC of the targeted microorganism.[6-9] Hence, their type of killing is referred to as concentration- dependent or dose-dependent killing. It has been shown that aminoglycosides and fluoroquinolones eradicate organisms best at levels approximately 10 to 12 times above the microbe's MIC (Fig. 1).[6,7,10] Figure 1. Pharmacodynamic relationship: Peak to MIC ratio Although fluoroquinolones exhibit concentration- dependent killing, unfortunately, excessively high concentrations of these agents can be associated with seizures and other potentially serious adverse reactions in the central nervous system. An integration of the area AUC with the MIC has been used to produce the pharmacodynamic relationship of AUC:MIC ratio to predict clinical outcomes with fluoroquinolones (Fig. 2). Data obtained from animal models of sepsis, in vitro pharmacodynamic experiments, and clinical outcome studies indicate that the magnitude of the AUC:MIC ratio can be used to predict clinical response. Forrest et al [11] demonstrated that an AUC:MIC ratio of >/= 125 was associated with the best clinical cure rates in the treatment of infections caused by gram-negative enteric pathogens. However, for gram-positive bacteria, it appears the AUC:MIC ratio can be appreciably lower. For instance, against Streptococcus pneumoniae, an in vitro model of infection in our laboratory demonstrated that for levofloxacin and ciprofloxacin an AUC:MIC ratio of approximately 30 was associated with a four-log kill; whereas ratios less than 30 were associated with a significantly reduced extent of bacterial killing and in some instances bacterial regrowth.[12] This observation is supported by data from non-neutropenic animal models of infection, in which maximal survival was associated with a AUC:MIC ratio of 25 against the pneumococcus.[13] These data are further supported clinically by the observation that there has been a significant number of treatment failures and superinfections involving meningeal seeding from S. pneumoniae in patients receiving ciprofloxacin, for which the AUC:MIC ratio is approximately 12.[14] Conversely, similar treatment failures or superinfections have not occurred with quinolones for which the AUC:MIC ratios against this bacterium are greater than 30.[15] Figure 2. Pharmacodynamic relationship: AUC:MIC ratio Protein Binding And Pharmacodynamics Because the ultimate goal of antimicrobial therapy is to eliminate microorganisms from specific sites of infection, consideration of the effect of an antibiotic's protein binding on this process seems reasonable. In the body, antibiotics exist in an equilibrium of free drug and drug bound to protein. Free drug moves readily from the central blood compartment into the extravascular spaces, whereas protein-bound drug cannot cross capillary walls and remains in the central compartment.[15,16] Moreover, it has been established that only free drug is pharmacologically active.[17-19] The affect of protein binding on the efficacy of antibiotics is a controversial issue. Excessively high (greater than 85 to 90%) protein binding has been shown to have an adverse impact on the microbiological activity of various antibiotics when used clinically to treat infections caused by organisms that were susceptible in vitro.[20.21] On the other hand, an agent that is highly protein bound may still exhibit excellent clinical efficacy because of favorable pharmacokinetics and compensational microbiological activity.[22] One must remember that in vitro susceptibility testing does not account for protein binding in vivo and total serum concentrations reflect both bound and unbound drug. When pharmacodynamic relationships are described mathematically and quantified as ratios or measurements (e.g., Cp:MIC, AUC:MIC, or time > MIC), it is sensible to incorporate the degree of protein into these calculations. This is logical given that the AUC of free drug in serum approximates that found in the interstitial fluid, the site of most bacterial infections. For instance, it is useful to consider the degree of protein binding when doing intraquinolone pharmacodynamic comparisons, for this may lead to more clinically relevant conclusions. Classification Of Quinolones By Generation The division of antibiotic classes into generations based on microbiological activity has always been controversial among academic infectious disease clinicians, but it has been extremely useful and practical to the practicing physician. For example, physicians usually know that when a cephalosporin is needed for gram-positive coverage, a first-generation agent should be selected, whereas the later-generation agents are more appropriate, with some exceptions, for situations in which gram-negative bacteria are the usual pathogens. Unfortunately, quinolone classification systems based on chronology of development or structure are of little value to the practicing physician.[23,24] Moreover, classifying agents based solely on microbiological activity may lead to poor clinical or research decisions. An illustration of the fallacy associated with considering only microbiological activity involves grepafloxacin. This agent is highly active in vitro against S. pneumoniae and was studied for the treatment of community-acquired respiratory tract infections at a dose of 400 mg per day. Pharmacody-namically, an unacceptable number of treatment failures involving S. pneumoniae would be predictable based on unfavorable pharmacodynamic profile of this agent at the studied dose. Because these concepts were not well-understood, the 400 mg dosing regimen resulted in the predictable failure of grepafloxacin against the pneumococcus.[25] Interestingly, when the dose of grepafloxacin was increased to 600 mg per day, the resulting AUC:MIC ratio exceeded 30:1 and successful outcomes were predictably reported. Our classification system, which was introduced a number of years ago, was the first to rely on the integration of both microbiological susceptibilities and pharmacokinetic data.