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Antimicrobial agents with primary activity against gram-negative bacteria
Gram-negative bacteria are ubiquitous microorganisms of particular concern, especially the gram-negative bacilli (GNB), because of the fast spread of multidrug resistance (MDR). GNBs have intrinsic abilities to find new pathways of resistance and to transmit genetic material that allows other bacteria to become resistant as well (i.e., resistance acquisition via horizontal gene transfer). Mutations lead to new phenotypes with modified antibiotic targets, such as ribosomal mutation, whereas genes encoding drug efflux permeases and genes encoding antibiotic-modifying enzymes, such as beta-lactamases, are most often acquired via horizontal transfer. , Specifically, the development of extended-spectrum beta-lactamases that confer resistance to penicillins and cephalosporins and of carbapenemases that confer resistance to carbapenems, as well, is considered of critical importance. It is noteworthy that in the World Health Organization (WHO) priority list, all the critical priority (Priority 1) microorganisms are gram-negative—carbapenem-resistant Acinetobacter baumanni (CRAB) , carbapenem-resistant Pseudomonas aeruginosa , third-generation cephalosporin-resistant and carbapenem-resistant Enterobacteriaceae (CRE); the vast majority of the high-priority ones (Priority 2).
In the intensive care setting GNBs are responsible for multiple infections, such as bloodstream infections, ventilator-associated pneumonia (VAP), device-associated infections, intraabdominal infections (IAIs), urinary tract infections (UTIs), and soft tissue infections. MDR GNBs represent a healthcare burden and are associated with poor outcomes (i.e., increased morbidity and mortality). The antimicrobial agents most commonly used in the intensive care unit (ICU) to combat MDR GNBs include beta-lactams, fluoroquinolones, aminoglycosides, polymyxins, newly introduced tetracyclines, and fosfomycin.
It should be highlighted that several reports have demonstrated suboptimal concentrations of antimicrobial agents in critically ill patients when conventional dosing schemes were used. Therefore during the last decade, apart from the efforts to develop new antimicrobial agents, research has focused on optimization of the use of the currently available antimicrobial agents in the critical care setting, aiming for both improvement of clinical outcomes and limiting resistance emergence. , For dose optimization, alternative dosing schemes have been recommended, based on the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of the antimicrobial agents and dosing individualization. For dosing individualization, nomograms validated in critically ill patients and dosing software can be used; however, therapeutic drug monitoring (TDM)–guided dosing is recommended as the safer and more effective means to achieve optimal antimicrobial exposures.
In this chapter we summarize the characteristics of the classes of antimicrobial agents used in the critical care setting for GNBs, including “older” antimicrobial agents that have been “reintroduced” as salvage treatments, and introduce novel approved antimicrobial agents.
Beta-lactams
Beta-lactams include penicillins, cephalosporins, carbapenems, and monobactams. They share a four-membered beta-lactam ring. Aztreonam is a monobactam that contains only the beta-lactam ring. In penicillins, the beta-lactam ring is connected to a five-membered thiazolidine ring and a side chain that distinguishes the different penicillins; in cephalosporins, it is connected to a six-membered sulfur-containing dihydrothiazine ring and two side chains that distinguish the different cephalosporins, whereas in carbapenems, the beta-lactam ring is connected to a five-membered thiazolidine ring that contains a carbon double bond instead of sulfur, and a side chain differentiates the different members of the class.
Mode of action of beta-lactams
Beta-lactams exert bactericidal action by inhibition of the synthesis of the peptidoglycan layer of the cell wall: via acylation of penicillin-binding protein transpeptidase enzymes (PBPs), they inhibit the cross-linkage of the peptidoglycan chains with subsequent bacteriolysis and cell death. The efficacy of a beta-lactam antimicrobial agent is determined, at least in part, by its ability to reach the target PBPs and its binding affinity to various PBPs.
Resistance to beta-lactams
Resistance to beta-lactams occurs via (1) PBP modifications that decrease their binding affinity (mainly in gram-positive bacteria), (2) loss or deficiency of outer membrane proteins that decrease permeability (in gram-negative bacteria), (3) presence of efflux pumps that force out the beta-lactams, and (4) hydrolysis by beta-lactamases (chromosomally encoded or via plasmids or transposons). Beta-lactamase production is the most common mechanism of beta-lactam resistance in clinically important gram-negative bacteria and is largely responsible for GNB resistance in hospitals and, particularly, in the critical care setting. Beta-lactamases are mainly classified either based on their molecular structure (i.e., their amino acid sequence) or based on their function. Molecular classification is the simplest and least controversial approach, whereby beta-lactamases are divided into four classes, A, B, C, and D (Ambler classification). The hydrolysis of the classes A, C, and D is done though an active-site serine, whereas class B includes metalloenzymes that hydrolyze beta-lactam through at least one active-site zinc. The functional classification, on the other hand, relates the varied beta-lactamases to their clinical role and classifies them in three groups with several subgroups. , Group 1 are cephalosporinases belonging to class C of molecular classification (including the AmpC beta-lactamases) that inactivate most cephalosporins and aztreonam and are not inhibited by clavulanate or tazobactam, and, moreover, in the case of large production, particularly in hosts with decreased beta-lactam accumulation, can inactivate carbapenems, especially ertapenem. , Group 2 are serine beta-lactamases belonging to molecular classes A and D and represent the largest group, as they include the extended-spectrum beta-lactamases (ESBLs) that hydrolyze third-generation cephalosporins and aztreonam (subgroup 2be), found in GNBs, particularly Enterobacteriaceae. , ESBLs are another beta-lactamase of particular concern, as the number of nosocomial infection outbreaks caused by ESBL-producing GNBs is high and ever increasing, and in many parts of the world ESBL-producing strains are endemic. , Group 3 are metallo-beta-lactamases (MBLs), a unique group both structurally and functionally, with the ability to hydrolyze carbapenems (although some serine beta-lactamases have also acquired this ability); the imipenemase (IMP) and Verona integron metallo beta-lactamase (VIM) that have appeared globally, mainly in lactose nonfermenting GNBs but also in Enterobacteriaceae , belong to this group. , , Contrary to the serine beta-lactamases, MBLs have poor hydrolytic capability for monobactams and are not inhibited by clavulanic acid or tazobactam. , Functional classification is more subjective than the molecular one; nevertheless, it correlates the properties of a specific beta-lactamase with the microbiologic resistance profile for an isolate that is more useful in the medical setting. , Finally, regarding resistance to beta-lactams, it should be emphasized that although ESBL- and AmpC- producing GNBs are susceptible to carbapenems, carbapenemase-producing strains have been rapidly increasing worldwide (and are already endemic in several countries) and represent a serious public health threat, as these strains generally display MDR, including all beta-lactams and aminoglycosides and fluoroquinolones.
