Antimicrobials Used to Treat Pneumonia

In community-acquired pneumonia (CAP), despite careful prospective studies, the etiologic agent is not found in 30% to 50% of cases. Moreover, the prevalence of polymicrobial infections – superinfection or coinfection, often by atypical pathogens – remains difficult to ascertain. Most studies indicate that S pneumoniae is still the most relevant pathogen and the atypical pathogens, including M pneumoniae,
C pneumoniae and Legionella spp, are also important, especially in the outpatient setting. This may reflect improved methods of detecting atypical pathogens. The most common pathogens among patients <65 years of age and without comorbid illnesses are:

• M pneumoniae
• S pneumoniae
• Respiratory tract viruses
• C pneumoniae.

More than one third of all pneumococcal isolates in the United States express intermediate resistance MICs of 0.12–1 mcg/mL) or high-level resistance (MICs of ≥2 mcg/mL) to penicillin. Over 25% of clinical isolates of H influenzae produce β-lactamase and between 25% and 33% of isolates are resistant to trimethoprim/sulfamethoxazole (TMP/SMX) in the United States. The same occurs in almost 100% of
M catarrhalis strains. Globally, there is wide variation in resistance rates among different pathogens. Further, there exists a disparity between rates of in vitro resistance and actual clinical failure. Nonetheless, there may be utility in consulting the local antibiogram to understand resistance patterns in a particular geographic area. Six international clones (serotypes 6A, 6B, 9V, 14, 19F, 23F) are responsible for most of the resistant isolates of S pneumoniae. The most common pathogens in patients who are >65 years of age with comorbid illnesses are:

• S pneumoniae
• Respiratory tract viruses
• H influenzae
• C pneumoniae
• Aerobic gram-negative bacilli
• S aureus.

Less common pathogens include M catarrhalis, Legionella spp, Mycobacterium tuberculosis (MTB), mycobacteria (MAI) and endemic fungi.

Among patients with hospital-acquired pneumonia (HAP), aerobic gram-negative bacilli, including Enterobacteriaceae, account for 60% to 80% of bacteria isolated, and aerobic gram-positive cocci, especially S aureus, for a further 20% to 30%. Other agents that are occasionally identified include
L pneumophila, viruses and fungi.

A large number of antimicrobials are available to treat pneumonia (Table 5-1). Although there is considerable overlap, different drugs and combinations are often used for CAP and HAP. The aminoglycosides, vancomycin, clindamycin and plazomicin all have limited and specific roles in the treatment of selected pathogens. The β-lactams (with or without β-lactamase inhibitors), cephalosporins, macrolides, fluoroquinolones and carbapenems are used as both empiric and organism-directed therapy.

β-Lactams

Penicillins

The basic structure of penicillin, 6-aminopeni­cillanic acid, is a combination of alanine and β-dimethylcysteine to form a penam nucleus. The β-lactam ring is essential for antimicrobial activity and side-chain modifications determine potency, spectrum and pharmacokinetics. Penicillins must penetrate the outer structure of the bacterial cell wall and bind to penicillin-binding proteins (PBPs). By binding to these proteins, penicillins cause termination of peptide-chain linkage and inhibit the formation of the normal peptidoglycan structure. The ability of individual drugs to penetrate the cell wall and the degree of affinity to the various penicillin-binding proteins (PBPs) determine the activity of the antibiotic. Resistance to the penicillins is related to:

• Alteration of the antibiotic target sites (PBPs)
• Inactivation of the drug by enzymes produced by the bacteria (β-lactamases)
• Reduction of drug permeability into the cell.

Of the three mechanisms, production of β-lactamases that cleave the β-lactam ring is the most common and clinically relevant among H influenzae and M catarrhalis. Alteration of PBPs accounts for reduced penicillin susceptibility. Among the various β-lactamases, the ampicillin and amoxicillin hydrolyzing TEM-1 and TEM-2 are the most commonly seen enzymes in H influenzae. In order to counteract the problem of resistance, a penicillin is often combined with a β-lactamase inhibitor. These inhibitors bind irreversibly to and inactivate the β-lactamase and possibly potentiate the activity of the β-lactam antibiotic by binding to the PBPs. The best studied of the inhibitors is clavulanic acid, which inhibits most of the important plasmid-mediated β-lactamases.

Penicillin is adequate therapy for most cases of pneumococcal pneumonia. However, the emergence of resistance and its short half-life have markedly limited the use of penicillin G in the treatment of pneumonia. While most clinicians are uncomfortable using penicillin to treat any strain that is not fully sensitive, failures in the treatment of pneumococcal pneumonia are rarely, if ever, seen with intermediately resistant strains. Nevertheless, the growing prevalence of resistance and the narrow spectrum of penicillin have markedly limited its use. In addition, its short half-life has made IV administration inconvenient. Penicillin must be given every 4 hours by the IV route or every 12 hours intramuscularly. Even if appropriate therapy is initiated early, treatment failure occurs in up to 10% to 15% of cases.

Aminopenicillins

The aminopenicillins are formed by the addition of an amino group to the basic structure of benzyl-penicillin. Esters, condensates and analogues have essentially the same activity as the parent compound. Combining amoxicillin with clavulanic acid stabilizes the activity of the aminopenicillin against β-lactamase-producing strains of H influenzae and M catarrhalis but does not change its activity against S pneumoniae. Ampicillin is incompletely absorbed (30%) following oral administration and reaches a peak serum concentration of 2 to 6 mg/L 2 hours after a single 500-mg dose. Amoxicillin is 90% absorbed after oral administration and a 500-mg dose produces peak serum concentrations of about 10 mg/L within 1 hour.

Approximately 75% of the drug is excreted renally, and there is 17% to 20% protein binding. Minimal dosing adjustments are required in the presence of renal failure. Amoxicillin/clavulanic acid is well absorbed from the GI tract. It has excellent penetration into most extravascular fluids and tissues, including lung and pleura. With the emergence of widespread resistance, amoxicillin has been relegated to second-line status for the treatment of severe infections. In respiratory tract infections, the increasing resistance of H influenzae to ampicillin and the recognition of M catarrhalis as an important pathogen (which, most of the time, is ampicillin-resistant) have led to the declining use of this agent. Amoxicillin/clavulanic acid is particularly useful when infections are due to β-lactamase-producing strains of H influenzae and M catarrhalis. Amoxicillin/clavulanic acid is available in 250-mg, 500-mg and 875-mg tablets, all of which contain 125-mg clavulanic acid. The usual dose is 500 mg three times a day or 750 mg amoxicillin/125 mg clavulanate twice daily. A higher dose containing 1,000 mg amoxicillin and 125 mg clavulanate is available to treat penicillin-resistant pneumococci (PRP).

The parenteral equivalents of amoxicillin/clavulanic acid are broad-spectrum compounds with activity against a number of gram-negative rods and with some activity against P aeruginosa (ticarcillin/clavulanic acid [Timentin], piperacillin/tazobactam [Zosyn]). The addition of the β-lactamase inhibitor improves the activity against S aureus, E coli, K pneumoniae, Bacteroides spp, H influenzae and M catarrhalis, but not against Pseudomonas, Enterobacter, Serratia, and Citrobacter spp. The appearance of chromosomally mediated β-lactamases that are not neutralized by these inhibitors, particularly among Enterobacter spp, has limited their use, especially in severe HAP. Side effects of these drugs include diarrhea, hypokalemia and minor antiplatelet activity. Ticarcillin and piperacillin are sodium salts and may precipitate heart failure in susceptible individuals. While ticarcillin and piperacillin have antipseudo­monal activity, the addition of the β-lactamase inhibitor does not change this activity. These drugs are not sufficient as monotherapy for proven Pseudomonas infection and an aminoglycoside or antipseudomonal fluoroquinolone (e.g., ciprofloxacin or levofloxacin) should be added in these cases.

Piperacillin/Tazobactam

Piperacillin/tazobactam is a β-lactam/β-lactamase inhibitor combination in a ratio of 8:1 with a broad spectrum of antibacterial activity covering most gram-positive and gram-negative aerobic bacteria and anaerobic bacteria, including many pathogens producing β-lactamases. It has good in vitro activity against methicillin-sensitive S aureus (MSSA), Streptococcus pyogenes and penicillin-sensitive strains of S pneumoniae. Most Enterobacteriaceae, including E coli, Klebsiella spp and Enterobacter spp, are susceptible and the respiratory pathogens H influenzae and M catarrhalis are exquisitely sensitive. Most strains of P aeruginosa are susceptible, as are most anaerobes, including Bacteroides fragilis and Clostridium spp.

In healthy volunteers, a single dose of 4.0/0.5 g of piperacillin/tazobactam leads to maximum serum concentrations (C_maxs) of piperacillin and tazobactam of 264.4 to 368 and 29.1 to 39 mg/L, respectively. Each component has a plasma elimination half-life (T_1/2) of 0.8 to 1 hour. About 50% to 60% of the administered dose is excreted renally. With moderate renal impairment, the dose has to be reduced. The recommended dose varies from 2/0.25 g every 6 to 12 hours for the treatment of mild infections to 4/0.5 g every 6 to 8 hours for more severe infections.

At a 6-hourly dosage of 3/0.75 g, piperacillin/tazobactam was more effective than ticarcillin/clavulanic acid 3/0.1 g qid in elderly patients with CAP. In patients with HAP, piperacillin/tazobactam 4/0.5 g qid plus amikacin 7.5 mg/kg twice daily was at least as effective as ceftazidime
1 g qid plus amikacin 7.5 mg/kg twice daily. In a similar group of patients, piperacillin/tazobactam 4/0.5 g qid was as effective as imipenem/cilastatin 0.5 g qid. Piperacillin/tazobactam is generally well tolerated, with diarrhea being the most common adverse event.

Ampicillin/Sulbactam

Ampicillin/sulbactam is a β-lactam/β-lactamase inhibitor combination that is a less potent β-lactamase inducer than cephalosporins, a feature that may help prevent the emergence of bacterial resistance. S pneumoniae, H influenzae and M catarrhalis are very susceptible to ampicillin/sulbactam. Many members of the Enterobacteriaceae family (e.g., K pneumoniae, Citrobacter spp, and Proteus spp), are susceptible, although ampicillin/sulbactam is less active compared with carbapenems, third- or fourth-generation cephalosporins, aminoglycosides and piperacillin/tazobactam. Morganella, Enterobacter and Serratia tend to be more resistant. Ampicillin/sulbactam is not active against P aeruginosa and Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBLs). Ampicillin/sulbactam may be an effective therapeutic option to treat severe nosocomial infections caused by MDR Acinetobacter baumannii. The active agent against A baumannii in the ampicillin/sulbactam combination is sulbactam.