[26-28] In other words, the unique pharmacodynamic profile displayed against S. pneumoniae and Bacteroides fragilis was used to characterize the clinical usefulness of each quinolone (Table 1). Such a classification system will likely prove useful, for the clinician is already being overwhelmed by the number of quinolones, potentially leading to unoptimized clinical decisions. First-Generation Quinolones Nalidixic acid (Fig. 3B), introduced in the United States in 1963, was the first oral quinolone that gained any significant usage. Because of its reliable activity against most Enterobacteriaceae, it became a popular choice for the treatment of uncomplicated urinary tract infections. In fact, it was often referred to as an oral form of kanamycin. Unfortunately, its serum and tissue concentrations were so low that it could not be employed for infections in other body sites and its half-life was so short it had to be given on a four times a day schedule. Several other similar quinolones (e.g., oxolinic acid and cinoxacin) were developed that were essentially identical with nalidixic acid but could be given less frequently. None of these first-generation quinolones exhibited any activity against Pseudomonas aeruginosa, anaerobes, or gram-positive bacteria. Figure 3. Structures of representative quinolones Second-Generation Quinolones Norfloxacin, the first second-generation quinolone, expanded quinolone bacterial coverage to include P. aeruginosa and staphylococci. This change was the result of the discovery that the placement of a fluorine into the C-6 position of the 4- quinolone molecule and the replacement of the C-7 methyl side chain of nalidixic acid with a piperazine group markedly enhanced microbiological activity (Fig. 3C).[29,30] As a result of the C-6 substitution, technically all compounds in this class should be referred to as fluoroquinolones. These quinolones have microbiological activity similar to that of the aminoglycosides, namely gentamicin, tobramycin, and amikacin. However, like the first-generation quinolones, the serum and tissue concentrations of these compounds are so low that they can only be used for the treatment of urinary tract infections. The replacement of norfloxacin's N-1 ethyl group with a cyclopropyl group resulted in compounds with greater bioavailability, such as ciprofloxacin (Fig. 3D).[29,30] Because to the summation of the C-6, C-7, and N-1 structural changes, compounds such as ciprofloxacin and ofloxacin can be used in many sites of infection outside of the uri-nary tract. Moreover, these quinolones exhibit high intracellular penetration, allowing for the therapy of the so-called atypical organisms, such as Chlamydia spp., Mycoplasma spp., and Legionella spp., which are also susceptible to these agents. The second-generation quinolones, therefore, can be divided into two subgroups. The first sub-group includes norfloxacin, lomefloxacin, and enoxacin, which are only useful for the treatment of urinary tract infections and are available only orally. The second subgroup includes ciprofloxacin and ofloxacin, which in addition to urinary tract infections can be used to treat many systemic sites of infection and are available in both intravenous and oral formulations. Third-Generation Quinolones Unfortunately, none of the second-generation quinolones exhibit adequate pharmacodynamic profiles against streptococci or have sufficient clinical outcome data to rely upon to treat serious infections caused by these organisms. Although, for a short time there was a fluoroquinolone, temafloxacin, with appreciable streptococcal activity, it had to be with-drawn from the market because of the emergence of a syndrome of hemolysis and renal dysfunction (e.g., temafloxacin syndrome).[31] This represented a serious problem for the clinician because the leading cause of community-acquired pulmonary and sinus infections is S. pneumoniae, and the major cause of pharyngitis, soft tissue infections, and skin infections is Streptococcus pyogenes. This opened the door for the creation of quinolones that expanded the coverage for these bacteria: levofloxacin, sparfloxacin, grepafloxacin, and gatifloxacin. The enhanced streptococcal activity of these compounds results from modifications to the piperazine group at C-7 of the quinolone nucleus. The addition of a sterically bulky methyl group(s) on this substituent not only improved both in vitro and in vivo activity against gram-positive organisms but also diminished the potential for adverse CNS events and drug interactions (Fig. 3E).[30] Pharmaco-dynamically, these agents possess AUC:MIC ratios that exceed 30, which as discussed earlier have been associated with successful treatment of infections caused by S. pneumoniae (WA Craig, personal communication).[12] These new agents allow for single-agent therapy in community-acquired lung infection because they provide coverage for the leading bacterial and atypical causes of this infection. Levofloxacin and eventually gatifloxacin are particularly attractive choices because they are or will be available in both intravenous and oral formulations, have essentially 100% bioavailability, and have a low incidence of adverse events.[32,33] Sparfloxacin and grepafloxacin were only available as oral formulations. Moreover, as discussed later, the clinical usefulness of sparfoxacin is further limited because of poor adverse event profiles compared with other third-generation quinolones, and grepafloxacin has already been removed from the market due to QTc interval prolongation. Fourth-Generation Quinolones The fourth-generation quinolones, such as trovafloxacin, have appreciable activity against anaerobes, including B. fragilis.