Spectrum of activity of Beta-lactams
Beta-lactam antimicrobial agents have a wide spectrum of activity against gram-positive and gram-negative aerobic and anaerobic bacteria. However, each individual class of beta-lactams has a unique microbiologic spectrum. Natural penicillins are seldom used in critical care settings because they lack activity against beta-lactamase–producing bacteria. The class of cephalosporins is categorized into five generations depending on their temporal discovery and their spectrum of activity. The first- and second-generation cephalosporins generally have only limited use in the critical care setting. Third-generation cephalosporins include the parenterally administered cefotaxime, ceftazidime, cefoperazone, ceftizoxime, and ceftriaxone. They provide a broad coverage of gram-negative bacteria, with expanded activity against the Enterobacteriaceae and Streptococcus pneumoniae but lack activity against enterococci, methicillin-resistant Staphylococcus aureus (MRSA), Listeria monocytogenes, Stenotrophomonas maltophilia , and many Acinetobacter spp. Based on their antipseudomonal activity, cefoperazone and ceftazidime have clinically useful potency against P. aeruginosa. Third-generation cephalosporins can be hydrolyzed by ESBL-producing GNBs. The fourth-generation cephalosporins, cefpirome (not available in the United States) and cefepime, have improved penetration to the outer membrane of gram-negative bacteria because of an additional quaternary ammonium group. Their spectrum is the widest of all cephalosporins: against gram-negative bacteria, their activity is similar to ceftazidime, but they are less susceptible to inactivation by AmpC beta-lactamases, whereas against gram-positives, they have activity similar to cefotaxime and ceftriaxone. , , Resistance to fourth-generation cephalosporins is increasing, and they can be inactivated by many new ESBLs and carbapenemases. Moreover, therapy for infections by ESBL-producing strains with maintained susceptible minimum inhibitory concentrations (MICs) is controversial. , Both third-generation (especially ceftriaxone and cefotaxime) and fourth-generation cephalosporins penetrate the blood-brain barrier. ,
Ceftaroline and ceftobiprole are considered fifth-generation cephalosporins and are the first ones with anti-MRSA activity. Their activity against gram-negative bacteria corresponds to that of the third-generation cephalosporins (i.e., they are hydrolyzed by ESBL and AmpC beta-lactamases). , Ceftaroline was approved by the Food and Drug Administration (FDA) in 2010 and by the European Medicines Agency (EMA) in 2012 for the indication of community-acquired pneumonia (CAP) and complicated skin and soft tissue infections (cSSSIs). Ceftobiprole has been approved in several European countries and in Canada for the treatment of CAP and hospital-acquired pneumonia (HAP), excluding VAP, but is not approved in the United States. , For further details on the anti-MRSA cephalosporins, ceftaroline and ceftobiprole, we refer the reader to the relevant chapter (i.e., antimicrobial agents against gram-positive bacteria).
The carbapenems are the broadest-spectrum beta-lactams and are typically reserved for severe nosocomial infections. Imipenem is degraded by the enzyme dehydropeptidase-1 (DHP-1) of the renal tubules and is combined with cilastatin, a DHP-1 inhibitor, whereas meropenem, doripenem, and ertapenem have increased stability towards the action of DHP-1. Carbapenems have a broad spectrum of in vitro activity, covering gram-positive bacteria, excluding MRSA and Enterococcus faecium, and gram-negative bacteria, excluding S. maltophilia , and anaerobes. Imipenem/cilastatin and meropenem are typically reserved for severe nosocomial infections, having established efficacy in the treatment of a variety of infections, including complicated UTIs (cUTIs; including pyelonephritis), complicated IAIs (cIAIs), SSSIs, CAP, nosocomial pneumonia (including VAP), meningitis (meropenem only), and febrile neutropenia. In general, doripenem has been demonstrated to have better in vitro activity than imipenem and similar or slightly better activity than meropenem against P. aeruginosa. However, its clinical use is more limited compared with meropenem and imipenem, as its approved indications include cIAIs and cUTIs (including pyelonephritis) only, whereas there is a labeling warning for increased risk of death for VAP patients. , Ertapenem’s spectrum of activity is less wide compared with imipenem, meropenem, and doripenem, as it is inactive against important lactose nonfermenting GNBs, including P. aeruginosa and A. baumannii , in addition to against Enterococci, and it is more suited for community-acquired than for nosocomial infections. Because of its favorable pharmacokinetic properties, it is also suitable for outpatient intravenous (IV) antimicrobial treatment. Carbapenems are stable against ESBL and AmpC beta-lactamase–producing GNBs but are susceptible to carbapenemases and MBLs. ,
Aztreonam is a monobactam with broad aerobic gram-negative activity, but it lacks efficacy against gram-positive bacteria and anaerobes.
Combination of beta-lactams with beta-lactamase inhibitors
One strategy for achieving beta-lactamase stability is combining beta-lactams with beta-lactamase inhibitors, such as clavulanate, sulbactam, and tazobactam and, more recently, with novel inhibitors such as avibactam, vaborbactam, relebactam, zidebactam, nacubactam, and taniborbactam. Although beta-lactamase inhibitors lack antibacterial activity at clinically relevant concentrations, they preserve and enhance the antibacterial activity of the partner beta-lactam against beta-lactamase–producing pathogens. For the co-formulation of a beta-lactam/beta-lactamase inhibitor, two main factors are taken into consideration, namely the activity of the inhibitor against the beta-lactamases that the partner beta-lactam is susceptible to and the similarities in the PK properties between the partners to warrant structural integrity protection of the beta-lactam throughout a given dosing interval. Ampicillin/sulbactam is active against gram-positive bacteria, including Enterococcus spp . , gram-negative cocci, and certain strains of Enterobacteriaceae (not ESBL-producing ones). Ticarcillin/clavulanate and piperacillin/tazobactam have a broader spectrum of activity, including P. aeruginosa, Enterobacteriaceae, and several anaerobes. Piperacillin has better antipseudomonal activity than ticarcillin. , However, the resistance rates of P. aeruginosa to piperacillin/tazobactam in the ICU are significantly increasing worldwide, necessitating optimization of drug exposure or combination therapy to ensure the efficacy against it.