Sulbactam is synergistic with ampicillin by inhibiting the hydrolysis of ampicillin by β-lactamases. As a result, the antimicrobial activity of the combination increases by 4- to 32-fold. Ampicillin/sulbactam is not well absorbed after oral administration and must be given parenterally. When the drugs are given in a dose of ampicillin 2 g and sulbactam 1 g, the C_max of ampicillin is ~80 mcg/mL and for sulbactam is ~40 g/mL. The half-life for both drugs is 1 hour. With this compound being mainly renally excreted, the T_1/2 and serum concentrations are increased in patients with renal impairment.

It is comparable to second- and third-generation cephalosporins in the treatment of lower respiratory tract infections, such as bronchitis, acute exacerbation of chronic bronchitis (AECB) and pneumonia. It has been proved comparable to clindamycin and imipenem/cilastatin in aspiration pneumonia. The drug has been recommended as a potential choice in combination with a macrolide or fluoroquinolone in the management of hospitalized patients with CAP.

Sulbactam/Durlobactam

Sulbactam/durlobactam is a combination of sulbactam (see above) and durlobactam, a non-β-lactam β-lactamase inhibitor. It received Food and Drug Administration (FDA) approval in 2023 for the treatment of adult patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) caused by bacteria of the Acinetobacter baumannii-calcoaceticus (ABC) complex. In this combination, sulbactam is bactericidal against ABC via inhibition of penicillin-binding protein (PBP) PBP1 and PBP3, while durlobactam protects sulbactam from degradation by certain serine-β-lactamases, including Ambler Class A (CTX-M-, TEM-, PER- and SHV-type extended spectrum b-lactamase (ESBLs) and KPC carbapenemase), Class C (ADC-type), and Class D (OXA-type) enzymes. It is not intended for use against bacteria other than the ABC complex.

At steady state in patients without renal impairment, the maximum serum concentration (C_max) of sulbactam and durlobactam are 32.4 mg/L and 29.2 mg/L, respectively. The major route of elimination is renal, with an elimination half-life of 11.6 hours for sulbactam and 9.96 hours for durlobactam.

The efficacy of sulbactam/durlobactam was assessed in a clinical trial of 177 adults hospitalized with HAP/VAP caused by ABC complex pathogens. In this noninferiority trial, sulbactam/durlobactam was compared to colistin; the primary efficacy endpoint was all-cause mortality at day 28. Sulbactam/durlobactam demonstrated noninferiority to colistin, with a 28-day mortality of 19.0%, compared to 32.3% with colistin.

The recommended dose of sulbactam/durlobactam is 2 g (sulbactam 1 g and durlobactam 1 g) administered by IV infusion over 3 hours. The frequency of administration depends on the patient’s renal function, as presented below:

• Estimated creatinine clearance (CrCl) ≥130 mL/min: every 4 hours
• Estimated CrCl 45-129 mL/min: every 6 hours
• Estimated CrCl 30-44 mL/min: every 8 hours
• Estimated CrCl 15-29 mL/min: every 12 hours
• Estimated CrCl ≤5 mL/min: Every 12 hours for the first 3 doses, followed by every 24 hours after the third dose; if the estimated CrCl drops to ≤5 mL in patients during the course of treatment, switch to once every 24 hour schedule.

The most common adverse reactions observed in the noninferiority trial of sulbactam/durlobactam were liver test abnormalities, diarrhea, anemia, hypokalemia, arrhythmia, acute kidney injury, thrombocytopenia and constipation.

Cephalosporins

Cephalosporins are a class of β-lactam antibiotics. They are usually classified into five generations:

• First-generation cephalosporins have excellent activity against gram-positive organisms, including pneumococci and staphylococci. Their role in empiric therapy is limited but may be used for organism-specific therapy.
• Second-generation cephalosporins demonstrate improved gram-negative coverage, particularly against H influenzae.
• Third-generation cephalosporins have a more extensive gram-negative coverage but are weaker against the gram-positives, especially S aureus.
• Fourth-generation cephalosporins have extensive gram-negative and gram-positive coverage. These agents are commonly used in the treatment of immunocompromised patients susceptible to gram-negative infections and in very sick patients, typically nursing-home residents, with CAP.
• Fifth-generation cephalosporins are active against methicillin-resistant staphylococci and penicillin-resistant pneumococci.

None of these compounds has any significant activity against atypical pathogens. Since C pneumoniae and Legionella are intracellular pathogens and β-lactamase antibiotics do not penetrate into cells, this outcome is predictable.

The development of effective oral cephalosporins has been limited by the hydrophilic nature of these compounds. Several oral cephalosporin derivatives have been developed that have an amino­thiazolyl-methoxyimino side chain added to the cephem nucleus, resulting in greater activity against gram-negative organisms. These are generally divided into two groups. The prodrug esters include cefuroxime axetil, cefetamet pivoxil and cefpodoxime proxetil, the side chains of which are hydrolyzed by esterases in the gut wall, releasing the active compound into the portal blood. Ceftibuten is a third-generation agent that is absorbed intact. Loracarbef and cefprozil are two other oral cephalosporin derivatives. The minimum concentration at which 90% of pathogens are inhibited (MIC₉₀) values for all discussed cephalosporins are displayed in Table 5-2. Pharmacokinetic properties are summarized in Table 5-3.

Cefuroxime Axetil

Cefuroxime axetil is a prodrug oral formulation of the injectable cefuroxime sodium. The 1-(acetyloxy) ethyl ester of cefuroxime undergoes complete hydrolysis during absorption to free cefuroxime, which is the active antimicrobial. It is considerably more active than cefaclor against S pneumoniae (MIC₉₀ 0.25 mg/L vs 4 mg/L), H influenzae (including β-lactamase-producing strains [MIC₉₀ 0.25 mg/L vs 4 mg/L]), and M catarrhalis (MIC₉₀ 0.25 mg/L vs 2 mg/L). Following a 500-mg oral dose, peak concentrations averaging 4.9 mg/L are observed within 2.3 hours. The T_1/2 ranges from 0.8 to 2 hours, similar to that of the injectable product. The oral bioavailability ranges from 30% to 45%, and it may be higher if the drug is given with food.

The major adverse event is gastrointestinal (GI) related, with most studies reporting diarrhea in 3% to 5% of patients. Nausea, vomiting and heartburn have occurred in <4% of patients. As with other cephalosporins, antibiotic-induced colitis has been reported with this agent. The usual dosage is 250 mg twice daily, but it may be increased to 500 mg twice daily for serious infections.

In patients with lower respiratory tract infections, cefuroxime axetil 250 or 500 mg every 12 hours has clinical and bacteriologic cure rates similar to those of cefaclor given in a dosage of 500 mg every 8 hours. Cefuroxime axetil has good activity against all major respiratory pathogens except for the atypical organisms such as C pneumoniae, M pneumoniae, or Legionella spp. It maintains a high degree of activity against β-lactamase-producing H influenzae and M catarrhalis. It appears to be clinically comparable to cefaclor and amoxicillin/clavulanic acid, and the relatively long half-life allows twice-daily dosing.

Cefetamet Pivoxil

Cefetamet pivoxil is an oral third-generation cephalosporin. It is the pivaloyloxymethylester of the semisynthetic third-generation aminothiazolyl cephalosporin, cefetamet. Cefetamet pivoxil has excellent in vitro activity against:

• S pneumoniae
• H influenzae
• M catarrhalis
• S pyogenes.

It is active against β-lactamase-producing strains of H influenzae and M catarrhalis. It has poor activity against penicillin-resistant S pneumoniae (PRSP), as well as staphylococci and Pseudomonas spp. The oral bioavailability of cefetamet pivoxil is about 50% after food; drug administration is recommended within 1 hour of a meal. The mean peak plasma concentration of 4 mg/L is attained 4 hours after a single 500-mg dose of cefetamet pivoxil; the plasma T_1/2 is 2.2 to 2.6 hours. Cefetamet is cleared predominantly by the kidneys, and dosage adjustment is needed in patients with renal impairment.

The recommended dosage is 500 mg twice daily, and in children under 12 years of age, it is 10 mg/kg twice daily. A dosage of 1,000 mg twice daily is recommended for use against less-sensitive isolates. Cefetamet pivoxil is an effective alternative oral therapy for outpatient treatment of community-acquired respiratory tract infections, especially when there is concern about β-lactamase resistance. Like other cephalosporins, it is not active against the atypical organisms.

Cefpodoxime Proxetil

Cefpodoxime proxetil is an orally administered prodrug that is absorbed and de-esterified to release the third-generation cephalosporin cefpodoxime. Cefpodoxime is highly active against both H influenzae and M catarrhalis, including β-lactamase-producing strains. It is also active against S pyogenes and S pneumoniae, while penicillin-resistant strains of S pneumoniae are moderately susceptible to cefpodoxime. Most strains of Staphylococcus epidermidis and S aureus are moderately susceptible to cefpodoxime, although the drug is inactive against methicillin-resistant strains of S aureus. P aeruginosa is resistant to cefpodoxime.

The active metabolite, cefpodoxime, has approximately 50% systemic availability. Bioavailability is significantly increased by food, whereas it is significantly reduced by agents that elevate gastric pH. Peak plasma concentrations of 2.1 to 3.1 mg/L are achieved 2 to 3 hours after single-dose administration of 200 mg, and plasma half-life is 2.1 to 3.6 hours. The drug is eliminated primarily by renal excretion. Cefpodoxime demonstrates a potent inhibitory activity against common respiratory pathogens (including β-lactamase-producing strains) and has the advantage of moderate activity against penicillin-resistant strains of S pneumoniae. It provides effective step-down therapy from parenterally administered third-generation cephalosporins in the treatment of serious respiratory infections.

Ceftibuten

Ceftibuten is an orally active third-generation cephalosporin. Ceftibuten has excellent in vitro activity against several major respiratory pathogens, including:

• β-Lactamase-positive strains of H influenzae and M catarrhalis
• S pyogenes
• Most strains of Enterobacteriaceae.

Ceftibuten has borderline activity against penicillin-sensitive strains of S pneumoniae (MIC₉₀ 4 to 8 mg/L). It is inactive against penicillin-resistant strains of S pneumoniae and against staphylococci, Pseudomonas, enterococci and Listeria spp. The bioavailability of ceftibuten following oral administration is excellent, ranging between 75% and 90%. Peak plasma concentrations of 10 to 12 mg/L are reached approximately 1.8 hours after administration of ceftibuten 200 mg. The rate and/or extent of absorption of ceftibuten is decreased when administered in doses >400 mg and when administered with food. The mean T_1/2 of ceftibuten is approximately 2.7 hours in healthy persons and is prolonged to 13.4 hours in patients with severe renal impairment.

Ceftibuten 400 mg once daily is the recommended dosage. Despite its rather poor activity against S pneumoniae, the results of clinical trials are encouraging. Presumably, the excellent pharmacokinetics (high bioavailability, high blood levels, prolonged half-life) compensate for the reduced microbiologic activity.

Loracarbef

The carbacephems are a synthetic class of β-lactam antibiotics that are structurally similar to cephalosporins but with enhanced chemical stability. Loracarbef is the first available drug of this class. In vitro, loracarbef shows good activity against:

• S pneumoniae
• S pyogenes
• S aureus
• M catarrhalis
• H influenzae, including β-lactamase-producing strains.