[34] This is associated with substituents attached to the C-8 position of the 4-quinolone nucleus. Although the C-8 methoxy group of moxifloxacin and gatifloxacin (Fig. 3E) confer some activity against anaerobes such as B. fragilis, a halogen substitution (e.g., clinafloxacin) at this position or N-8 substitution (trovafloxacin, tosufloxacin) provides for superior activity (Fig. 3F).[30,34-36] At the present time it remains unclear if 8-methoxy quinolone's anaerobic activity will translate into clinical efficacy against B. fragilis. We tentatively classified the 8-methoxy quinolones gatifloxacin and moxifloxacin as third- and fourth-generation agents, respectively. It is important to recognize that the optimum pharmacodynamic parameters of quinolones and B. fragilis have not been well-elucidated. The generation classification is based solely on clinical outcome data and relative differences between trovafloxacin's AUC:MIC of 50 compared with other quinolones, which are generally lower than 15. However, the optimal AUC:MIC ratio may be significantly higher. In an in vitro model of infection, et al[37] reported that an AUC:MIC ratio of trovafloxacin and levofloxacin of 50 against B. fragilis was associated with regrowth and the development of resistance, whereas a ratio of 150 was not. Structure-Adverse Event Relationships Phototoxicity Unfortunately, phototoxicity will limit the clinical usefulness of several second-, third-, and fourth-generation quinolone agents. The introduction of a halogen (e.g., fluorine or chlorine) at the C-8 position of the 4-quinolone nucleus results in enhanced phototoxic potential in human and animal models.[29,30] Compounds that are limited by this substitution include lomefloxacin, sparfloxacin, fleroxacin, and clinafloxacin. Interestingly, compounds with an 8-methoxy substitution (e.g., gatifloxacin and moxifloxacin) have essentially no phototoxic potential, which may be due to stabilization of the quinolone to ultraviolet light degradation (Fig. 3E).[38-41] Digoxin The clinician should be cognizant that drugs and food additives can be modified by intestinal anaerobes. For instance, Eubacterium lentum, which is a gram-positive anaerobic bacilli constituent of the bowel flora, can reduce digoxin to an inactive form.[41] Approximately 10% of the general population and up to 30% of urban populations have E. lentum as part of their fecal flora and typically require increased dosages of this agent. For this reason, the administration of antibiotics that have activity against this organism may result in up to a twofold increase in digoxin levels.[43] Like macrolides and tetracyclines, quinolones as a class have activity against this bacterium.[44,45] Morphine Sulfate Morphine sulfate decreases the secretion of hydrochloric acid in the stomach by inhibition of the opioid receptors on parietal cells.[46] Because of antagonism of these receptors, the pH of the stomach generally rises toward neutral (e.g., physiological or pH 7.14). Moreover, morphine diminishes the transfer of fluid and electrolytes into the lumen of the small intestine via direct effects on the submucosal plexus and within the central nervous system.[47] The dissolution of drugs that are more soluble in water at acidic pH, therefore, may be affected by the coadministration of morphine sulfate. Fluoroquinolones are zwitterionic compounds in nature, which is due to the presence of both a carboxylic acid and a basic amine group. At low pH, these groups are fully protonated and these compounds carry a net positive charge. Conversely, at high pH the amine is free in the base form and the carboxyl group exists as a carboxylate anion, which results in a net negative charge. For this reason, these compounds tend to be more soluble at acidic and basic pH and less at physiological. The bioavailability of trovafloxacin mesylate and ciprofloxacin is significantly affected when coadministered with opioids. The AUC of trovafloxacin and ciprofloxacin is decreased approximately 50% when administered concomitantly with these agents.[48,49] Currently, no data exist describing similarly clinically relevant interactions with other advanced generation fluoroquinolones. Moreover, it is possible that more soluble fluoroquinolones, such as gatifloxacin, may not exhibit a similar limitation; however, further studies are necessary. Cytochrome P-450 Several quinolones (e.g., ciprofloxacin, grepafloxacin, enoxacin) have been shown to reduce the clearance of theophylline by inhibition of the cytochrome P-450 enzyme system. On the other hand, 8-fluoro (sparfloxacin), 8-methyoxy (gatifloxacin and moxifloxacin), and C-7 bicyclic (trovafloxacin) substituted quinolones have been studied and exert no change on theophylline pharmacokinetics.[50] Lack of interaction with the cytochrome P-450 system may also be related to dimethylation of the piperazine group at the C-7; however, this is subject to controversy.[30,50] Clinical Usefulness Of Quinolones Second-Generation Quinolones Ciprofloxacin, a second-generation quinolone, remains the most potent antipseudomonal quinolone in terms of in vitro activity. For instance, ciprofloxacin is consistently two to four times more active in vitro compared with trovafloxacin. Pharma-codynamically, ciprofloxacin's AUC:MIC ratio against P. aeruginosa is superior to any other available quinolone. Although this advantage is not clinically relevant in the therapy of cystitis because high urinary tract concentrations are achieved with almost all quinolones with antipseudomonal activity, it may have importance in respiratory tract infections that involve this organism. One must consider, however, that ciprofloxacin's strength against P. aeruginosa is counterbalanced by poor in vitro activity against many gram-positive microorganisms. For instance, ciprofloxacin