PK/PD of Beta-lactams
Beta-lactam antibacterial agents are generally hydrophilic, with a low volume of distribution ( V d ) similar to the extracellular fluid, and the main route of elimination is the kidneys (although in piperacillin/tazobactam, biliary excretion may be important, and ceftriaxone has significant biliary excretion as well). Frequent physiologic alterations in critically ill patients, such as increased V d because of sepsis and/or fluid resuscitation and augmented renal clearance (increased glomerular filtration rates [GFR], lead to inadequate (subtherapeutic) concentrations of beta-lactams. , On the other hand, acute renal injury may lead to higher plasma concentrations and increased toxicity. The protein binding of beta-lactams is moderate (30%–50%) to low (<30%); however, they are members of a class with high protein binding, which includes ertapenem (∼95%), ceftriaxone, flucloxacillin, and oxacillin. For these agents, the hypoalbuminemia that is common in critical illness may lead to low unbound concentrations towards the end of the dosing interval, because of the higher clearance of the (increased) free fraction. , The in vivo half-lives of beta-lactams vary. ,
Beta-lactams are time-dependent killing antibiotics; the PK/PD index associated with optimal beta-lactam activity is the percentage of time that the free serum concentration is above the pathogen MIC (% f T>MIC). Data from critically ill patients suggest that longer beta-lactam exposures (e.g., 100% fT>MIC) and higher concentrations (e.g., 2–5 × MIC) than previously described may be beneficial with maximal killing effect and suppressed bacterial resistance. , Finally, a recent analysis of pooled data of critically ill patients with monomicrobial gram-negative bloodstream infections reported that beta-lactam fCmin/MIC >1.3 was a significant predictor of a positive clinical outcome and recommended it as an antibiotic dosing target.
Dosing and monitoring of beta-lactams
As mentioned earlier, because of the physiologic alterations of critically ill patients, conventional antibiotic dosing of beta-lactams antimicrobial agents may lead to subtherapeutic concentrations. , A recent position paper on TDM of antimicrobial agents in critical care recommended an initial loading dose of beta-lactams followed by prolonged infusion, continuous or extended (3–4 hours), in order to maximize PK/PD target attainment and possibly improve clinical outcomes. The panel recommended routine TDM of beta-lactams to optimize dosing of critically ill patients, achieving therapeutic targets in the critically ill populations, and at the same time, minimizing toxicity. For continuous administration, samples can be taken any time point during the infusion (with target Css>MIC). For intermittent administration, minimum concentration (C min ) should be monitored (with target 100% fT>MIC); sampling should occur 24–48 hours after treatment initiations, with one sample taken 30 minutes before or just before the administration of the following dose.
Prolonged dosing of beta-lactams. Some evidence exists that suggests better outcomes are achieved with prolonged administration of beta-lactams (i.e., continuous or extended 3-hour IV infusions) compared with the standard intermittent administration, especially for critically ill patients with infections by resistant GNBs. Although results from randomized controlled trials (RCTs) are controversial, a meta-analysis of three RCTs comparing continuous with standard intermittent bolus administration of beta-lactam antibiotics in septic critically ill patients found decreased hospital mortality with continuous beta-lactam administration, but no difference in clinical cure rates. BLING III is an ongoing, prospective, international phase III RCT with a recruitment target of 7000 critically ill patients with sepsis, which compares continuous with intermittent administration of beta-lactams (piperacillin-tazobactam or meropenem), aiming to provide evidence to support one method of administration over the other.
Synergy of beta-lactams in combination with other antimicrobials
Synergy (i.e., effect of a combination greater than expected based on individual antimicrobial agents) is frequently reported with the combination of a cell wall–active antimicrobial, such as a beta-lactam, with other agents, most commonly, an aminoglycoside or a fluoroquinolone, even against pathogens with higher MICs. Several studies have demonstrated survival benefit from early administration of such a combination therapy in patients with sepsis and septic shock. Other studies have not shown benefit from a combination, such as an RCT in patients with septic shock in a country with a quite low level of MDRs, which failed to demonstrate a decrease in organ failure when fluoroquinolones were added to carbapenems. Nevertheless, it should be noted that for the empiric management of septic shock, the Surviving Sepsis Campaign guidelines suggest the empiric combination of at least two antibiotics of different antimicrobial classes, targeting the most likely potential pathogens, noting that the recommendation is weak and the quality of evidence low. ,
Adverse events of Beta-lactams
Beta-lactams are the most commonly reported antibiotic classes to cause allergic drug reactions, especially penicillins (∼10%) and cephalosporins (less than penicillins; 1%–7%), whereas the incidence of allergic reactions caused by carbapenems is lower (<3% in the general population). , , , Immediate hypersensitivity reactions are immunoglobulin E (IgE)–mediated and usually occur within 6 hours (typically within 1 hour) from last drug administration, whereas the nonimmediate hypersensitivity reactions are mediated by the T cells and may occur any time after the first drug administration, typically after several days of treatment. Immediate reactions usually present with symptoms and signs from the skin (e.g., itching, rash, angioedema), the upper and lower respiratory system (e.g., sneezing, nasal congestion, hoarseness, wheezing), the gastrointestinal system (e.g., mild abdominal pain, nausea, diarrhea), and the cardiovascular system (e.g., tachycardia, hypotension); they can appear isolated or in combination as severe anaphylaxis. Nonimmediate hypersensitivity reactions are most commonly manifested with maculopapular exanthema and urticaria.
Penicillins can cause gastrointestinal disturbances, particularly diarrhea, but hematologic toxicity is rare. , Also, high doses of penicillins cause abnormalities of platelet aggregation, while Coombs-positive hemolytic anemia is a rare adverse event. , , Renal toxicity of penicillins varies and can range from allergic angiitis to interstitial nephritis.
Cephalosporins have low toxicity and are generally safe and well tolerated. The most frequent adverse reactions of cephalosporins include nausea, vomiting, lack of appetite, and abdominal pain. Less common reactions include hypersensitivity reactions, drug-induced immune hemolytic anemia, pseudomembranous colitis, disulfiram-like reactions, vitamin K deficiency, and enhancement of the nephrotoxicity of aminoglycosides.