Like many other β-lactams, an increase in the inoculum size from 10⁴ to 10⁷ increases the MIC of loracarbef for β-lactamase-resistant strains of bacteria (inoculum effect). Methicillin-resistant staphylococci and many Enterobacteriaceae are resistant to loracarbef. After oral administration of a 400-mg capsule, a peak plasma concentration of 12 mg/L is obtained in 1.1 to 1.3 hours and is minimally affected by food. The T_1/2 of loracarbef is 1.1 hours, and excretion is primarily by the renal route.

Adjustment in dosage should be made in moderate to severe renal impairment. For loracarbef, 200 or 400 mg twice daily is the recommended dosage. It is not the best choice in severely ill patients or in cases where there is a strong suspicion of gram-negative pathogens.

Cefprozil

Cefprozil is an orally active second-generation cephalosporin. Its structure differs from that of other cephalosporins by the addition of a 1-propenyl substituent group at C-3 and a p-hydroxy-phenyl moiety at C-7. The antibacterial spectrum of cefprozil is similar to that of cefaclor, another second-generation cephalosporin. Major respiratory pathogens that are inhibited by cefprozil include:

• S pyogenes
• S pneumoniae
• S aureus
• H influenzae
• M catarrhalis.

Against β-lactamase-producing strains of H influenzae and penicillin-resistant strains of S pneumoniae, this drug is generally more active than cefaclor and cephalexin. Enterobacteriaceae are moderately susceptible to cefprozil. Peak plasma concentrations of 5.7 to 18.3 mg/L are obtained within 1 to 2 hours of ingestion and are not significantly affected by food intake. The mean T_1/2 is 1 to 1.4 hours. The majority of the drug is recovered unchanged in the urine, and a dosage reduction is recommended in patients with severe renal dysfunction.

The recommended dosage is 500 mg twice daily. In three randomized clinical trials of patients with community-acquired lower respiratory tract infections, cefprozil 500 mg twice daily was as efficacious as cefaclor 500 mg three times a day, and amoxicillin/clavulanate 500 mg three times a day, both in clinical response and in bacterial eradication. Cefprozil 500 mg twice daily is an effective alternative in the treatment of CAP and is possibly superior to other second-generation cephalosporins in infections caused by β-lactamase-producing organisms.

Ceftriaxone

Ceftriaxone is a parenteral third-generation cephalosporin with broad-spectrum in vitro activity.
H influenzae (including β-lactamase-producing strains), S pneumoniae (including penicillin-resistant strains) and most Enterobacteriaceae are highly sensitive to the drug. P aeruginosa and Acinetobacter spp are resistant to ceftriaxone. MSSA and Streptococcus spp are generally susceptible to ceftriaxone, but the drug is not active against methicillin-resistant Staphylococcus aureus (MRSA). S aureus bacteremia should not be treated with ceftriaxone as failures are likely to occur.

Mean peak plasma concentrations are 151 and 257 mg/L following 30-minute infusions of 1 and 2 g IV. Trough concentrations are 9.3 and 12 to 20 mg/L (total drug) and 0.5 and 1.2 mg/L (free drug). These are still above the MIC₉₀s of most respiratory pathogens. Adequate concentrations of drug have been measured in most body tissues and fluids, including purulent sputum, bronchial mucosa and lung tissue. Approximately two thirds of a dose is eliminated via glomerular filtration, while the rest is excreted mainly in the bile. Dosage adjustments in the presence of moderate renal or hepatic disease are not necessary.

Many clinical trials have established the efficacy of this agent in CAP and HAP. Third-generation cephalosporins, such as ceftriaxone, are generally recommended as initial empiric therapy for serious infections such as HAP or severe CAP. However, ceftriaxone, like most other third-generation cephalosporins, should not be administered empirically in patients with severe HAP of unknown etiology if P aeruginosa is the suspected pathogen.

Ceftazidime

Ceftazidime is an aminothiazolyl, third-generation cephalosporin. It is an antibacterial agent whose action is mediated, like other agents in this class, through binding with PBPs and inhibiting the cross-linking of bacterial peptidoglycan. In vitro data from many countries suggest that in general, the common HAP pathogens of Enterobacteriaceae, such as E coli, K pneumoniae and Proteus mirabilis, remain highly susceptible to ceftazidime. Activity against other important gram-negative pathogens (e.g. Enterobacter spp and Serratia marcescens) is less predictable and may encourage the emergence of ESBL-producing organisms. There is a wide range of susceptibility of P aeruginosa, with approximately 85% of strains remaining susceptible. Ceftazidime remains active against the respiratory tract pathogens H influenzae and M catarrhalis. However, it is not active against MRSA, and ceftazidime is less active than the other parenteral agents against PRP.

Following the administration of a 1- and 2-g IV dose, a C_max of 59 to 83 mg/L and 159 to 185 mg/L, respectively, can be anticipated. Ceftazidime is renally excreted and dosage adjustments are required with renal insufficiency. Adequate concentrations have been reported in bronchial secretions, lung tissue and pleural fluid. Ceftazidime, either as monotherapy or as a component of an antibacterial regimen, remains effective in the treatment of serious hospital-acquired infections, especially those associated with gram-negative bacteria. The usual adult dosage is 3 to 6 g/day by IV infusion or injection given three times a day. Higher doses may be required in patients with CF, and dosage reduction is essential in patients with renal impairment.

Ceftazidime/Avibactam

The combination of ceftazidime (see above) and avibactam, a non-β-lactam β-lactamase inhibitor that protects ceftazidime by inhibiting certain β-lactamases that inhibit it, received FDA approval in 2015 for the treatment of complicated abdominal and urinary infections in adult patients. In 2018, approval was granted for the treatment of HAP/VAP in adult patients, and in 2019, it was approved for use in pediatric patients for these indications.

This combination has demonstrated activity against Enterobacter cloacae, E coli, H influenzae, K pneumoniae, P mirabilis, P aeruginosa and S marcescens in both clinical (i.e., HAP/VAP) and in vitro contexts. In vitro data also supports activity against Citrobacter koseri, Enterobacter aerogenes, Morganella morganii, Providencia rettgeri, and Providencia stuartii. Ceftazidime/avibactam has no activity against bacteria that produce metallo-β lactamases.

Following multiple IV infusions of ceftazidime/avibactam, the steady state C_max of ceftazidime was 90.4 mg/L and that of avibactam was 14.6 mg/L. Both drugs are primarily renally eliminated, with a half-life of 2.76 hours (ceftazidime) and 2.71 hours (avibactam).

The efficacy of ceftazidime/avibactam was compared to that of meropenem in a noninferiority trial which enrolled 870 adult patients hospitalized with HAP or VAP. Clinical cure, defined as resolution or significant improvement in HAP/VAP signs and symptoms and cessation of antibacterial treatment for HAP/VAP, was a major efficacy endpoint. It was achieved by 67.2% of patients in the ceftazidime/avibactam group and 69.1% of those in the meropenem group, establishing the noninferiority of ceftazidime/avibactam. Ceftazidime/avibactam was shown to be safe for use in pediatric patients of at least 31 weeks of gestational age in several trials in other infections, and a trial of children with HAP/VAP 11.6 months to 9.4 years of age.

Ceftazidime/avibactam is administered by IV infusion. The recommended dose for adult patients with HAP/VAP is 2.5 g (ceftazidime 2 g and avibactam 0.5 g) administered as a 2-hour infusion every 8 hours over 7-14 days. In pediatric patients, the infusion time, infusion frequency and duration of treatment are the same, but the dose depends on the age and body weight of the child:

• ≤28 days: 25 mg/kg (ceftazidime 20 mg/kg and avibactam 5 mg/kg)
• 28 days to <3 months: 37.5 mg/kg (ceftazidime 30 mg/kg and avibactam 7.5 mg/kg)
• 3-<6 months: 50 mg/kg (ceftazidime 40 mg/kg and avibactam 10 mg/kg)
• 6 months to <2 years: 62.5 mg/kg (ceftazidime 50 mg/kg and avibactam 12.5 mg/kg)
• 2-<18 years: 62.5 mg/kg to a maximum of 2.5 g (ceftazidime 50 mg/kg and avibactam 12.5 mg/kg to a maximum dose of ceftazidime 2 g and avibactam 0.5 g).

The recommended dosage for adults and children 2 years of age and older with renal impairment depends on the degree of renal impairment. The dosage adjustment for adult is as follows:

• Estimated CrCl 31-50 mL/min: 1.25 g (ceftazidime 1 g and avibactam 0.25 g) every 8 hours
• Estimated CrCl 16-30 mL/min: 0.94 g (ceftazidime 0.75 g and avibactam 0.19 g) every 12 hours
• Estimated CrCl 6-15 mL/min: 0.94 g (ceftazidime 0.75 g and avibactam 0.19 g) every 24 hours
• Estimated CrCl ≤5 mL/min: 0.94 g (ceftazidime 0.75 g and avibactam 0.19 g) every 48 hours.
• The recommended dose adjustment in pediatric patients 2 years of age and older is given below:
• Estimated CrCl 31-50 mL/min: 31.25 mg/kg to a maximum of 1.25 g (ceftazidime 25 mg/kg and avibactam 6.25 mg/kg to a maximum dose of ceftazidime 1 g and avibactam 0.25 g) every 8 hours
• Estimated CrCl 16-30 mL/min: 23.75 mg/kg to a maximum of 0.94 g (ceftazidime 19 mg/kg and avibactam 4.75 mg/kg to a maximum dose of ceftazidime 0.75 g and avibactam 0.19 g) every 12 hours
• Estimated CrCl 6-15 mL/min: 23.75 mg/kg to a maximum of 0.94 g (ceftazidime 19 mg/kg and avibactam 4.75 mg/kg to a maximum dose of ceftazidime 0.75 g and avibactam 0.19 g) every 24 hours
• Estimated CrCl ≤5 mL/min: 23.75 mg/kg to a maximum of 0.94 g (ceftazidime 19 mg/kg and avibactam 4.75 mg/kg to a maximum dose of ceftazidime 0.75 g and avibactam 0.19 g) every 48 hours.

In the HAP/VAP trial of ceftazidime/avibactam in adult patients, the most common adverse events were nausea and pruritus.

Cefepime

Cefepime is a fourth-generation parenteral cephalosporin with activity against both gram-positive and gram-negative aerobic bacteria. Cefepime has greater inhibitory activity than ceftazidime against S pneumoniae and staphylococcal species. Similar to other cephalosporins, it is not active against MRSA. A useful feature of this agent, in contrast to previous generations of cephalosporins, is that it maintains its activity against derepressed bacteria. In addition, cefepime is not susceptible to hydrolysis by plasmid-mediated β-lactamases expressed by gram-negative bacteria, particularly Enterobacter spp. Unlike imipenem and some second-generation cephalosporins, cefepime is a poor inducer of type I β-lactamases. Cefepime has activity similar to that of ceftazidime against P aeruginosa.