is at least two to four times less active against Staphylococcus aureus and S. pneumoniae compared with gatifloxacin, levofloxacin, moxifloxacin, and trovafloxacin. Moreover, ciprofloxacin is pharmacodynamically inferior to any of these third- and fourth-generation agents in this regard. Therefore, ciprofloxacin's place in the therapy of respiratory tract infections should be limited to those that are likely or known to involve P. aeruginosa. Moreover, the use of ciprofloxacin should be avoided in the therapy of community-acquired respiratory tract infections, such as pneumonia, acute bacterial exacerbation of chronic bronchitis, and sinusitis for the aforementioned pharmacodynamic reasons. Third-Generation Quinolones The third-generation quinolones have perhaps the broadest potential for use of all agents in this class. Because of optimal pharmacodynamic profiles, these agents are useful in a variety of community-acquired infections, such as pneumonia, acute exacerbation of chronic bronchitis, sinusitis, cystitis, gonorrhea, and skin and soft tissue infections. However, there are significant differences between these agents in terms of toxicity and safety. For instance, because of phototoxicity sparfloxacin has not gained significant usage. Moreover, grepafloxacin use has been hampered by taste perversion similar to claritromycin, in addition to having the potential to generate arrhythmia (QTc prolongation). These agents are also only available as oral formulations. On the other hand, levofloxacin is well-tolerated, with an overall adverse event rate of less than 3%. Similarly, gatifloxacin also appears to be exceptionally well-tolerated and like levofloxacin will be available in intravenous and oral formulations. Gatifloxacin is twofold more active in vitro than levofloxacin against the pneumococci and generally has greater AUC:MIC ratios against gram-positive organisms. However, it is unclear if this will translate to a greater probability for clinical success in community-acquired respiratory tract infections. Fourth-Generation Quinolones The fourth-generation agents (e.g., trovafloxacin, clinafloxacin, and moxifloxacin) have expanded the spectrum of activity of the third-generation quinolones to include anaerobes. However, this breadth of spectrum can be viewed as an advantage and a disadvantage. Although these agents have a clear use in mixed aerobic and anaerobic infection, such as intra-abdominal infection and diabetic foot infection, their spectrum is too broad for most community- acquired infection, in which the causative pathogen is rarely anaerobic. Additionally, these agents also have significant toxicity issues. Trovafloxacin usage is associated with severe dizziness, which generally resolves after the third day of dosing, and hepatotoxicity. In fact, trovafloxacin FDA labeling has already been changed to highlight hepatotoxicity, which can occur during both short- and long-duration therapy. Clinafloxacin, as mentioned earlier, has significant phototoxic potential. Clinically, in the critical care unit (CCU), clinafloxacin toxicity should be bal-anced against its impressive pharmacodynamic profile against multidrug resistant bacteria. Clinafloxacin is highly active against P. aeruginosa, Xanthamonas maltophilia, and other difficult to treat pseudomonads. Concepts In Resistance And Advances In Cephalosporins Bacterial Resistance And Newer Therapies Because the infectious etiology of pneumonia varies significantly based on community versus nosocomial acquisition, empirical antimicrobial treatment strategies in the CCU must reflect these differences. The increasing complexity of patients admitted to the CCU because of advanced age and severity of underlying condition underscores the need for optimal initial therapy. Because these patients are often treated with multiple antibiotics in or prior to admission to the CCU, they are in essence reservoirs for multiply resistant pathogenic bacteria. As a result, further consideration must be given to organisms harboring altered or reduced susceptibilities to traditionally used treatment selections. The evolving process of bacterial resistance has not changed since Fleming's discovery of penicillin that revolutionized the treatment of infectious diseases. Soon after the widespread introduction of penicillin and its availability as an oral dosage form, staphylococci that were once routinely susceptible progressively resisted the effects of this powerful agent. Ominously, Fleming predicted this in an interview with the New York Times in 1945 in which he proclaimed that the misuse of penicillin would lead to the selection of mutant strains untreatable by penicillin, a situation that he had already simulated in his laboratory. Resistance would be amplified when an oral formulation became available, Fleming predicted, because unlike the controlled hospitalized environment, appropriate outpatient use would be unmonitored and difficult to control. Unfortunately, today, the appropriate use of anti-infective agents, both in inpatient and outpatient venues, is often difficult to control despite educational efforts regarding the continual increase in bacterial resistance. The less sophisticated ß-lactamases produced by mutant staphylococci over time disallowed the use of penicillin for the treatment of staphylococcal infections. Similar situations subsequently occurred in Haemophilus influenzae and Neisseria gonorrhea isolates in the decades that followed. At the present time, we are rapidly losing once-potent therapies in the ongoing battle with the mighty microbe. ß-lactamases continue to rapidly evolve, requiring molecular experts to monitor and classify (and reclassify) them. This is often burdening and confusing for the practicing clinician treating these patients. Therefore, the following sections will focus on the