Carbapenems are generally well-tolerated. The most common adverse events include gastrointestinal disturbances, such as nausea, vomiting and diarrhea, headache, dermatologic reactions such as rash, and injection site effects such as phlebitis. As carbapenems have minimal hepatic metabolism, clinically significant hepatotoxicity is rare, although mild-to-moderate asymptomatic increases in serum aminotransferases may occur, but rapidly resolve after drug discontinuation. Also, carbapenems are considered to have low propensity for nephrotoxicity, coagulation disorders, and Clostridium difficile diarrhea. Seizures are the most serious adverse event, particularly for imipenem (1%–2% compared with 0.1%–0.3% for the other carbapenems), especially when higher doses are used (≥4 g/day). , Although seizures are overall rare, the incidence increases in cases with renal impairment, lower body weight, and history of seizures or other central nervous system (CNS) comorbidities. Carbapenems do not have significant drug interactions, although concomitant administration with valproic acid may lead to subtherapeutic levels of valproic acid.
Aztreonam is generally well tolerated, with more common adverse events including infusion site reactions such as phlebitis, gastrointestinal disturbances (nausea, vomiting, and diarrhea), and rash.
It should be noted that the more aggressive beta-lactam dosing to account for altered drug PK in critically ill patients might have led to excessive drug exposure being increasingly reported over the last decade. TDM of beta-lactams, apart from helping to optimize exposures, can help in decreasing related toxicities. C min samples at steady state, or even earlier when dosing software is used, can help avoid overexposure to beta-lactams. ,
Cross-reactivity of beta-lactams. Although subjects can be sensitized by any of the beta-lactam’s components, the side chains are those structures that have the main contribution to immunologic recognition and therefore cause cross-reactivity among beta-lactam antibiotics. The immunologic cross-reactivity related to the common β-lactam ring (i.e., cross-reactivity between all beta-lactams) is very rare, especially in subjects with T-cell–mediated allergy. If a complete allergy workup cannot be performed and there is an urgent need to use a beta-lactam, the evaluation can be done with skin tests with beta-lactam agents that do not share identical/similar side chains with the culprit agent; in case of negative results, the alternative beta-lactam can be administered with graded challenges. In case of patients with history of mild, nonimmediate beta-lactam hypersensitivity reaction and no time available for delayed pretreatment skin test reading, the administration of a full dose of a beta-lactam structurally unrelated to the culprit is an option.
Novel approved beta-lactamase/beta-lactamase inhibitor combinations
Ceftolozane/tazobactam
Ceftolozane/tazobactam is a combination of the novel oxyimino-aminothiazolyl cephalosporin ceftolozane with the irreversible beta-lactamase inhibitor tazobactam. , It was approved in 2014 by the FDA for the indication of cUTIs and for cIAIs in combination with metronidazole, whereas EMA approval was granted in 2015 for cIAIs, acute pyelonephritis, and cUTIs. , In 2019 the EMA approved ceftolozane/tazobactam for the indication of HAP/VAP as well. ,
Mode of Action, Spectrum of Activity, and Resistance Mechanisms . Ceftolozane/tazobactam is active mostly against gram-negative pathogens, including Enterobacteriaceae and P. aeruginosa, whereas its activity against gram-positive pathogens and anaerobes is very limited. , Ceftolozane’s MIC against P. aeruginosa is 9–16 times lower than the MICs of ceftazidime, imipenem, and ciprofloxacin, having also an earlier in vitro and a faster in vivo killing than ceftazidime. Nevertheless, it is still vulnerable to the action of Ambler class A (e.g., ESBLs) and class C beta-lactamases (although the stability to AmpC enzymes varies). Although tazobactam seems to add little to the antipseudomonal activity of ceftolozane, this addition does provide ceftolozane stability against several class A and C enzymes produced by other GNBs and thus increases ceftolozane’s coverage, including several ESBL-producing strains, particularly of the CTX-M family, and in part strains producing AmpC. , Ceftolozane/tazobactam does not have appreciable activity against GNBs producing Klebsiella pneumoniae carbapenemases (KPCs) or MBLs or class D beta-lactamases (e.g., OXA-carbapenemases). , Resistance mechanisms to the action of ceftolozane/tazobactam include production of class A beta-lactamases (some of ESBLs and most of KPCs), class B MBLs, class D carbapenemases (OXA-48-like), and hyperproduction of AmpC (not in P. aeruginosa ). ,
PK/PD. Ceftolozane/tazobactam has dose-independent linear PKs and has a relatively short half-life of 2.7 hours in healthy, uninfected adults, without significant accumulation after multiple doses. The protein binding of ceftolozane/tazobactam is low (16%–21% for ceftolozane and 30% for tazobactam). It is renally cleared with minimal metabolism, and the clearance of tazobactam is not affected by the combination with ceftolozane. Both ceftolozane and tazobactam penetrated well into the lung parenchyma, with the epithelial lining fluid (ELF) to plasma area under the inhibitory curve (AUC) ratio of 48% and 44%, respectively. ,
Clinical efficacy. In a phase II RCT (NCT01147640) that compared ceftolozane/tazobactam (in combination with metronidazole) with meropenem in cIAIs, the microbiologic success was 100% against P. aeruginosa and against K. pneumoniae, and 89.5% against Escherichia coli . In a phase III RCT (NCT01345929) in patients with cUTIs, superiority was demonstrated for ceftolozane/tazobactam compared with levofloxacin, with microbiologic eradication at test-of-cure (TOC) 88.9% and 74.4%, respectively. , ASPECT-NP, a double-blind phase III RCT (NCT02070757) that compared ceftolozane/tazobactam with meropenem (3 g ceftolozane/tazobactam versus 1 g meropenem IV every 8 hours for 8–14 days) in patients with gram-negative nosocomial pneumonia (VAP or ventilated HAP) demonstrated noninferiority of ceftolozane/tazobactam on both clinical cure at TOC and mortality at day 28. It is noteworthy that based on the ELF/plasma ratio, the dose used in the ASPECT-NP trial is double the dose used for cIAIs and cUTIs. , Regarding resistance development, in the ceftolozane/tazobactam arm of a phase III RCT, no emergence of nonsusceptibility was reported for any participant with susceptible P. aeruginosa at baseline. ,
Dosage. See Table 107.1 for dosages. The recommended duration of treatment is 7 days for cUTIs, including acute pyelonephritis; 4–14 days for cIAIs; and 8–14 days for HAP/VAP.