A dose of 2 g IV produces a C_max of 126 to 193 mg/L. Cefepime has an T_1/2 of approximately 2 hours, allowing twice-daily dosing. Plasma protein binding is low, and the drug distributes widely into body tissues and fluids. Renal clearance of the drug dictates a reduction in dosage in the presence of significant renal insufficiency. Cefepime, administered 2 g twice daily, is comparable in clinical and microbiologic efficacy to ceftazidime administered 2 g three times a day or cefotaxime 2 g three times a day in patients with hospital-acquired and community-acquired lower respiratory tract infections.

Ceftaroline

Ceftaroline, the active moiety of ceftaroline fosamil, is a parenteral, broad-spectrum cephalosporin approved by the FDA for treatment of patients with community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of the following Gram-positive and Gram-negative micro-organisms:
S pneumoniae (including cases with concurrent bacteremia), S aureus (methicillin-susceptible isolates only), H influenzae, K pneumoniae and E coli. Ceftaroline is bactericidal against S aureus due to its affinity PBP2a, and against S pneumoniae due to its affinity for PBP2x. Ceftaroline does not possess activity against P aeruginosa and exhibits reduced activity against E cloacae, Proteus vulgaris and Providencia spp. Ceftaroline exhibits in vitro MICs of ≤1 mcg/mL against most (≥ 90%) isolates of Streptococcus dysgalactiae, C koseri, Citrobacter freundii, E cloacae, E aerogenes, M catarrhalis, M morganii, P mirabilis and H parainfluenzae. However, the safety and effectiveness of ceftaroline in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. Development of resistance to ceftaroline occurs rarely in Gram-positive bacteria and at a similar rate to that of other oxyimino-cephalosporins in Gram-negative bacteria.

After parenteral administration, the inactive prodrug, ceftaroline fosamil, is rapidly converted by plasma phosphatases to ceftaroline. After IV doses of 600 mg given over 1 hour every 12 hours for 14 days, the maximum plasma concentration was 19.0 mcg/mL and 21.0 mcg/mL for first and last dose, respectively. Ceftaroline fosamil has a volume of distribution (Vd) of 0.37 L/kg, low protein binding (<20%), and a serum half-life of 2.6 hours. No drug accumulation occurs with multiple doses and elimination occurs primarily through renal excretion (49.6%).

The efficacy of ceftaroline 600 mg IV every 12 hours compared with ceftriaxone 1 g IV every 24 hours, both for 5 to 7 days, in terms of clinical cure rates was demonstrated in two phase 3, randomized, double-blind noninferiority trials in a total of 1153 hospitalized adult patients with CABP. At Day 4 in trial 1, the response rates were 69.6% with ceftaroline and 58.3% with ceftriaxone (treatment difference 11.2 [95% CI -4.6, 26.5]). In trial 2, the response rates were 69.0% with ceftaroline and 61.4% with cetriaxone (treatment difference 7.6 [95% CI -6.8, 21.8]). An analysis of this end point required patients to meet sign and symptom criteria at Day 4 of therapy: a responder had to both (a) be in stable condition according to consensus treatment guidelines of the IDSA and the ATS, based on temperature, heart rate, respiratory rate, blood pressure, oxygen saturation and mental status; (b) show improvement from baseline on at least one symptom of cough, dyspnea, pleuritic chest pain, or sputum production, while not worsening on any of these four symptoms.

At the test-of-cure (8 to 15 days after the end of therapy), the clinical cure rates in trial 1 were 86.6% for ceftaroline and 78.2% with ceftriaxone (treatment difference 8.4 [95% CI 1.4, 15.4]). In trial 2, the clinical cure rates were 82.3% with ceftaroline and 77.1% with ceftriaxone (treatment difference 5.2 [95% CI -2.2, 12.8]).

No dosage adjustment is needed for patients with mild renal impairment (CrCl >50 mL/min). However, dosage adjustment is recommended for patients with moderate renal impairment (CrCl >30 to ≤50 mL/min), severe renal impairment (≥15 to ≤30 mL/min), in patients with ESRD and those undergoing hemodialysis.

Ceftolozane/Tazobactam

A combination of ceftolozane, a fifth-generation cephalosporin, and the β-lactamase inhibitor tazobactam, was initially approved by the FDA in 2014 for the treatment of complicated intra-abdominal and urinary infections; in 2019, an indication for HAP/VAP in adult patients was approved. Like other cephalosporins, ceftolozane binds PBPs and inhibits bacterial cell wall synthesis. Tazobactam protects ceftolozane by inhibiting certain penicillinases and cephalosporinases.

Ceftolozane/tazobactam shows in vitro and clinical (in the context of HAP/VAP) activity against E cloacae, E coli, H influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, P mirabilis, P aeruginosa and S marcescens. It also has documented activity in vitro against C koseri, Klebsiella aerogenes, M morganii, P vulgaris, P rettgeri, P stuartii, Serratia liquefaciens, Streptococcus agalactiae and Streptococcus intermedius. This antibiotic combination is not active against bacteria that produce serine carbapenemases (e.g., K pneumoniae carbapenemase [KPC]) and metallo-β-lactamases.

After multiple IV infusions of ceftolozane/tazobactam, the steady state C_max for ceftolozane and tazobactam in patients with HAP or VAP were 105 mg/L and 26.4 mg/L, respectively. Both drugs are eliminated renally, with a half-life of 3-4 hours for ceftolozane and 2-3 hours for tazobactam.

The efficacy of ceftolozane/tazobactam for the treatment of HAP and VAP was assessed in a noninferiority trial against meropenem. The trial enrolled a total of 726 adult patients who were intubated on mechanical ventilation, regardless of the etiology of their pneumonia (HAP or VAP). Clinical cure, defined as complete resolution or significant improvement in HAP/VAP signs and symptoms at the test-of-cure visit (7-14 days after the end of treatment) was a major efficacy endpoint. Ceftolozane/tazobactam demonstrated noninferiority to meropenem in both HAP and VAP. Among patients with VAP, 55.9% and 57.0% achieved clinical cure in the ceftolozane/tazobactam and meropenem group, respectively. Among patients with ventilated HAP, the proportions were 50.5% for ceftolozane/tazobactam and 44.4% for meropenem.

The recommended dose of ceftolozane/tazobactam for the treatment of HAP/VAP in adult patients is 3 g (2 g ceftolozane and 1 g tazobactam), administered every 8 hours as a 1-hour IV infusion. The recommended treatment duration is 8-14 days. In patients with renal impairment, the dose should be modified according to the degree of kidney dysfunction:

• Estimated CrCl 30-500 mL/min: 1.5 g (1 g ceftolozane and 0.5 g tazobactam) every 8 hours
• Estimated CrCl 15-29 mL/min: 0.75 g (0.5 g ceftolozane and 0.25 g tazobactam) every 8 hours
• End-stage renal disease (ESRD) on hemodialysis: a single loading dose of 2.5 g (1.5 g ceftolozane and 0.75 g tazobactam) followed by a 0.45 g (0.3 g ceftolozane and 0.15 g tazobactam) maintenance dose every 8 hours.

The most common adverse reactions observed in the trial in patients with HAP/VAP included liver transaminase elevations, renal impairment/failure, diarrhea, intracranial hemorrhage, emesis, and Clostridioides difficile infection.

Cefiderocol

Cefiderocol, a fifth-generation cephalosporin, received FDA approval in 2019 for the treatment of complicated urinary tract infections; in 2020, the FDA approved an additional indication for the treatment of HAP and VAP in adult patients. Like other cephalosporins, cefiderocol exerts its bactericidal effect by inhibiting PBP, essential cell wall components. Cefiderocol acts as a siderophore and can bind extracellular iron; this allows it to be transported into the periplasmic space of bacterial cells both passively (through porins) and actively (though the siderophore iron uptake pathway).

In the context of HAP and VAP and in vitro, cefiderocol has activity against the following gram-negative pathogens: A baumannii complex, E coli, E cloacae complex, K pneumoniae, P aeruginosa and S marcescens. In vitro data also support efficacy against other gram-negative bacteria, including Achromobacter spp, Burkholderia cepacia complex, C freundii complex, C koseri, K aerogenes, Klebsiella oxytoca, M morganii, P vulgaris, P rettgeri and Stenotrophomonas maltophilia. Cefiderocol is not active against most gram-positive organisms or anaerobic bacteria.

In patients with HAP or VAP, the steady state C_max of cefiderocol after multiple IV infusions of 2-g doses is 111 mg/L. After a single dose in healthy volunteers, the C_max is 91.4 g/L. It is eliminated renally, with an elimination half-life of 2-3 hours.

Cefiderocol was assessed for efficacy against meropenem in a noninferiority trial of 298 adult patients hospitalized with HAP/VAP. Clinical cure, defined as resolution or substantial improvement in signs and symptoms of HAP/VAP with no additional antibacterial therapy needed, was the major efficacy endpoint assessed at test-of-cure visit (7 days after the end of treatment). This was achieved by 64.8% of patients in the cefiderocol group and 66.7% of patients in the meropenem group, establishing the noninferiority of cefiderocol.

Cefiderocol is administered by IV infusion over 3 hours; the dosing depends on renal function, with the recommended doses as follows:

• Estimated CrCl ≥120 mL/min: 2 g every 6 hours
• Estimated CrCl 60-119 mL/min: 2 g every 8 hours
• Estimated CrCl 30-59 mL/min: 1.5 g every 8 hours
• Estimated CrCl 15-29 mL/min: 1 g every 8 hours
• Estimated CrCl <15 mL/min, with or without intermittent hemodialysis: 0.75 g every 12 hours.

In the clinical trial of cefiderocol in patients with HAP/VAP, the most common adverse reactions were liver test elevations, hypokalemia, diarrhea, hypomagnesemia and atrial fibrillation.

Ceftobiprole

Ceftobiprole is a fifth-generation cephalosporin that received FDA approval in 2024. It is currently approved for the treatment of:

• Adult patients with bacteremia caused by S aureus
• Adult patients with acute bacterial skin infections
• Adult and pediatric patients (3 months of age and older) with CAP.

Ceftobiprole shares the mechanism of action with other cephalosporins, exerting its bactericidal activity by bindings to PBPs, with highest activity against PBP 1-4.

In the context of CAP and in vitro, ceftobiprole has demonstrated activity against S aureus, S pnuemoniae, E coli, K pneumoniae, H influenzae, H parainfluenzae. It also has established in vitro activity against S epidermidis, Staphylococcus hominis, Staphylococcus lugdunensis, S agalactiae, Streptococcus mitis group, S dysgalactiae, S anginosus group, C koseri, E cloacae, K aerogenes, M catarrhalis, M morganii and P mirabilis. It is not active against organisms producing TEM, SHV, or CTX-M family ESBLS, serine carbapenemases, class B metallo-β-lactamases, AmpC cephalosporinases and Ambler class D β-lactamases.