newer ß-lactamases and their clinical relevance. ß-Lactam Resistance Once uniformly susceptible bacteria are now frustrating even our most potent antimicrobial therapies, in particular the ß-lactams. Resistance mechanisms to ß-lactam antibiotics include alteration of target binding sites (e.g., penicillin binding proteins), decreased permeability into the bacterial cell (e.g., altered porin channels), and, most commonly, the production of ß-lactamases. Similar to the earlier described penicillin-staphylococci situation, many clinically important Enterobacteriaceae have developed resistance to ß-lactams through the elaboration of more complex chromosomal or plasmidmediated ß-lactamases, or both. The result of these increasingly common mutants has precluded the use of the third-generation cephalosporins (e.g., ceftazidime) in many institutions and has unfortunately led to the increased use of carbapenems (e.g., imipenem, meropenem) in some hospitals. Therapeutic issues concerning chromosomally mediated Class C (Bush group 1) ß-lactamases and the plasmid-mediated extended spectrum ß-lactamases (ESBLs) will be discussed. The class C ß-lactamase, first documented following the introduction of the potent ß-lactamase inducer cefoxitin in 1978, is particularly worrisome because its expression confers resistance to all cephalosporins (except the newer fourth-generation agents), all penicillins, aztreonam, and ß-lactamase inhibitors (e.g., tazobactam, clavulanate, sulbactam).[51] The gene encoding class C ß-lactamases (amp C gene) is naturally present in many species of enteric and some nonenteric bacteria, including P. aeruginosa, Enterobacter spp., Citrobacter spp., ella spp., and Serratia marcescens, organisms that are responsible for infection in the respiratory tract, gastrointestinal tract, wounds, and urinary tract. Although the amp C gene is present in all of these mentioned bacteria, clinical expression of the ß-lactamase does not always occur. The dormant gene must be activated and can be done so by induction or, even more devastating, by the selection of a permanently activated (stably derepressed) mutant. Induction, or the temporary expression of the amp C ß-lactamase resulting in a mild elevation in MIC from baseline occurs as a result of burdening the amp D enzyme that is responsible for recycling cell wall fragments (Fig. 4). Potent inducers of the class C ß-lactamase include ceftazidime, cefoxitin, and the carbapenems. Permanent production of this ß-lactamase occurs when the amp D enzyme undergoes a significant mutational event, allowing the buildup of murein cell wall fragments within the bacterial cell, leading to the subsequent unrelenting production of the amp C ß-lactamase (e.g., stably derepressed mutant). The last of these mechanisms results in clinically significant elevations in MIC values for organisms expressing these enzymes that, as will be discussed later, have led to treatment failures. Figure 4. Chromosomially mediated ß-lactamase production (Adapted from Medeiros [52] ). Extended Spectrum ß-lactamases ESBLs, first described in 1983 following the introduction of cefotaxime to clinical use, are mutant derivatives of the basic and well-described TEM and SHV ß-lactamases.[53] ESBLs have been gradually increasing in prevalence since their original description, and, although described in numerous Enter-obacteriaceae, they are most commonly associated with Escherichia coli and Klesiella pneumoniae. In contrast to the class C ß-lactamase-producing organisms discussed before, bacteria expressing ESBLs typically acquire the ability to produce such enzymes via plasmids, rather than by uniformly possessing the chromosome that encodes the ß-lactamase. Plasmids are often exchanged by bacteria to one another via conjugation. Possessing an ESBL confers resistance to the cephalosporin group of antibiotics with the exception of the cephamycins (e.g., cefoxitin and cefotetan) and the fourth- generation cephalosporins (e.g., cefepime and cefpirome). Unlike with the class C ß-lactamases, ß-lactamase inhibitor combinations (e.g., piperacillin-tazobactam and ticarcillin-clavulanate) remain active against ESBLs. Characteristically, plasmids encoding ESBLs may also encode for additional resistance mechanisms that confer resistance to the aminoglycosides (e.g., via aminoglycoside-modifying enzymes) and fluoroquinolones (e.g., via efflux pumps). Alarmingly, plasmids containing the chromosomal class C ß-lactamase have recently been identified conferring resistance to additional agents. Metallo-ß-lactamases, another type of plasmid-mediated enzyme produced by Stenotrophomonas maltophilia, that render the carbapenems inactive have also been identified. Recently published studies have again showed that squeezing one end of the balloon merely leads to inflation of resistance somewhere else.[54,55] Rahal and colleagues[52] restricted ceftazidime use during an outbreak of ESBL producing K. pneumoniae infections resulting in increased carbapenem use. The result, although not unexpected, was the eradication of the ESBL producing Klebsiella spp. at the expense of an increase in resistance to P. aeruginosa. The removal of potent ß-lactamase inducers from the environment seems justified at this point in time. What should replace them, however, is less obvious. Paterson et al[56] reviewed more than 400 consecutive isolates and their resulting infections caused by K. pneumoniae, 80 of which were associated with ESBL-producing strains. The primary end-point was mortality, a crude estimate of efficacy, that may or may not be associated with antibiotic efficacy depending on various other factors, such as underlying disease. Carbapenems (e.g., imipenem and meropenem) were used to treat the majority of cases resulting in the lowest mortality rate (5%). The mortality rate of patients