TABLE 107.1
Recommended Adult Dosing Regimens and Dosing Alterations *
| Antimicrobial Agents | Adult Dose §§ | Dosing Alteration (Renal or Hepatic Impairment) | ||
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| B-Lactams ± | ||||
| Ampicillin/sulbactam |
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| Ticarcillin/clavulanate | 3.1 g q4–6h |
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| Piperacillin/tazobactam | 2.25–4.5 g q6h |
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| Cefazolin | 1–1.5 g q6–8h |
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| Cefotetan | 2–3 g q12h |
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| Cefoxitin | 2 g q4–6h |
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| Cefuroxime | 1.5 g q8h |
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| Ceftazidime | 1–2 g q8h |
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| Ceftriaxone | 1–2 g q24h |
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| Cefepime | 1–2 g q8–12h |
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| 1 Ceftobiprole | 500 mg q8h |
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| Ceftaroline |
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| Ceftazidime/avibactam | 2.5 (2 + 0.5) g q8h (2-h IV infusion) |
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| Ceftolozane/tazobactam |
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| Imipenem | 500 mg–1 g q6–8h |
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| Imipenem/cilastatin/relebactam | 1.25 g (0.5 + 0.5 + 0.25) q6h (30 min IV infusion) |
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| Meropenem |
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| Meropenem/vaborbactam | 4 (2 + 2) g q8h (3-hr IV infusion) |
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| Ertapenem | 1 g q24h |
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| Doripenem | 500 mg q8h |
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| Aztreonam | 1–2 g q8h |
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| Cefiderocol |
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| Aminoglycosides † | ||||
| Gentamicin and tobramycin | 1.5–2.5 mg/kg q8h or 5 mg/kg q24h once-daily dose recommended |
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| Amikacin | 7.5 mg/kg q8h or 15 mg/kg q24h once-daily dose recommended |
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| Plazomicin ≠ | 15 mg/kg q24h |
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| Fluoroquinolones | ||||
| Ciprofloxacin | 400 mg q8–12h |
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| Levofloxacin | 750 mg q24h |
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| Tetracyclines | ||||
| Tigecycline |
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| Eravacycline |
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| Omadacycline ^ |
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No dosage adjustment is warranted in patients with renal or hepatic impairment | ||
| Polymyxins | ||||
| Colistin (polymyxin E) ‡ |
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CrCl | mg CBA daily dose 4 | million IU daily dose 4 |
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| Polymyxin B ‡ |
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Unnecessary renal dose adjustments may lead to underexposure and clinical failure | ||
| Miscellaneous | ||||
| Fosfomycin |
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CBA, Colistin base activity; CMS, colistimethate (also known as colistin methanesulfonate); CRAB: carbapenem-resistant A. baumannii; CrCl, creatinine clearance; CRRT, continuous renal replacement therapy; CVVHF, continuous venovenous hemofiltration; ESRD, end-stage renal disease; h, hours; HD, hemodialysis; IHD, intermittent hemodialysis; LD, loading dose; min, minutes; q, every; SLED: sustained low-efficiency dialysis,
* Data compiled from package insert information and references included in the relevant sections of the chapter. CrCl in mL/min, calculated using the Cockcroft-Gault formula.
± Renal replacement therapy can efficiently eliminate most beta-lactam antimicrobial agents.
† For aminoglycoside dosing, adjusted body weight should be used: (0.45 × [total body weight − ideal body weight] + ideal body weight). For plazomicin, however, the dosage should be calculated using TBW; for patients with TBW greater than IBW by ≥25%, adjusted body weight should be used.
‡ For colistin, dosing should be based on adjusted body weight. For polymyxin B, the dose should be based on total body weight; PK data do not support capping an upper absolute loading dose in milligrams in obese patients, but there are limited data with administration of >200 mg per infusion.
§§ All administration is intravenous; dosing is for serious, life-threatening infections.
∞ In critically ill patients with augmented renal clearance, dose of 3 g/8 h achieved respective PD targets.
# On hemodialysis days, administer the dose at the earliest possible time after completion of dialysis; for critically ill patients undergoing CVVHF, a population PK model-guided evaluation of ceftolozane/tazobactam dosing suggested a front-loaded regimen: a single loading dose of 3 g followed by 0.75 g/8 h.
≠ Assessment of creatinine clearance before initiation and daily afterwards is recommended; for TDM, the plasma collection time is approximately 30 minutes before the second dose, targeting to maintain plasma trough concentrations <3 μg/mL.
^ Omadacycline must not be administered with any solution containing multivalent cations (e.g., calcium and magnesium) through the same intravenous line.
1 IV infusion of 2 hours; in patients with a supranormal CrCl (>150 mL/min), prolongation of the infusion duration to 4 hours is recommended.
2 IV infusion of 5–60 minutes; in patients with supranormal CrCl and standard dose, an infusion time of 60 minutes may be preferable.
3 High doses for cSSTI confirmed or suspected to be caused by S. aureus with an MIC to ceftaroline of 2 mg/L or 4 mg/L to ceftaroline; high dose to be administered as 120-minute IV infusion.
4 To achieve a desired target plasma colistin C ss,avg of 2 mg/L for patients with narrow windows of creatinine clearance; daily dose administered in two divided doses 12 hours apart; in cases of renal impairment, the loading dose and the maintenance dose should be adapted to renal function that should be monitored daily.
5 The high-dose regimen in three divided doses should be used in severe infections known or expected to be caused by less susceptible bacteria. Acute osteomyelitis and nosocomial lower respiratory tract infections: 12–24 g in two to three divided doses; cUTI: 12–16 g in two to three divided doses; Bacterial meningitis: 16–24 g in three to four divided doses. Safety data for doses >16 g/day are limited; special caution advised. Individual doses must not exceed 8 g.
Adverse events. Mild to moderate nausea, headache, constipation, diarrhea, and pyrexia were the most common (≥3%) adverse reactions in pooled phase III RCTs of cUTIs and cIAIs. There are warnings related to decreased efficacy in a subgroup of patients with baseline CrCl of 30–50 mL/min, serious anaphylactic reactions in patients with hypersensitivity to beta-lactams, and C. difficille –associated diarrhea.