The steady state C_max of ceftobiprole (following multiple IV doses) is 33.0 mg/L, with a half-life of 3.3 hours. It is renally eliminated.

The efficacy of ceftobiprole for the treatment of CAP was assessed in a clinical trial which enrolled a total of 638 adult patients hospitalized for CAP. The primary endpoint was clinical cure, defined as survival with resolution of CAP signs and symptoms or improvement to the extent that no further antimicrobial therapy was required, with improvement or stabilization of radiographic findings and no receipt of non-study antibacterial treatment. Ceftobiprole demonstrated noninferiority to the active comparator (ceftriaxone, with linezolid in suspected or confirmed MRSA cases), with 76.4% of patients achieving clinical cure, compared to 79.3% in the comparator group. The approval of ceftobiprole for pediatric patients was based on the efficacy results in adult patients and the positive safety results in a pediatric trial of 138 patients with CAP requiring hospitalization (94%) and HAP (6%).

The recommended dose of ceftobiprole for the treatment of CAP in adult patients is 667 mg every 8 hours, administered over a 2-hour IV infusion. For pediatric patients, the dose depends on body weight and age: for children 3 months to <12 years of age, the recommended dose is 20 mg/kg (up to 667 mg); for children 12 to <18 years of age, the recommended dose is 13.3 mg/kg (up to 667 mg). The recommended treatment course for both adult and pediatric patients is 7-14 days. In adult patients with renal impairment, the dose should be reduced as follows:

• Estimated CrCl 30-<50 mL/min: 667 mg every 12 hours
• Estimated CrCl 15-<30 mL/min: 333 mg every 12 hours
• Estimated CrCl <15 mL/min, including hemodialysis: 333 mg every 24 hours.

In children with renal impairment, dosage adjustment depends on both age and degree of renal impairment. For children 2 to <6 years of age:

• Estimated CrCl 30-<50 mL/min: 13.3 mg/kg (up to 667 mg) every 12 hours
• Estimated CrCl 15-<30 mL/min: 13.3 mg/kg (up to 333 mg) every 24 hours.

For children 6 to <12 years of age:

• Estimated CrCl 30-<50 mL/min: 10 mg/kg (up to 667 mg) every 12 hours
• Estimated CrCl 15-<30 mL/min: 10 mg/kg (up to 333 mg) every 24 hours.

For children 12 to <18 years of age:

• Estimated CrCl 30-<50 mL/min: 10 mg/kg (up to 667 mg) every 12 hours
• Estimated CrCl 15-<30 mL/min: 10 mg/kg (up to 333 mg) every 12 hours.

The most common adverse reactions observed in the trial of ceftobiprole in patients with CAP included nausea, liver enzyme elevations, emesis, diarrhea, headache, rash, insomnia, abdominal pain, phlebitis, hypertension and dizziness.

Imipenem/Cilastatin

Imipenem is the N-formimidoyl derivative of thienamycin, a β-lactam antibiotic produced by Streptomyces cattleya. It is coadministered with cilastatin, a specific inhibitor of the renal enzyme dehydro­peptidase-1 (DHP-1), to prevent rapid renal metabolism of imipenem. Imipenem is active against a wide range of Enterobacteriaceae, including a greater proportion of E cloacae and C freundii than third- or fourth-generation cephalosporins. It is generally less active than ciprofloxacin against E coli, K pneumoniae,
E cloacae and S marcescens. Imipenem has excellent activity against methicillin-susceptible S aureus,
S pyogenes and S pneumoniae. The activity against the B fragilis group, other Bacteroides and Clostridium spp is comparable to that of metronidazole. Although a strong inducer of class I β-lactamases, imipenem is not hydrolyzed by these enzymes and has remained active against a wide range of β-lactamase- and non-β-lactamase-producing bacteria.

Single-dose IV administration of imipenem/cilastatin 500 mg or 1,000 mg results in mean plasma concentrations of 30 to 35 mg/L and 60 to 70 mg/L, respectively, which decline to 0.5 and 2 mg/L, respectively, 4 to 6 hours later. The T_1/2 of both imipenem and cilastatin is about 1 hour after IV administration. In patients with severely impaired renal function, the T_1/2 of cilastatin is prolonged to a greater degree than that of imipenem. In severe lower respiratory tract infections, addition of an aminoglycoside has been recommended to reduce the likelihood of development of resistant P aeruginosa. Seizures have occurred in patients with central nervous system dysfunction and renal failure, in conjunction with unadjusted dosage regimens. The usual IV dose is 500 to 750 mg administered every 6 hours, depending on the severity of the infection.

Imipenem/Cilastatin/Relebactam

A combination of imipenem/cilastatin and relebactam, a β-lactamase inhibitor, received FDA approval in 2019. It is currently approved for the treatment of adult patients with HAP or VAP with bacterial etiology, as well as certain non-respiratory infections. Relebactam possesses no intrinsic antibacterial activity, but protects imipenem by inhibiting β-lactamases, including SHV, TEM, CTX-M, P99, PDC, AmpC-type and KPC.

In the context of HAP/VAP, imipenem/cilastatin/relebactam demonstrated in vitro and clinical activity against a number of gram-negative aerobic pathogens, including Acinetobacter calcoaceticus-baumannii complex, E cloacae, E coli, H influenzae, K aerogenes, K oxytoca, K pneumoniae, P aeruginosa and S marcescens. In rodent models of lung infection, the addition of relebactam restored the activity of imipenem/cilastatin against imipenem-non-susceptible KPC-producing Enterobacteriaceae and imipenem-non-susceptible P aeruginosa.

The steady-state C_max of imipenem and relebactam after multiple 30 min intravenous infusions of imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg administered every 6 hours were 122.7 µM and 80.0 µM, respectively. The penetration of imipenem and relebactam into the pulmonary epithelial lining fluid is comparable (55% and 54%, respectively, of their unbound plasma concentration). Like imipenem, relebactam is renally eliminated, with a half-life of 1.2 hours.

The recommended dosage is imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg administered every 6 hours by intravenous infusion over the course of 30 minutes. This should be reduced in patients with renal impairment accordingly:

• Estimated CrCl 60-89 mL/min: imipenem 400 mg/cilastatin 400 mg/relebactam 200 mg
• Estimated CrCl 30-59 mL/min: imipenem 300 mg/cilastatin 300 mg/relebactam 150 mg
• Estimated CrCl 15-29 mL/min, or end-stage renal disease on hemodialysis: imipenem 200 mg/cilastatin 200 mg/relebactam 100 mg.

Common adverse reactions reported in clinical trials of imipenem/cilastatin/relebactam in patients with HAP or VAP included anemia, increased AST, increased ALT, diarrhea, constipation, hypokalemia, hyponatremia, pyrexia and rash.

Meropenem

Meropenem is a broad-spectrum carbapenem antibacterial agent that is stable in the presence of DHP-1 such that it does not require concomitant administration of a DHP-1 inhibitor such as cilastatin. Meropenem has a broad spectrum of in vitro activity against gram-positive and gram-negative pathogens, including ESBL- and AmpC-producing Enterobacteriaceae. The drug is generally more active than imipenem against Enterobacteriaceae, including hospital-acquired clinical isolates resistant to ceftazidime, cefotaxime, ceftriaxone, piperacillin and gentamicin. Meropenem is active against S aureus but is less active than imipenem against other gram-positive organisms. S pneumoniae, including penicillin-resistant strains, is inhibited by low concentrations of meropenem. It is as active or more active than imipenem against anaerobic bacteria.

After a 30-minute IV infusion of 1 g meropenem, the peak plasma concentration varies from 53 to 61 mg/L. The T_1/2 is approximately 1 hour, and the excretion is mainly renal. Randomized trials indicate a clinical efficacy in patients with lower respiratory tract infections similar to that of imipenem/cilastatin and ceftazidime, with or without an aminoglycoside. It has similar efficacy to comparator antibacterial agents such as clarithromycin plus ceftriaxone or amikacin in severe CAP, and greater efficacy than ceftazidime plus amikacin or tobramycin in patients with nosocomial pneumonia. The recommended IV dosage of meropenem is 0.5 to 1 g every 8 hours, which should be decreased in the presence of renal insufficiency.

Meropenem/Vaborbactam

Meropenem can be combined with vaborbactam, a novel non-β-lactam β-lactamase inhibitor derivative of boric acid which protects meropenem from class A and C β lactamases. This combination received FDA approval in 2017 for the treatment of complicated urinary tract infections in adult patients. While not yet approved for the treatment of pneumonia in the United States, it is a good option for the treatment of HAP or VAP caused by carbapenem-resistant Enterobacterales.

Meropenem/vaborbactam has demonstrated activity against E cloacae, E coli and K pneumoniae both in vitro and in clinical infections. It also has in vitro activity against C freundii, C koseri, E aerogenes, K oxytoca, M morganii, P mirabilis, Providencia spp, P aeruginosa and S marcescens.

The mean C_max of meropenem and vaborbactam, following a 3-hour infusion of meropenem 2 g and vaborbactam 2 g, was 57.3 mg/L and 71.3 mg/L, respectively. The half-lives of meropenem and vaborbactam are 1.22 and 1.68 hours, respectively.

The FDA-recommended dosage in adults with normal renal function is meropenem 2 g and vaborbactam 2 g, administered as an intravenous infusion over 3 hours, administered every 8 hours for up to 14 days. Note that, while not FDA-approved for the treatment of pneumonia, meropenem/vaborbactam has been used at this dose to treat pneumonia in clinical trials, including the TANGO II trial. The dosage should be reduced in patients with impaired renal function, as follows:

• Estimated CrCl 39-49 mL/min: meropenem 1 g/vaborbactam 1 g every 8 hours
• Estimated CrCl 15-29 mL/min: meropenem 1 g/vaborbactam 1 g every 12 hours
• Estimated CrCl <15 mL/min: meropenem 0.5 g/vaborbactam 0.5 g every 12 hours

The most common adverse events observed in the TANGO II trial included diarrhea, anemia, hypokalemia, hypotension, sepsis, septic shock and acute renal failure.

Doripenem

Doripenem is a broad-spectrum carbapenem with in vitro activity against gram-positive and gram-negative bacteria, including extended ESBL- and AmpC-producing Enterobacteriaceae, and anaerobic bacteria. This is the first carbapenem that is suitable for prolonged infusions that may be required to achieve pharmacodynamic/pharmacokinetic targets for bactericidal activity (and therefore efficacy) against pathogens with increased MICs.