receiving ciprofloxacin was 21%. Only eight patients were treated with either cefepime or piperacillin and tazobactam, four each. Two of four patients treated with cefepime died. The majority of all isolates tested during the study period were susceptible to cefepime (87%). Two of four patients who were treated with piperacillin and tazobactam died as well, and, interestingly, only 38% of Klebsiella isolates were susceptible to this agent. Difficulties with this study are the endpoint used to evaluate antibiotic efficacy, and, with the exception of the number of patients receiving a carbapenem, the sample sizes were too small to make meaningful conclusions regarding other therapies. The interesting observation that only 38% of the ESBL-producing Klebsiella isolates were susceptible to piperacillin and tazobactam, an agent that has demonstrated activity against the ESBL-producing organisms, suggests the presence of additional mechanisms of resistance, possibly including chromosomally mediated ß-lactamases. The role of the fluoroquinolones, piperacillin and tazobactam or the fourth-generation cephalosporins in the treatment of ESBL outbreaks is still not well-established, and further comparative studies should be designed to answer this question. The good in vitro activity of ciprofloxacin (82%) and cefepime (87%) in this study should warrant further studies with these agents. Clinical Importance Of Bacterial Resistance Recent epidemiological data from an extensive global effort documenting geographic bacterial susceptibilities have been useful in identifying emerging resistance trends.[57-60] Among the problematic organisms identified that are capable of causing nosocomial respiratory tract infections are Enterobacter spp., Citrobacter spp., indole-positive Proteeae, Klebsiella spp, E. coli, and S. aureus. Nearly one quarter and one third of K. pneumoniae and Enter-obacter cloacae isolates, respectively, demonstrated resistance to ceftazidime. Now that clinicians are faced with this type of data, specific antimicrobial management and infection control countermeasures must be employed to steer away from the current predicament. Clinical failures to third-generation cephalosporins have been reported, further substantiating the in vitro descriptive data being generated.[61-68] Clinical failures are important for several reasons. The most compelling, perhaps, is that organisms such as E. cloacae have been associated with a high mortality rate specifically attributable to infection. [63,69] A prospective study evaluated Enterobacter bacteremias and demonstrated a strong association between third-generation cephalosporin use and the emergence of resistant Enterobacter spp. during therapy.[68] In this study, multidrug resistant Enter-obacter strains were associated with significantly higher mortality rates than were their susceptible counterparts, an association that was confirmed via multivariate regression analysis. In addition, combination therapy failed to prevent the emergence of resistance. and Ramphal[61] also reported substantial mortality associated with ceftazidime-resistant Enterobacter infections compared with infection due to susceptible strains in neutropenic patients. In addition to the assessment of the clinical impact of such failures, the costs associated with these treatment failures due to resistant bacteria have been evaluated.[67,70] Although difficult to quantify, costs associated with bacterial resistance are significant. In fact, it has been shown that, for community-and hospital-acquired infections caused by drug-resistant organisms, mortality, likelihood for hospital admission, and length of hospital stay were commonly twice as great compared with infection caused by the same, but drug-susceptible, bacteria.[70] Ambrose and colleagues[67] evaluated the efficacy of cefepime compared with ceftazidime for the treatment of nosocomial pneumonia. A cost-effectiveness analysis demonstrated a reduction in total costs (e.g., drug acquisition, supplies, additional antibiotics required for treatment failures, and hospitalization costs) when cefepime was utilized (cefepime cost/cure = $235.89 and cost/failure = $375.44 versus ceftazidime cost/cure = $319.81 and cost/failure = $520.11). Significantly more treatment failures occurred in patients receiving ceftazidime (40%) compared with those patients that received cefepime (20%) (p = 0.04). Current Treatment Options Currently available ß-lactams able to resist the class C ß-lactamases and ESBLs include the fourth-generation cephalosporins (e.g., cefepime and cef-pirome) and the carbapenems (e.g., imipenem and meropenem). The fluoroquinolones remain highly active against many of these ß-lactamase-producing bacteria and are likely to result in good outcomes; however, ESBL-producing strains can often confer multidrug resistance, so therapy should be modified when susceptibility data become available. As discussed in earlier sections, pharmacodynamic indices may be used not only to optimize patient outcome but also to minimize the development of resistance. Specifically, against inducibly resistant strains of E. cloacae and P. aeruginosa, Aronoff and Shlaes[71] demonstrated that the frequency of bacterial mutation under antimicrobial pressure was directly related to the ratio of drug concentration to the MIC of the bacteria. Furthermore, the time the drug concentration remains in excess of the MIC at the site of infection has been shown to be predictive of clinical and bacteriologic outcome for ß-lactam antibiotics.[72] Familiarity with these concepts allows the practicing clinician to compare agents for potential efficacy based on pharmacodynamic indices (e.g., time above MIC, Cp:MIC ratio, and AUC:MIC ratio) resulting in the selection of regimens that will maximize bacterial killing. Consequently, it was shown recently that patients receiving antibacterial therapy yielding suboptimal pharmacodynamic indices were more likely to select for resistant bacterial populations during therapy.