Ceftazidime/avibactam
Ceftazidime/avibactam is a combination of the cephalosporin ceftazidime and the novel beta-lactamase inhibitor avibactam. It was approved by the FDA in 2015 for the indications of cUTIs, including acute pyelonephritis, and, in combination with metronidazole, cIAIs, and in 2018 it was approved for hospital-acquired bacterial pneumonia (HABP)/ventilator-associated bacterial pneumonia (VABP). ,
Mode of Action, Spectrum of Activity, and Resistance Mechanisms. Although ceftazidime is resistant to hydrolysis by several older narrow-spectrum beta-lactamases (such as TEM-1 or SHV-1) or by most of the class D carbapenemases, it is hydrolyzed by class A ESBLs and class C beta-lactamases (AmpC type) and carbapenemases, such as KPCs and MBLs. , Avibactam is a diazabicyclooctane, a first-in-class non-beta-lactam beta-lactamase reversible inhibitor without intrinsic antimicrobial activity, which binds covalently to beta-lactamases by a process that, contrary to beta-lactam beta-lactamase inhibitors, does not involve hydrolysis. , , , When avibactam is combined with ceftazidime, it protects ceftazidime from hydrolysis by class A and C beta-lactamases and increases its antimicrobial activity. , , In in vitro studies, it is active against >99.9% of meropenem-, ceftazidime- and piperacillin/tazobactam-resistant isolates of Enterobacteriaceae and P. aeruginosa, including KPC and OXA-48 producers. , Although ceftazidime/avibactam covers ESBL-producing and most KPC-producing isolates, it is inactive against MBL-producing ones. The addition of avibactam does not provide any additional activity towards the limited antimicrobial spectrum of ceftazidime against gram-positive microorganisms and anaerobes. Combinations of ceftazidime/avibactam with aztreonam, meropenem, amikacin, and fosfomycin have been reported to be synergistic in vitro against MDR K. pneumoniae and P. aeruginosa. Regarding resistance development, the main mechanism to ceftazidime/avibactam includes production of class B MBLs, hyperexpression of efflux pumps, porin alteration, increased expression of the eblaKPC gene or mutations on-loop of KPC enzymes, whereas mutations in PBPs occur rarely.
PK/PD. Ceftazidime/avibactam has linear PKs. The V d after multiple doses is 17 L and 22.2 L for ceftazidime and avibactam, respectively. The protein binding of ceftazidime/avibactam is low (<10% for ceftazidime and 5.7%–8.2% for avibactam). It is primarily renally excreted as unchanged drug (>80% of ceftazidime and >95% of avibactam). It has modest lung penetration, and in a phase I study of healthy subjects, the mean ELF/plasma ratio was 35% and 31% for avibactam and ceftazidime, respectively, and the concentration increased in a dose-dependent way.
Clinical efficacy. Ceftazidime/avibactam demonstrated noninferiority in several phase III RCTs: versus doripenem in a phase III RCT (RECAPTURE; NCT01595438) in hospitalized adult patients with cUTIs; versus the best available treatment (BAT) in patients with cUTIs or cIAIs caused by ceftazidime-resistant strains (REPRISE; NCT016 44643); combined with metronidazole versus meropenem in patients with cIAIs (NCT01726023); and versus meropenem in patients with HAP, including VAP (REPROVE; NCT01808092).
Dosage. S ee Table 107.1 for dosages. , The recommended duration of treatment is 5–14 days for IAIs and 7–14 days for cUTIs and HABP/VABP. ,
Adverse events. Ceftazidime/avibactam is generally well tolerated, usually with mild adverse events. The most frequent events were gastrointestinal disturbances, such as diarrhea and/or nausea and/or vomiting (≥5% in patients with cIAIs (combined with metronidazole) and in patients with HABP/VABP and 3% in patients with cUTIs). Other adverse events include hypokalemia, liver function test alteration, headache, and fever. Less common (<1%) adverse events include blood count alterations such as eosinophilia, thrombocytosis or thrombocytopenia, candidiasis, and seizures. There is a warning about decreased efficacy in patients with cIAIs with baseline CrCl of 30–50 mL/ min and a recommendation of at least daily monitoring of CrCl and dose adjustment accordingly. . In the phase III trial in patients with cIAIs, mortality in the subgroup with baseline CrCl 30–50 mL/min was 19.5% and 7% for the ceftazidime/avibactam plus metronidazole arm and the meropenem arm, respectively, but patients in the ceftazidime/avibactam arm received 33% lower daily doses than suggested. There are also warnings related to hypersensitivity reactions, C. difficile diarrhea, and CNS reactions, especially in patients with renal impairment.
Meropenem/vaborbactam
Meropenem/vaborbactam is a combination of the broad-spectrum carbapenem meropenem and the novel cyclic boronic acid–based beta-lactamase inhibitor vaborbactam. Approval was granted by the FDA in 2017 for the indication of cUTIs. In 2018 the EMA granted marketing authorization for meropenem/vaborbactam for the indications of cUTIs, including pyelonephritis, cIAIs, HAP (including VAP), bacteremia associated or suspected to be associated with any of the previously mentioned indications, and infections caused by aerobic GNBs with limited treatment options. ,
Mode of Action, Spectrum of Activity, and Mechanisms of Resistance. Meropenem covers a wide range of gram-positive, gram-negative, and anaerobic bacteria and is stable to hydrolysis by penicillinases and cephalosporinases. Nevertheless, it is vulnerable to hydrolysis by other beta-lactamases, such as serine beta-lactamases and MBLs. Vaborbactam exerts potent inhibition of serine beta-lactamases of class A (including ESBLs and KPCs) and class C (including AmpC) by forming reversible covalent bonds with them, and although it does not have intrinsic antimicrobial activity, when combined with meropenem, it provides protection to meropenem against degradation by these enzymes. , , Vaborbactam does not inhibit class B (MBL)– and class D (OXA)-beta-lactamase–producing strains. , , , Therefore the spectrum of activity of meropenem/vaborbactam is that of meropenem, supplemented with activity against several serine beta-lactamase–producing strains. , , Combined with vaborbactam, a decrease of meropenem’s MIC against most Enterobacteriaceae ranging from 2- to >1024-fold, in addition to activity close to 100% against KPC-positive Enterobacteriaceae isolates, have been reported. , Vaborbactam does not increase the activity of meropenem against strains of P. aeruginosa with MDR phenotypes mediated by porin changes and/or efflux mechanism changes or against A. baumannii strains producing primarily class D (OXA-type) beta-lactamases. , Also, resistance to meropenem/vaborbactam has been reported in S. maltophilia, Elizabethkingia, and Aeromonas. , It should be noted that vaborbactam does not enhance meropenem’s activity against gram-positive bacteria and anaerobes. ,
The main mechanisms of resistance to meropenem/vaborbactam include class B MBLs, class D carbapenemases (OXA-48-like), porin alterations (e.g., loss of outer membrane porins OmpK36 and 35 used by vaborbactam to penetrate the bacterial cell, decreased expression of other porins), and hyperexpression of efflux pumps. , In summary, meropenem/vaborbactam is active against most Enterobacteriaceae, particularly KPC-producing strains, in addition to ESBL- and AmpC-producing ones, but is inactive against MBL- and class D–producing strains, whereas for P. aeruginosa it has similar activity as meropenem.