Doripenem is active against gram-positive pathogens, including S aureus (methicillin/oxacillin-susceptible isolates), S pneumoniae (including penicillin-, ceftriaxone- or multidrug-resistant strains), S pyogenes and S agalactiae (MIC₉₀ ≤1 mg/L; susceptibility rate of 100%). Doripenem is also quite active against clinically relevant Enterobacteriaceae (Citrobacter spp, Enterobacter spp, E coli, Klebsiella spp, M morganii, Proteus spp and Serratia spp). The MIC₉₀ is generally ≤0.5 mg/L and susceptibility rates are 93% to 100%. Doripenem has activity against ESBL- and AmpC-producing Enterobacteriaceae, with little or no change in MIC₉₀ values compared with non-ESBL- and non-AmpC-producing strains. Doripenem is also active against
H influenzae, M catarrhalis and Providencia spp (MIC₉₀ ≤1.56 mg/L). Doripenem MIC₉₀ values were 0.2–12.5 mg/L against susceptible isolates of P aeruginosa and 8-64 mg/L against carbapenem- or ceftazidime-resistant isolates. Doripenem demonstrated in vitro activity against a range of anaerobic pathogens, including B fragilis,
Bacteroides thetaiotaomicron, and Prevotella spp (MIC₉₀ 0.062-2 mg/L; susceptibility rates of 96% to 100%).

After prolonged (4-hour infusion) IV administration of doripenem 500 mg or 1 g in healthy volunteers, mean C_max values were ~8 mcg/mL and ~17 mcg/mL, and mean AUC values from time zero to infinity were ~34 and ~68 mcg/mL. Doripenem penetrates tissues well, and achieves drug concentrations at or above those required to inhibit most susceptible bacteria. It is metabolized via DHP-1 to a biologically inactive metabolite and is primarily excreted as the unchanged drug via the kidneys.

Doripenem was not inferior to meropenem in the treatment of lower respiratory infections, either CAP or chronic respiratory disease with acute infection, in a Japanese trial. Doripenem was not inferior to imipenem/cilastatin therapy, or piperacillin/tazobactam in patients with nosocomial pneumonia, including those with VAP.

Doripenem is approved in the European Union (EU) for use in adult patients with nosocomial pneumonia (including VAP), complicated intra-abdominal infections, and complicated urinary tract infections. The recommended dosage in the EU is 500 mg every 8 hours for 5 to 14 days, infused over 1 to 4 hours in patients with nosocomial pneumonia (including VAP).

Macrolides

Erythromycin is the principal compound in the class of macrolides. These drugs have been used extensively in the treatment of lower respiratory tract infections, especially in patients allergic to β-lactam antibiotics or with infections due to intracellular organisms (Chlamydia, Legionella and Toxoplasma spp) and atypical pathogens such as Mycoplasma spp. The activity of erythromycin against gram-negative species is poor. Macrolide antibiotics exhibit their antimicrobial action by binding to the 50S subunit of the 70S ribosome, thereby inhibiting bacterial RNA-dependent protein synthesis. Erythromycin has poor oral bioavailability, requiring dosing three to four times a day, is unstable in an acid environment, and lacks efficacy against H influenzae. Although not serious, the drug causes dose-related GI symptoms, including nausea, vomiting and diarrhea. The IV formulation of the drug causes severe local phlebitis and requires a large volume for administration.

Its 14-membered ring has now been modified to produce semisynthetic derivatives, including clarithromycin, dirithromycin, roxithromycin and others. Azithromycin is a 15-membered ring, which confers upon it acid stability. These new compounds have an increased spectrum of activity, demonstrate increased stability in acid solutions, and are better tolerated following oral administration. MIC₉₀ values are summarized in Table 5-4 and pharmacokinetic properties are compared in Table 5-5. Common drug interactions are listed in Table 5-6. The potential anti-inflammatory properties of this drug class are currently being investigated.

Clarithromycin

Clarithromycin is a 14-membered lactone ring attached to two sugar moieties. The primary metabolite of clarithromycin is the 14-hydroxy(R) epimer, which also has antimicrobial activity, and this has been shown to be additive or synergistic to that of the parent compound against a variety of bacteria, particularly H influenzae. Clarithromycin has a spectrum of antimicrobial activity similar to that of erythromycin with activity against:

• S pneumoniae
• S aureus
• β-Hemolytic Streptococcus
• S pyogenes
• M pneumoniae
• M catarrhalis (including β-lactamase-producing strains).

Clarithromycin demonstrates greater in vitro activity than erythromycin against certain respiratory pathogens, including C pneumoniae, Legionella spp, and H influenzae. It also exhibits a potent postantibiotic effect against S aureus, S pneumoniae, and H influenzae.

Clarithromycin is well absorbed from the GI tract, but undergoes substantial first-pass metabolism, reducing systemic bioavailability to 55%. Macrolides are lipid-soluble, resulting in extensive body fluid and tissue distribution. In animal and human studies, clarithromycin demonstrated greater concentrations in tissues and organs than in blood. The mean T_1/2 ranges from 2.6 to 2.8 hours, while the half-life for the 14-hydroxy(R) epimer is greater than that of the parent compound (3.9 to 5.1 hours) after single-dose administration. A new sustained-release formulation of clarithromycin has been developed allowing once-daily dosing. The recommended oral dosage of clarithromycin for the treatment of pneumonia is 250 or 500 mg twice daily or 1,000 mg every day taken with or without food.

The clinical success rate for clarithromycin in patients with lower respiratory tract infections is 94% to 99%. Clarithromycin is effective against most respiratory tract pathogens causing pneumonia, including atypical pathogens (e.g., C pneumoniae, M pneumoniae, and Legionella spp). Its pharmacokinetic properties are superior to those of erythromycin, allowing once-daily dosing with the potential for greater compliance.

Azithromycin

Azithromycin is a 15-membered ring erythromycin analogue with a nitrogen inserted into the lactone ring; this confers acid stability and improved tissue pharmacokinetic properties. Azithromycin is the prototype of the semisynthetic macrolides known as the azalides. Azithromycin is marginally less active than erythromycin in vitro against gram-positive organisms and has similar activity against atypical intracellular pathogens (e.g., C pneumoniae, L pneumophila, M pneumoniae). It is more active than other new macrolides against many gram-negative pathogens, including H influenzae, H parainfluenzae and M catarrhalis. Like other macrolides, it is unaffected by β-lactamase production. However, erythromycin-resistant strains are azithromycin- and clarithromycin-resistant as well.

Following oral administration, azithromycin is rapidly cleared from the circulation into intracellular compartments, resulting in high tissue concentrations. The oral bioavailability of a single 500-mg dose in a fasting state is 37%. It is then released slowly, demonstrating a long terminal T_1/2 (10 to 40 hours) compared with that of erythromycin (1.7 hours). Azithromycin is eliminated unchanged principally in the feces and to a lesser extent via the kidneys. Azithromycin is usually given as a single or divided 500-mg dose on day 1 followed by 250 mg once daily for an additional 4 days. An alternate dosing regimen used in Europe (500 mg daily for 3 days) is equally efficacious. It is recommended that azithromycin be used with caution in patients with severe renal impairment and not used at all in those with severe hepatic disease.

In comparative studies, azithromycin shows overall efficacy comparable with that of erythromycin, josamycin, amoxicillin (with or without clavulanic acid), or cefaclor. Azithromycin is an orally active, acid-stable antimicrobial that offers an effective alternative to erythromycin in the treatment of lower respiratory tract infections. It has the best gram-negative coverage of all the available macrolides but does not cover Enterobacter or Pseudomonas spp. The possibility of once-daily administration and a shorter duration of treatment due to its pharmacokinetic properties are attractive as a means of improving patient compliance and possibly lowering overall costs of treatment. The long half-life may be a mixed blessing since there are studies suggesting that previous antibiotic administration, particularly with azithromycin, may be associated with the development of macrolide-resistant pneumococci.

Roxithromycin

Roxithromycin is a semisynthetic derivative of erythromycin modified at the C-9 position. It has not received FDA approval to date, but is available in other countries. The in vitro activity of roxithromycin resembles that of the parent compound. It is active against:

• S pneumoniae
• S pyogenes
• M catarrhalis
• L pneumophila
• M pneumoniae
• Chlamydia trachomatis.

Activity against H influenzae is borderline. It has variable activity against methicillin-susceptible S aureus. Bioavailability is reduced when the drug is administered 15 minutes after a standard meal; therefore, it is recommended that it be given at least 15 minutes before food. The mean T_1/2 of roxithromycin (8.4 to 15.5 hours) is much longer than that of the parent compound, erythromycin (1.5 to 3 hours). The drug is strongly and saturably bound to β-1-acid glycoprotein in plasma from which it is released for distribution and elimination. This may be the mechanism for its nonlinear pharmacokinetics. Roxithromycin is primarily excreted in the feces. A 50% reduction in daily dose has been recommended in patients with liver cirrhosis.

The recommended daily oral dosage of roxithromycin in adults is 300 mg administered either once daily or in two divided doses. A reduced dose of 150 mg is recommended in patients with liver cirrhosis, but no dosage adjustment is required in severe renal failure. In summary, it should not be used in cases in which infection due to H influenzae is likely. It is useful in people with severe renal failure since most of its elimination is hepatic. The long T_1/2 allows for once- or twice-daily dosing and it is better tolerated than erythromycin.

Dirithromycin

Dirithromycin is an orally active macrolide with a 14-membered lactone ring. Discontinued in the United States, it is still available in other countries. Dirithromycin is readily hydrolyzed to its biologically active metabolite, erythromycylamine. The in vitro inhibitory activity of dirithromycin against gram-positive clinical isolates is similar to that of the other macrolides, erythromycin, roxithromycin and azithromycin, and generally less than that of clarithromycin. The spectrum of activity includes:

• S pneumoniae
• S pyogenes
• Penicillin-sensitive strains of S aureus
• Listeria monocytogenes
• M catarrhalis (including some β-lactamase-producing strains)
• Atypical pathogens.

Dirithromycin has no relevant activity against Brucella spp and some strains of H influenzae. Its activity against L pneumophila is inferior to that of other macrolide antibiotics. Systemic availability is 10% and food has a minimal effect on absorption. The drug rapidly leaves the circulation and localizes in selected soft tissues and has a long T_1/2 of 28 (16 to 60) hours. Elimination is primarily by liver and feces.

The suggested dosage of dirithromycin is 500 mg once daily in adults. No dosage reduction is required in patients with mild to moderate hepatic or renal impairment. Dirithromycin is similar to erythromycin in its microbiologic spectrum of activity as well as in its tolerability. The high tissue penetration, slow efflux from tissues and cells and longer half-life result in a more convenient once-daily dosing. Further comparative studies with the other new members of the macrolide class are required.

Fluoroquinolones

Fluoroquinolones exert their effect by interfering with topoisomerase IV and DNA gyrase, thereby inhibiting DNA synthesis. In general, the fluoroquinolones have excellent activity against gram-negative pulmonary pathogens such as:

• H influenzae
• Enterobacteriaceae
• Pseudomonas spp (ciprofloxacin and levofloxacin).