[73] These data further emphasize the need for clinicians to optimize both antibacterial selection and its dosing regimen based on known pharmaco-dynamic principles. The fourth-generation cephalosporins and the carbapenems both reach concentrations well in excess of typical bacterial MICs in lung tissue and epithelial lining fluid for a significant period of the dosing interval. Furthermore, and colleagues have reported the successful treatment of patients with cefepime that were infected with multiply-resistant Enterobacter species, including ceftazidime-resistant strains.[74] Included in this group were chronically infected patients who had responded poorly to imipenem, aminoglycosides, and ciprofloxacin. The success rate of cefepime in this group of patients was 88.2%, and the development of resistance was not reported to occur during therapy. Combination Therapy The use of combination therapy in the treatment of infection has been controversial, and the results of clinical studies are often contradictory.[73-76] Compounding the difficulty in the interpretation of combination therapy studies is the fact that resistance mechanisms continue to evolve, patient populations (e.g., immune system status) vary, the end-points of such studies can be questionable, and knowledge of optimal antibiotic dosing strategies (e.g., once-daily aminoglycoside administration) are emerging. With this in mind, it is difficult to prospectively study rational antibiotic combinations in a controlled fashion that employs optimal dosing strategies against a large enough sample of a variety of infecting organisms on which to base firm conclu- sions from these studies. So in clinical practice, some clinicians continue to treat infections due to organisms with a propensity to develop resistance quickly with combination therapy, if based on nothing else but circumstantial evidence. A distillation of the data from studies evaluating combination therapy has revealed a benefit when treating systemic infection caused specifically by P. aeruginosa. Examining the patient populations within these studies in greater detail further emphasizes the benefit of combination antipseudomonal therapies in neutropenic patients. For infection due to gram-negative bacilli other than P. aeruginosa, combination therapy has not been shown to have a significant impact on patient outcome. When combination therapy targeted against gram-negative bacilli is felt to be clinically indicated, an aminoglycoside or fluoroquinolone is optimally combined with a -lacta-mase- stable ß-lactam (e.g., fourth-generation cephalosporin, carbapenem). In proven ß-lactam- intolerant patients, aztreonam could be substituted for the ß-lactam and combined with either an aminoglycoside or a fluoroquinolone. Quinolone-aminoglycoside combinations, although popular in certain geographic regions, are infrequently synergistic against gram-negative bacteria in direct contrast with ß-lactam-aminoglycoside and ß-lactam- quinolone combinations.[79-81] Formulary Optimization Restricting antibiotic use and using rotational antimicrobial strategies are among the methods employed to control the development of antibiotic resistance. In light of the Armageddon that we are now facing, the solution to resistance prevention has not been clearly established. In large part, the solution will employ vigilant infection control measures in concert with effective antimicrobial management strategies to relieve selective pressure. What has been demonstrated is that by removing known offending agents from use within the institutional environment, particular outbreaks of resistant pathogens can be eliminated. What to replace these offending agents with is the difficult question. Compounds with intense gram-negative potency are the logical choice; however, the ß-lactamase induction potential possessed by the agent is also an important consideration. For instance, during the ESBL-producing K. pneumoniae outbreak, imipenem replaced ceftazidime, subsequently leading to an increase in P. aeruginosa resistance. Optimizing the antimicrobial Formulary has been recently shown to have a favorable impact on the susceptibilities of problematic gram-negative bacilli in several institutions. Restricting the use of ceftazidime in a pediatric intensive care unit resulted in a small but not significant reduction in ceftazidime- resistant gram-negative bacteria. When the data were further analyzed, however, the number of known class C ß-lactamase-producing organisms substantially decreased from 68.2% to 45.9%, p ß 0.05.[82] Improved susceptibilities appear to be even greater when ceftazidime has been replaced by a fourth-generation cephalosporin. Goldman and colleagues 83 showed a dramatic increase in E. cloacae susceptibilites to a variety of antibiotic classes following a Formulary conversion from ceftazidime to cefepime in six CCUs at the Cleveland Clinic Foundation. Mebis and colleagues[84] replaced ceftazidime-based combination regimens with cefepime-based combination therapy in the treatment of fever and neutropenia. This conversion was in response to E. cloacae resistance rates of 75% (ceftazidime), 52.5% (ciprofloxacin), and 36% (amikacin). Ten months following a single antibiotic change, resistance rates decreased to 35% (ceftazidime), 24% (cipro-floxacin), and 18% (amikacin). Similar results were observed in the oncology units when our institution converted from ceftazidime to cefepime as the preferred monotherapeutic regimen.