PK/PD. The V d of meropenem/vaborbactam at steady state is 20.2. L and 18.6 L, the protein binding is 2% and 33%, and the half-life is 1.22 and 1.68 hours for meropenem and vaborbactam, respectively. , Meropenem/vaborbactam is primarily renally excreted. , Meropenem has a minor pathway of metabolism by hydrolysis (22%), whereas vaborbactam is not metabolized, but excreted unchanged in the urine. , The lung disposition profile is favorable , with ELF-to-plasma unbound concentration ratios of 65% for meropenem and 79% for vaborbactam in healthy subjects. ,
Clinical efficacy. Meropenem had similar efficacy to piperacillin/tazobactam (clinical success and microbiologic eradication) in a phase III RCT (TANGO I study; NCT02166476) in patients with cUTIs. In another open-label, phase III RCT (TANGO II study; NCT02168946) in patients with cUTIs, IAIs, HABP/VABP, or bacteremia caused by CRE, meropenem/vaborbactam achieved increased clinical cure rate and decreased 28-day all-cause mortality versus BAT, along with decreased nephrotoxicity.
Dosage. See Table 107.1 for dosages. , The recommended duration of treatment is up to 14 days: 5–10 days for cUTIs and IAIs, 7–14 days for HAP/VAP, and duration according to the site of infection for bacteremia and MDR GNB infections with limited treatment options. ,
Adverse events. Meropenem/vaborbactam has a favorable safety profile, similar to comparators. In the phase III TANGO II clinical trial, the most common (≥3%) adverse events reported for meropenem/vaborbactam included headache, phlebitis, and diarrhea, and other adverse events occurring ≥1% included hypersensitivity, nausea, increases of alanine and aspartate aminotransferases, pyrexia, and hypokalemia. , , There are warnings related to hypersensitivity reactions, seizures, and other CNS reactions; C. difficile –associated diarrhea; and decreased levels of valproic acid when coadministered with meropenem.
Imipenem/cilastatin/relebactam
Imipenem/cilastatin/relebactam is a novel triple antimicrobial agent that combines the carbapenem imipenem, the dehydropeptidase inhibitor cilastatin, and the novel beta-lactamase inhibitor relebactam. It was approved by the FDA in 2019 for the cUTIs, including pyelonephritis, and cIAIs caused by susceptible GNBs when there are limited or no alternative options; in 2020 it was approved for HABP/VABP as well. , EMA approval was granted in 2020 for the indications of HAP (including VAP), bacteremia with to (or suspected to be associated with) HAP/VAP, and infections caused by gram-negative microorganisms with limited treatment options. ,
Mode of Action, Spectrum of Activity, and Resistance Mechanisms . Imipenem/cilastatin/relebactam covers Enterobacteriaceae and lactose nonfermenting GNBs. Relebactam, which is structurally related to avibactam, inhibits class A and C beta-lactamases and enhances the antimicrobial spectrum of imipenem/cilastatin, increasing the activity of imipenem against most Enterobacteriaceae and P. aeruginosa, as shown by a 2- to 128-fold and 8-fold decrease of MIC, respectively. Imipenem/cilastatin/relebactam is active against E. coli (including ESBL- and KPC-producing isolates), K. pneumoniae (including ESBL, KPC, AmpC, and imipenem-resistant K. pneumoniae expressing AmpC beta-lactamases or KPC carbapenemases), and P. aeruginosa isolates with AmpC expression or outer membrane protein D (OprD) deficiency. , , Nevertheless, it is inactive against A. baumannii; imipenem-resistant isolates of Enterobacteriaceae producing IMPs, VIMs, or New Delhi metallo-beta-lactamase (NDM) MBLs; and P. aeruginosa producing IMP or VIM MBLs. Moreover, although there is a theoretical background for activity against OXA-producing isolates, the reported data are variable, and a quite recent surveillance study failed to demonstrate such activity. It has similar gram-positive activity as imipenem/cilastatin. The main mechanisms of resistance to imipenem/cilastatin/relebactam include production of class B MBLs, class D carbapenemases (OXA-48-like), specific class A carbapenemases (such as GES), hyperexpression of KPC, and porin alterations. In summary, imipenem/cilastatin/relebactam can be used for various resistant Enterobacteriaceae (such as ESBL-, KPC-, and AmpC-producing ones), excluding MBL- and class D–producing strains, and for carbapenem-resistant P. aeruginosa, as relebactam reinstates imipenem’s activity in 80% of imipenem-resistant P. aeruginosa strains.
PK/PD. The best PD predictor of activity of relebactam in animal and in vitro models is f AUC 0–24hr /MIC. The half-life of relebactam is approximately 1.2 hours. The steady-state V d of imipenem/cilastatin/relebactam is 24.3 L, 13.8 L, and 19 L, respectively, and the protein binding is 20%, 40%, and 22%, respectively, and independent of concentration. Imipenem/cilastatin/relebactam is mainly renally excreted by glomerular filtration and active tubular secretion. Relebactam has minimal metabolism, and >90% is excreted unchanged in the urine, whereas the percentage of imipenem and cilastatin that is excreted unchanged is 63% and 77%, respectively. Relebactam and imipenem have similar penetration to ELF, with exposure relative to plasma 55%.
Clinical efficacy. The FDA granted approval to imipenem/cilastatin/relebactam based on the results of two phase II RCTs that compared it with imipenem/cilastatin in patients with cIAIs (NCT01506271) and cUTIs (NCT01505634). Imipenem/cilastatin/relebactam also demonstrated noninferiority compared with piperacillin/tazobactam in a phase III RCT (RESTORE IMI-2; NCT02493764) conducted in bacterial HAP and VAP. In another phase III RCT (RESTORE IMI-1 study; NCT02452047) that included only infections by imipenem-nonsusceptible but colistin- and imipenem/cilastatin/relebactam-susceptible pathogens (HAP/VAP, cUTIs, cIAIs), imipenem/cilastatin/relebactam monotherapy had similar efficacy to an imipenem/cilastatin and colistin combination.