Newer respiratory fluoroquinolones (e.g., gemifloxacin, moxifloxacin, delafloxacin) are highly active against Streptococci. Activity against anaerobes is good for moxifloxacin and gemifloxacin. Atypical pathogens, such as M pneumoniae and Chlamydia spp, are usually susceptible and Legionella spp are inhibited by fluoroquinolones. MIC₉₀ values are displayed in Table 5-7. The fluoroquinolones and their dosing are shown in Table 5-8, while the concentration of the fluoroquinolones in lung tissue is presented in Table 5-9. The relationship between the pharmacokinetics, pharmacodynamics and MIC₉₀ values of the newer fluoroquinolones against S pneumoniae are shown in Table 5-10, Table 5-11 and Table 5-12. Since bacterial killing of fluoroquinolones is concentration-dependent, a fluoroquinolone with a concentration significantly above the MIC₉₀ (as reflected by a high area under the curve above the concentration required to inhibit 90% of strains [AUIC]) would be expected to be successful in eradicating this pathogen.

Fluoroquinolones should not be administered to children or pregnant or lactating women due to the potential for articular damage. Patients on fluoroquinolones should not receive concomitant mineral supplements, vitamins, iron or other minerals, antacids, or sucralfate.

Ciprofloxacin

Ciprofloxacin is the benchmark fluoroquinolone against which all other fluoroquinolones are compared (Table 5-8). It is available in oral, IV, otic and optic formulations. The primary mechanism of action is inhibition of bacterial DNA gyrase, which disrupts bacterial DNA replication. Ciprofloxacin is active in vitro against most gram-negative bacteria, including M catarrhalis and
H influenzae. S pneumoniae, including penicillin-resistant strains, is generally susceptible or moderately susceptible (MIC₉₀ 1 or 2 mg/L).

Ciprofloxacin has a bioavailability of approximately 70% after oral administration and reaches a C_max of 3.9 mg/L 1 to 2 hours after a single 750-mg dose. It is concentrated in many body tissues and fluids, particularly lung tissue and alveolar macrophages. Clearance is mainly renal and age-related adjustments in dosage may be necessary. Despite the concern regarding the marginal S pneumoniae activity, the clinical and bacteriologic efficacy of ciprofloxacin is similar to that of more traditional agents. It has been used successfully in the management of COPD exacerbations and acute bronchitis where
H influenzae is the predominant pathogen but S pneumoniae may coinfect. However, its use in primary pneumococcal pneumonia is not recommended since the new respiratory fluoroquinolones are much more potent and treatment failures have been reported.

Levofloxacin

Levofloxacin is an oral and IV fluoroquinolone which is the L-enantiomer of ofloxacin. Its in vitro activity is generally twice as potent as that of ofloxacin. Levofloxacin demonstrates better gram-positive coverage than previous fluoroquinolones against both MSSA, MRSA and most Streptococcus spp. The oral bioavailability of levofloxacin is close to 100% and is unaffected by food. Maximum plasma drug concentrations of 5.7 mcg/mL are reached in 0.8 to 2.4 hours after the administration of a 500-mg dose and 7.13 ± 1.44 mcg/mL after a 750-mg dose. Concentrations of drug in tissues or body fluids are generally higher than those observed in plasma, due to the wide distribution of the drug throughout the body. The mean plasma T_1/2 is 4 to 7 hours. Excretion occurs primarily through the urine, and dosage adjustment is necessary in patients with impaired renal function. A 750-mg once-daily dosage for the management of patients with CAP and HAP is recommended. A mean steady-state peak concentration of 12.1 mcg/mL is achieved if the drug is given IV and 8.6 mcg/mL if given orally.

The usual dose is 500 mg once daily, although there is good rationale and supportive data to increase the dose to 750 mg once daily and shorten the total exposure from 7 to 10 days to only 5 days. Although twice daily dosing is common in Europe and three times a day dosing is used in Japan, once-daily dosing has equivalent efficacy to multiple dosing regimens and facilitates IV-to-oral switch therapy in hospitalized patients. The shortened course of therapy with the higher dose may diminish the risk of emergence of resistance while on therapy. Levofloxacin possesses comparable or better activity than ciprofloxacin and ofloxacin against gram-positive bacteria that are pathogens in pneumonia. At the higher dose, it is comparable to ciprofloxacin for the treatment of gram-negative infections.

Moxifloxacin

Moxifloxacin is an 8-methoxyquinolone that combines enhanced in vitro activity against gram-positive organisms while maintaining activity against gram-negative organisms, including β-lactamase-producing strains of H influenzae and M catarrhalis. It covers all of the usual respiratory pathogens, including M pneumoniae, C pneumoniae and Legionella spp, and has useful anaerobic activity as well. A single dose of 400 mg produces a C_max of 3.2 to 4.5 mg/L, a half-life of 11 to 15 hours, an AUC of 25 to 40 mg/L/hour, and a Vd of 2.5 to 3.5 L/kg. Bioavailability is >85%, and approximately 20% of the clearance is via the kidneys. The drug concentrates in bronchial mucosa, lung epithelial fluid and alveolar macrophages at concentrations that are considerably higher than that required to kill common respiratory pathogens. No dosage adjustment is required in patients with renal failure or mild liver disease, but the dose must be adjusted among patients with hepatic Child-Pugh Class C disease. There are no important drug interactions except with antacids and iron or other divalent cation preparations similar to all the other fluoroquinolones.

Clinical trials have demonstrated bacteriologic and/or clinical success rates of approximately ≥90% for CAP, AECB, or acute sinusitis. A slight prolongation of QTc interval (a class effect associated with all fluoroquinolones) has been identified in the range of 6 milliseconds, which is clinically insignificant. A prospective, randomized trial comparing moxifloxacin 400 mg daily with levofloxacin 500 mg daily in elderly patients admitted to hospital with CAP demonstrated equivalent cardiac safety results as the primary end point. There is an oral formulation and an IV formulation available. The usual dosage is 400 mg taken once daily for 5 days by patients with AECB and 10 days among patients with CAP.

Gemifloxacin

Gemifloxacin is a novel fluoronaphthyridone with a pyrrolidine moiety at the C7 position comprised of a racemic mixture of equipotent enantiomers. The primary target for this compound is topoisomerase IV, one of the key enzymes required for bacterial replication but is also highly bound to DNA gyrase at therapeutic concentrations. Gemifloxacin is 5-fold more potent than ciprofloxacin in binding to this enzyme. It is over 30-fold more active than ciprofloxacin against S pneumoniae (MIC₉₀ 0.03 vs 2 mg/L). Compared with other respiratory fluoroquinolones, it is 4- to 8-fold more active than moxifloxacin, and 32-fold more active than levofloxacin. It is the most active agent against S pneumoniae, even those strains demonstrating penicillin resistance and ciprofloxacin resistance. Among ciprofloxacin-resistant strains (MIC₉₀ ≥4 mg/L), gemifloxacin inhibited 95% of isolates at 0.5 mg/L, whereas moxifloxacin inhibited 63% and 59% of isolates, respectively, at the same concentration. It is highly active against other respiratory pathogens, such as H influenzae, M catarrhalis, and the atypical organisms, M pneumoniae, C pneumoniae and Legionella spp. It has variable potency against anaerobic species, with generally higher potency against oral gram-positive anaerobes and fusobacteria. It has moderate but variable potency against gram-negative anaerobes. This might be advantageous in treating respiratory tract anaerobic infections with a lower potential for disturbing the normal enteric anaerobic bacteria.

At steady state, healthy volunteers have a C_max of 1.61 ± 0.51 mcg/mL in 0.5 to 2 hours (T_max), and the AUC is 9.93 ± 3.07 mcg/hour/mL (range 4.71–20.1 mcg/hour/mL). Serum protein binding is in the range of 60% to 70%. The half-life is 7 ± 2 hours, and approximately 30% of the dose is excreted renally. There are no interactions with theophylline, digoxin, oral contraceptives, omeprazole, or warfarin. Concentrations of gemi­floxacin in BAL fluid exceed those in the plasma. Gemifloxacin penetrates well into lung tissue and fluids. After five daily doses of 320-mg gemifloxacin, concentrations in plasma, broncho­alveolar macrophages, epithelial lining fluid, and bronchial mucosa at approximately 2 hours are 90, 2, and 7 times higher, respectively, than a simultaneously drawn plasma level. A QTc prolongation of 3.7 milliseconds (clinically insignificant) has been noted.

In clinical trials of 6775 patients, the incidence of rash was higher in patients receiving gemifloxacin than in those receiving comparator drugs. Rash was more commonly observed in patients <40 years of age, especially females, including postmenopausal females taking hormone replacement therapy. The incidence of rash also correlated with longer treatment duration (>7 days). The incidence of rash is <2% of patients taking the drug for 5 days. The rash is maculopapular and of mild to moderate severity. The rash resolves spontaneously without treatment in the majority of patients.

Seven large-scale phase 3 trials have been performed studying the efficacy of gemifloxacin in the treatment of respiratory tract infections: four in CAP and three in AECB. Gemifloxacin has been compared with ceftriaxone/cefuroxime, trovafloxacin, amoxicillin/clavulanate, and cefuroxime + clarithromycin in non­inferiority studies of patients with CAP. As expected, the outcomes of patients treated with gemifloxacin were at least as good as and, in some cases, superior to those in patients treated with the comparators. Gemifloxacin has been compared with clarithromycin, amoxicillin/clavulanate, and levofloxacin in noninferiority studies of patients with AECB. Traditional outcomes are similar with the different treatment arms but one study looking at long-term outcomes suggested that gemifloxacin was associated with fewer relapses than clarithromycin. The recommended dose for gemifloxacin is 320 mg/day for 5 days in patients with AECB, 320 mg daily for 7 to 10 days for sinusitis, and 7 to 14 days for pneumonia.

Delafloxacin

Delafloxacin is the newest fluoroquinolone on the market, receiving FDA approval in 2017 for the treatment of skin infections, and in 2019 for the treatment of CAP in adult patients. Like all fluoroquinolones, delafloxacin exerts its antibacterial activity by inhibiting bacterial topoisomerase IV and DNA gyrase. Delafloxacin is available both in a tablet form for oral administration and in powder form for reconstitution and intravenous administration.

Delafloxacin has demonstrated activity in vitro and in CAP-related clinical contexts against the following organisms: S pneumoniae, S aureus (but not MRSA), E coli, H influenzae, H parainfluenzae, K pneumoniae, P aeruginosa, C pneumoniae, L pneumophila and M pneumoniae. In vitro, it also shows activity against S dysgalactiae, E aerogenes, K oxytoca, P mirabilis and M catarrhalis.

The steady state C_max of delafloxacin is 7.46 mg/L when administered as a tablet (450 mg every 12 hours) and 9.29 mg/L when administered as an IV infusion (300 mg every 12 hours). The mean half-life was 3.7 hours after a single IV dose, and 4.2-8.5 hours after multiple oral doses. The oral bioavailability of a single 450 mg oral dose of delafloxacin is 58.8%.