[85] Although these situations occurred in oncology units, they provided meaningful data. Because the antibiotic regimens used in the oncology unit tend to be monopolistic, with preference given to a select few choices, the outcome of a single regimen substitution can be quantified with less confounding variables. Information from such studies can be useful to study the impact of regimen selection in other infectious diseases, including respiratory tract infections. Conclusion Many new antibiotics have been made available for use over the last year, most of which are indicated for the treatment of either community- or hospital- acquired pulmonary infections. The introduction of such agents comes at a time when resistant pathogens are becoming an emerging threat to patient survival. The emergence of bacterial resistance in our most severely ill patient populations has extensive implications associated with mortality, morbidity, and cost of care. Broad sweeping surveillance studies are useful to detect regional susceptibility changes; however, the most important data to the practicing clinician must be obtained locally to determine pathogens that must be addressed on an institutional level. Improved diagnostic testing may assist the clinician in the determination of an etiologic agent or in confirming the presence or absence of infection. Newer antibiotic therapies may save patients or stave off resistance, temporarily. From a larger perspective, however, nothing may have a greater impact on the prevention of resistance and ultimately increase survival, than the judicious use of existing therapies and employing sound clinical judgment in the antibiotic selection process as well as in the design of optimal dosing regimens. Table 1. Quinolone Generations (Pharmacodynamic Classification) First Second Third Fourth Nalidixic Acid Lomefloxacin Ofloxacin Levofloxacin *Trovafloxacin Oxolinic Acid Norfloxacin Ciprofloxacin Gatifloxacin Moxifloxacin Cinoxacin Enoxacin *Sparfloxacin Clinafloxacin *Grepafloxacin Sitafloxacin SB-265805 Microbiological Activity Enterobacteriaceae Enterobacteriaceae Enterobacteriaceae Enterobacteriaceae Enterobacteriaceae + + P. aeruginosa P. aeruginosa P. aeruginosa atypicals atypicals atypicals P. aeruginosa + Streptococci streptococci + anerobes Site of Infection Urine Urine Systemic Systemic Systemic only only + +/- +/- urine urine urine *Significant nonrenal elimination pathways exist References Eagle H, Fleischman R, Levy M. Continuous vs discontinuous therapy with penicillin. N Engl J Med 1953;238:481-488 Eagle H. Effect of schedule of administration on therapeutic efficacy of penicillin: Importance of aggregate time penicillin remains at effectively bactericidal levels. 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Pharmaco Ther 1999;19:496-497 ---------------------------------------------------------------------------- ---- Home Site Map Marketplace My Medscape CME Center Feedback Help Desk Medscape Search Options Clinical Content News Info for Patients Medical Images MEDLINE AIDSLINE Drug Info Bookstore Dictionary Whole Web Dow Library ($) Select a database to search, enter a search term, then click " go. " Advanced Search Forms All material on this website is protected by copyright. Copyright © 1994-2000 by Medscape Inc. All rights reserved. This website also contains material copyrighted by 3rd parties. Medscape requires 3.x browsers or better from Netscape or Microsoft. Initial Results Positive With Chemotherapy/stem-Cell Rescue For Rheumatoid Disease ---------------------------------------------------------------------------- ---- By Sue Mulley BEIJING, Jun 07 (Reuters Health) - Early data suggest that high-dose chemotherapy with stem-cell rescue can benefit patients with severe refractory rheumatoid disease, according to data presented here at the ninth Asia Pacific League of Associations for Rheumatology. Dr. M. of the University of Queensland in Brisbane, Australia, reported that an increasing number of patients with autoimmune disease, such as rheumatoid arthritis and systemic lupus erythematosus, have had significant responses when treated with high-dose chemotherapy combined with stem-cell rescue. " While some patients have relapsed, many have had a sustained remission of their underlying connective tissue disorder, " he said. Dr. and his colleagues treated eight patients with severe rheumatoid arthritis with 100 mg/kg or 200 mg/kg cyclophosphamide and stem-cell rescue and followed them for more than 18 months,. " All of the higher dose cohort responded well, although a complete response was only noted in one patient. All the other patients, however, have significantly less disease activity than prior to treatment, and have been able to reduce their prednisolone and disease-modifying therapy. One patient became pregnant and delivered a normal child, " Dr. told the conference. An additional 30 patients have been randomised to receive 200 mg/kg cyclophosphamide and then to receive either unmanipulated or T-cell depleted autologous stem cells. " While the initial treatment has been carried out with a low incidence of side effects...the study is ongoing...and will provide important information on whether T-cell depletion is necessary, " he noted. " Allogeneic transplants with their attendant problems of graft-versus-host disease should not be considered for patients with autoimmune disease at present, " Dr. emphasized, adding that stem cell transplantation for autoimmune disease should only be carried out in " experienced " centres where the mortality of stem cell transplant in other conditions is less than 3%, and then only as part of a clinical trial. Dr. also called for the long-term follow up of all patients undergoing high-dose chemotherapy and stem-cell rescue to assess infection rates and the possible development of neoplasia--either solid tumours or haematologic malignancies. Quote Link to comment Share on other sites More sharing options...
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