Dosage. For dosages, see Table 107.1 . The FDA recommends a duration of treatment ranging from 4 to 14 days depending on the severity and location of the infection and clinical response, whereas the EMA recommends 7–14 days for HAP/VAP. ,
Adverse events . Treatment-related adverse events in the RESTORE IMI-2 trial were 11.7% and 9.7% for imipenem/cilastatin/relebactam and piperacillin/tazobactam, respectively. In RESTORE IMI-1, the serious adverse events of the imipenem/cilastatin/relebactam arm were 16% compared with 31% of the imipenem/cilastatin plus colistin arm, and the nephrotoxicity was 10% and 56%, respectively. The most common (≥2%) adverse events of imipenem/cilastatin/relebactam include gastrointestinal disturbances (diarrhea, nausea, vomiting), increases of alanine and aspartate aminotransferases, infusion site reactions/phlebitis, pyrexia, and hypertension. Other adverse events include blood and lymphatic system disorders (agranulocytosis, increased eosinophils, hemolytic anemia, seizures, hepatobiliary disorders including jaundice and liver failure, rash, increased lactate dehydrogenase, and positive Coombs test). There are warnings regarding hypersensitivity, seizures, and CNS adverse reactions; avoidance of concomitant use with valproic acid because of the risk of decreased serum concentrations of valproic acid and breakthrough seizures; and C. difficile diarrhea. Concomitant use of imipenem/cilastatin/relebactam with ganciclovir should be avoided (unless the expected benefit outweighs the risk), as there are reports of cases of generalized seizures when used with imipenem/cilastatin.
Novel siderophore cephalosporins
Cefiderocol is the first siderophore cephalosporin, and in 2019, was granted approval by the FDA for the treatment of adults with cUTIs, and in 2020 it was approved also for the treatment of bacterial HAP and VAP caused by susceptible GNBs: A. baumannii complex, E. coli , Enterobacter cloacae complex, K. pneumoniae , P. aeruginosa, and Serratia marcescens. , The EMA approved cefiderocol in 2020. ,
Mode of Action, Spectrum of Activity, and Resistance Mechanisms . Cefiderocol has a unique structure, that is, combination of a catechol-type siderophore with a cephalosporin core that has similar side chains to cefepime and ceftazidime, which enhances its stability against many beta-lactamases, such as ESBLs and carbapenemases. Cefiderocol chelates with ferric ion and, apart from entering the gram-negative bacteria by passive diffusion via membrane porins like the other beta-lactams, it uses their iron uptake system to penetrate the siderophore-iron complex pathway, bypassing their outer membrane barriers. Its unique mode of action enables cefiderocol to overcome resistance by decreased porin expression. Moreover, the chelation with iron provides cefiderocol resistance to hydrolysis by all beta-lactamases (Ambler class B included). , As soon as it is within the periplasmic space, cefiderocol dissociates from iron and binds to PBPs, particularly PBP3, inhibiting peptidoglycan synthesis like the other beta-lactams.
Cefiderocol is active against a wide range of gram-negative bacteria, including both lactose-fermenting, such as E. coli , Klebsiella spp., Enterobacter spp., Proteus spp., Providencia spp., Salmonella spp., Yersinia spp., and Vibrio spp., and nonfermenting GNBs, such as Acinetobacter spp., Pseudomonas spp., Burkholderia spp., and S. maltophilia . Cefiderocol is stable against many beta-lactamases, such as ESBLs (e.g., CTX-M) and carbapenemases (e.g., Ambler class B metallo-beta-lactamases [NDM, VIM, IMP] and serine-type beta-lactamases [OXA-23, OXA-48-like, OXA-51-like, OXA-58]). However, cefiderocol has weak in vitro activity against aerobic gram-positive bacteria and anaerobic bacteria, demonstrating high MICs. , Reduced susceptibility to cefiderocol may occur via the mutation or differential expression of specific iron-transporters.
PK/PD. The PD target best associated with the efficacy of cefiderocol is similar to the other cephalosporins. Cefiderocol appears to display linear pharmacokinetics, its V d is 18 L, it has an elimination half-life of 2.72 hours, the protein binding (mainly albumin) is 40%–60%, and it is primarily renally excreted unchanged. Cefiderocol appears to distribute fast and in parallel from plasma to ELF, with lung penetration of approximately 24%, whereas the penetration to alveolar macrophage seems to be much lower; further studies in critically ill patients are needed. ,
Clinical efficacy. In an open-label phase III RCT (CREDIBLE-CR study; NCT02714595) conducted in critically ill patients with infections caused by carbapenem-resistant GNBs (sepsis/bloodstream infection, cUTI, healthcare–associated pneumonia [HCAP]/HAP/VAP), cefiderocol was compared with BAT. Patients in the cefiderocol arm received monotherapy, whereas the BAT arm mostly received combination therapy (more frequently, colistin-based regimens). In the CR-mITT population, clinical cure rates at TOC were comparable between arms overall and for each individual disease state, but all-cause mortality at day 14, day 28, and day 49 was numerically higher in the cefiderocol arm, particularly in patients with HCAP/HAP/VAP and bloodstream infections/sepsis. The greater mortality imbalance was at day 49 in patients with A. baumannii. In another phase III RCT (APEKS-NP study; NCT03032380) cefiderocol was compared with meropenem (both combined with linezolid for at least 5 days) in patients with HAP, VAP, or HCAP and demonstrated noninferiority with respect to mortality. , A phase II RCT that compared cefiderocol with BAT in patients with bloodstream infections is still ongoing.
Dosage. For dosages, see Table 107.1 . The recommended duration is 7–14 days.
Adverse events. Based on data of the clinical trials, cefiderocol appears to be well tolerated and with a similar safety profile as other cephalosporins. In the CREDIBLE-CR trial the reported treatment-related adverse events were 14.9% in the cefiderocol arm versus 22.4% in the BAT arm; the most common adverse events for cefiderocol, with incidence ≥10%, were diarrhea, increased transaminases, pleural effusion, and chest pain. It should be noted that cefiderocol has a labeled warning for an increase in all-cause mortality that was observed in patients treated with cefiderocol compared with BAT in the CREDIBLE-CR trial; the increased mortality occurred in patients with nosocomial pneumonia, bloodstream infections, or sepsis. ,
Fluoroquinolones
Fluoroquinolones were discovered in the early 1960s and are antimicrobial agents with a broad spectrum of activity. The most commonly used members of the class are ciprofloxacin, levofloxacin, and moxifloxacin, and recently the use of a new fluoroquinolone, delafloxacin, was approved.
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