Delafloxacin demonstrated noninferiority to moxifloxacin in a trial of 859 adults with CAP, with 88.9% of patients treated with delafloxacin exhibiting clinical response (survival with improvement in ≥2/4 CAP symptoms from baseline without deterioration in any of the symptoms, and without use of additional antimicrobial therapy due to lack of efficacy) within 72-120 hours, compared to 89.0% of patients treated with moxifloxacin.

The FDA-recommended dose of delafloxacin is either 300 mg every 12 hours by IV infusion over 60 minutes, or 450 mg every 12 hours orally, or a combination of the two (ie, starting with IV administration and switching to oral at the discretion of the physician). The recommended treatment duration for CAP is 5-10 days. In patients with renal impairment, the dosage should be modified accordingly:

• Estimated CrCl 30-89 mL/min: no dosage adjustment
• Estimated CrCl 15-29 mL/min: no dosage adjustment for tablets, decrease to 200 mg every 12 hours by IV infusion
• Estimated CrCl <15 mL/min, including patients on hemodialysis: delafloxacin not recommended.

Diarrhea and liver transaminase elevations were the most common adverse events observed with delafloxacin use in clinical trials for CAP.

Tetracycline Class Antibiotics

Tigecycline

Tigecycline is a first-in-class glycylcycline antibacterial for IV use. The glycylcyclines are synthetic analogues of the tetracycline family that were developed to overcome mechanisms of tetracycline resistance and provide a treatment option for patients with difficult-to-treat infections. Tigecycline has a broad spectrum of activity that encompasses numerous gram-positive and gram-negative aerobes, atypical respiratory bacterial strains and anaerobes. Its mechanism of action is similar to the tetracyclines, namely by binding to the bacterial 30S ribosomal subunit preventing the incorporation of amino acid residues into elongating peptide chains. Tigecycline is very active against gram-positive organisms commonly associated with CAP, including S pneumoniae and
S aureus. MIC₉₀ values for these bacteria range from ≤0.03 to 0.5 mcg/mL. The activity persists in the face of penicillin resistant for S pneumoniae and methicillin resistance for S aureus. It also demonstrates good activity against H influenzae, M catarrhalis and K pneumoniae, other important respiratory pathogens.

The standard dosing regimen is an initial IV loading dose of 100 mg, followed by maintenance IV doses of 50 mg every 12 hours, given over 30 to 60 minutes. Tigecycline mean C_max at steady state in healthy volunteers who received the recommended dosage was 0.87 mcg/mL after a 30-minute infusion and 0.63 mcg/mL after a 60-minute infusion. The pharmacokinetics of tigecycline are shown in Table 5-13.

The clinical efficacy of tigecycline in hospitalized adults with CAP (n = 859) has been compared with that of levofloxacin in two randomized, double-blind, multicenter, phase 3, noninferiority studies. In the clinically evaluable population, the percentage of patients cured at the test-of-cure visit was 89.7% with tigecycline and 86.3% with levofloxacin, demonstrating a lack of inferiority. There was no significant difference between tigecycline and levofloxacin recipients in the mean length of hospital stay during primary hospitalization (9.8 vs 9.8 days) or in the mean duration of study antibacterial therapy. Tigecycline was associated with a significantly higher incidence of nausea and vomiting than levofloxacin.

Omadacycline

Omadacycline, a member of the aminomethylcycline subclass of tetracycline derivatives, is an inhibitor of the bacterial 30S ribosome subunit. It exerts its bacteriostatic, and in some cases bactericidal, activity by antagonizing protein synthesis. First approved by the FDA in 2018 for the treatment of CAP and skin infections, it is available for both oral and IV administration.

In vitro and in the context of CAP, omadacycline is active against the following gram-positive and gram-negative bacteria: S pneumoniae, S aureus (non-MRSA strains), H influenzae, H parainfluenzae, K pneumoniae, C pneumoniae, L pneumophila and M pneumoniae. It also possesses in vitro activity of unknown clinical significance against Enterococcus faecium (both vancomycin-susceptible and vancomycin-resistant strains), S agalactiae, E aerogenes, E coli, C freundii, C koseri, K oxytoca and M catarrhalis.

With IV doses of 100 mg, omadacycline reaches a steady state C_max of 2.12 mg/L and with 300 mg oral dosing, 0.95 mg/L. Its elimination half-life under these conditions is 16.0 and 15.5 hours, respectively. The oral bioavailability of omadacycline is 34.5% with a single 300 mg dose.

The efficacy of omadacycline for the treatment of CAP was compared to that of moxifloxacin in a trial of 774 adult patients. The two antibiotics were compared with respect to the proportion of patients achieving clinical success at the early clinical response timepoint (72-120 hours after the first dose), defined as survival with improvement in ≥2/4 symptoms of pneumonia and without deterioration in any of the symptoms. Omadacycline was shown to be noninferior to moxifloxacin, with 81.1% of patients in the omadacycline group achieving early clinical success, compared to 82.7% of patients in the moxifloxacin group.

For both methods of administration, omadacycline is given as an initial (loading) dose, followed by daily maintenance doses. For IV administration for the treatment of CAP, the loading dose is a single 60-minute infusion of 200 mg or two 30-minute infusions of 100 mg. The maintenance dose is a once-daily 30-minute infusion of 100 mg. For tablets, the loading dose is 300 mg twice daily, followed by 300 mg once daily as a maintenance dose. No dosage adjustment is necessary for patients with renal impairment.

Based on clinical trial experience in patients with CAP, the most common adverse reactions with omadacycline included ALT elevations, hypertension, gamma-glutamyl transferase elevations, insomnia, vomiting, constipation, nausea, AST elevations and headache.

Oxazolidinones

Linezolid

Linezolid is the first of a new class of synthetic antibacterial agents, the oxazolidinones. They inhibit the initiation phase of bacterial protein synthesis. Linezolid is active against staphylococci, including strains resistant to methicillin, glycopeptides and other antibacterial agents. The in vitro activity of linezolid against MRSA isolated between 1997 and 1999 reported 100% susceptibility to the drug MIC₉₀ 4 mg/L. Linezolid also shows good activity against penicillin-susceptible S pneumoniae (mean weighted MIC₉₀ 1 mg/L) and against strains of S pneumoniae with reduced susceptibility to penicillin (mean weighted MIC₉₀ 1.6 mg/L) and S pyogenes. Linezolid shows only moderate in vitro inhibitory activity against H influenzae (MIC₉₀ 8 mg/L) and M catarrhalis (MIC₉₀ 4 to 8 mg/L). Enterobacteriaceae and P aeruginosa are not susceptible to linezolid.

Linezolid is rapidly and completely absorbed after oral administration, with a mean absolute bioavailability of about 100%. In volunteers, steady-state peak plasma concentrations were ~12 and 18 mg/L after twice-daily administration of 375-mg and 625-mg oral doses, respectively. IV infusion of linezolid 500 or 625 mg twice daily for 7.5 days produced respective steady-state minimum serum concentration with multiple dosing (C_min) values of 3.5 and 3.8 mg/L. Linezolid is primarily metabolized by oxidation of the morpholine ring, resulting in the formation of two inactive metabolites. The T_1⁄2 is 4.5 to 5.5 hours at steady-state or after a single dose. The pharmacokinetics of linezolid are shown in Table 5-14.

Linezolid is an effective treatment for pneumonia, including nosocomial pneumonia and CAP requiring hospitalization. In a comparative trial, linezolid was as effective as established treatments including third-generation cephalosporins in patients with pneumonia. Oral linezolid 400 or 600 mg twice daily was as effective as clarithromycin 250 mg twice daily or cefpodoxime proxetil 200 mg twice daily in the treatment of patients with uncomplicated skin and skin structure infections or CAP. The most frequently reported adverse events in linezolid-treated patients are diarrhea (incidence 8.3%), headache (6.5%), nausea (6.2%) and vomiting (3.7%). Thrombocytopenia (platelet count <75% of the lower limit of normal and/or baseline values) occurred at a rate of 2.4% (range 0.3 to 10%) in patients treated with linezolid ≤600 mg twice daily for ≤28 days in phase 3 trials. In patients with infection caused by vancomycin-resistant E faecium or MRSA, the recommended dosage of linezolid is 600 mg every 12 hours. The drug may be given via IV infusion or orally. The recommended dosage of linezolid for the treatment of patients with nosocomial or CAP or complicated skin or skin structure infection is 600 mg every 12 hours for 10 to 14 days.

Pleuromutilin Class Antibiotics

Lefamulin

Lefamulin is a pleuromutilin class antibiotic approved by the FDA in 2019 for the treatment of CAP in adult patients. It binds the 50S subunit of the bacterial ribosome, inhibiting protein synthesis. At clinically relevant concentrations, lefamulin is bactericidal against certain species (S pneumoniae, H influenzae and M pneumoniae) and bacteriostatic against others (S aureus and S pyogenes). It is available in both an oral and powder form (for IV infusion).

Lefamulin has demonstrated activity in both in vitro and clinical settings against S pneumoniae, S aureus (non-MRSA), H influenzae, M pneumoniae, C pneumoniae and L pneumophila, and in vitro activity against S aureus (MRSA), S agalactiae, S anginosus, S mitis, S pyogenes, Streptococcus salivarius, H parainfluenzae and M catarrhalis. Lefamulin is not active against P aeruginosa or organisms in the Enterobacteriaceae family.

The steady-state C_max of lefamulin is 3.60 mg/L and 2.24 mg/L for IV and oral administration, respectively. The mean oral bioavailability of lefamulin is 25%, and the mean half-life is ~8 hours.

The efficacy of lefamulin for the treatment of CAP was assessed in two noninferiority clinical trials that enrolled a total of 1289 patients. The comparator antibiotic was moxifloxacin, and the primary efficacy endpoint was early clinical response (i.e., improvement in at least two pneumonia symptoms with no worsening of any symptom and no non-study antimicrobial treatment), assessed at 72-120 hours after the start of treatment. Lefamulin was shown to be noninferior to moxifloxacin in both trials. In the first trial, which tested the IV formulation of lefamulin, 87.3% and 90.2% of patients in the lefamulin and moxifloxacin group, respectively, achieved the primary endpoint. Similarly, in the second trial, which tested the oral formulation of lefamulin, primary endpoint attainment rates did not differ between the two groups (90.8% for lefamulin and 90.8% for moxifloxacin).

The recommended dose of lefamulin is 150 mg in a 60-minute IV infusion given every 12 hours for 5-7 days, or 600 mg by mouth every 12 hours for 5 days. Patients who start a course of treatment with the IV route can complete their treatment course by switching to the oral route at any point, at the discretion of the treating physician. No dosage adjustment is required for patients with impaired renal function.

The most common adverse events in the IV lefamulin trial included administration site reactions (infusion site pain, infusion site phlebitis and injection site reaction), liver enzyme elevations, nausea, hypokalemia, insomnia and headache. In the oral lefamulin trial, the most common adverse events included diarrhea, nausea, vomiting and liver enzyme elevations.