It has been reported that for every 1-hour delay of effective antimicrobial therapy in patients with septic shock, there is a 7.6% decrease in survival.^1,2 Inadequate empiric therapy has also been associated with increased length of hospital stay.^3,4 In addition to timing and choice of antimicrobials, understanding the pharmacokinetics is vital to providing adequate coverage while minimizing resistance.⁵

Antibiotics can interfere with protein synthesis or common metabolic pathways of the target cells and/or compromise the integrity of the cell wall. They can be classified as either bacteriostatic—ie, inhibiting the growth and replication of bacteria—or bactericidal. Bacteriostatic antibiotics rely on the host’s immune system in order to effectively clear the ­bacteria, whereas agents that are bactericidal are able to kill bacteria independent of the immune response.^6,7 These terms, however, are general categories and may not always apply for a given agent. For example, ampicillin and daptomycin, which are both regarded as bactericidal agents, are bacteriostatic against Enterococcus.⁸ Azithromycin, a member of the traditionally bacteriostatic macrolide class, is bactericidal against Legionella.⁹

The minimum inhibitory concentration (MIC) is conventionally used to describe the susceptibility of the microorganism to an antimicrobial agent and is set by the Clinical and Laboratory Standard Institute (CLSI) using microbiologic, pharmacodynamic/kinetic, and clinical data.¹⁰ It should be noted that MIC values are unique to the antibiotic with respect to an organism and cannot be compared across different agents. For example, levofloxacin with an MIC of less than 2 µg/mL is not less effective against Pseudomonas aeruginosa than piperacillin/tazobactam with an MIC of 4 µg/mL. In fact, in this scenario, levofloxacin would actually be categorized as “resistant,” since the MIC breakpoint for P aeruginosa is 1 µg/mL or less.¹¹ Although MICs are useful in identifying potentially effective antibiotics, these values must be interpreted cautiously, as they do not reflect variable in vivo processes such as penetration of the antibiotic into the site of infection.^10,12

Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) properties of antibiotics can potentially optimize drug therapy and increase clinical effectiveness. By combining relative MICs with the PK/PD parameters of the drugs, antibiotics can be categorized as time-dependent or concentration-dependent. Figure 21-1 and Table 21-1 illustrate the pharmacokinetic and pharmacodynamics indices and associated antibiotics. Antibiotics that are considered to be concentration-dependent, such as fluoroquinolones or aminoglycosides, require a high concentration above the MIC in order to ensure maximal bactericidal activity. For time-dependent antibiotics, activity against microorganisms correlates best with the duration of time the concentration remains above the MIC (T > MIC).¹² In order to reach optimal bactericidal activity against Gram-negative bacteria, the free drug concentration needs to exceed the MIC for 60% to 70% of the dosing interval for penicillins, 70% to 80% for cephalosporins, and 40% to 50% for carbapenems.^13,14 Therefore, to optimize dosage for time-dependent antibiotics, one may consider giving doses more frequently rather than increasing the administered dose.

Alternatively, continuous infusion or an extended duration (3–4 hours) of infusion may be an appropriate method of administration in select circumstances. Studies utilizing Monte Carlo simulations to predict clinical response have supported the use of prolonged infusion strategies for infections caused by Gram-negative organisms with higher MICs. As demonstrated by Lodise et al, the probability of obtaining adequate bactericidal activity for treating P aeruginosa with an MIC of 16 mg/L (the susceptibility breakpoint) utilizing a 30-minute standard infusion of piperacillin/tazobactam 3.375 g intravenously (IV) every 6 hours was less than 25%, while a 4-hour infusion of 3.375 g every 8 hours had a probability of target attainment of 100%.¹⁵

The β-lactam ring is a core component of many antibiotic classes, such as the penicillins, cephalosporins, carbapenems, and monobactams. Penicillins are among the first antibiotics that were developed and initially maintained excellent activity against staphylococci, but due to the development of resistance, most staphylococci now are resistant to natural penicillins. However, the class still has excellent activity against most streptococci, including Streptococcus pneumoniae, and Treponema pallidum, while maintaining moderate activity against enterococci. The antistaphylococcal penicillins (ie, nafcillin, oxacillin, and methicillin) were developed with modifications that provided this class with activity against methicillin-sensitive Staphylococcus aureus (MSSA). The aminopenicillins, such as ampicillin or amoxicillin, have increased activity against some enteric Gram-negative organisms and Haemophilus species; however, this class does not have adequate antistaphylococcal activity because staphylococci usually produce penicillinases. Piperacillin is currently the only penicillin antibiotic that possesses activity against the Pseudomonas species, but it must be combined with a β-lactamase inhibitor like tazobactam to have antistaphylococcal activity.¹⁶ The addition of β-lactamase inhibitors like tazobactam, sulbactam, or clavulanate not only enables activity against Staphylococcus species to the penicillins but also provides activity against anaerobes and β-lactamase–producing enteric Gram-negative organisms.^16,17

The cephalosporin class is categorized into 5 “generations” that correspond to their spectrum of activity. The Gram-negative activity of the cephalosporins increases with each increase in generation, but only cefepime and ceftazidime possess antipseudomonal activity. Alternatively, the Gram-positive activity of the cephalosporins declines as the ­generations increase, with the exception of the fifth-­generation antibiotics ceftaroline and ceftobiprole, which have activity against MRSA.^16-18

Carbapenems, which represent the most broad-­spectrum class, have activity against most Gram-negative, Gram-positive, and anaerobic organisms. The exception is ertapenem which is inactive against Pseudomonas species, Enterococcus species, and Acinetobacter species.¹⁸ The last member of the β-lactam antibiotics is aztreonam—the only monobactam, which has activity against Gram-negative organisms only, including Pseudomonas, and does not cover anaerobes.¹⁹ In general, the β-lactam antibiotics are very well tolerated, with nausea, vomiting, and diarrhea being the most reported side effects. All β-lactams, however, can cause hypersensitivity reactions ranging from mild rash to acute interstitial nephritis or anaphylaxis. Some β-lactams can have increased incidence of neurotoxicity (eg, seizures from carbapenems), which can occur when toxic levels of the antibiotic accumulate due to renal dysfunction.^17,18

Glycopeptide antibiotics (eg, vancomycin), linezolid, and daptomycin only possess activity against Gram-positive organisms including MRSA. The latter agents are also effective against vancomycin-resistant Gram-positive organisms (eg, vancomycin-resistant Enterococcus spp, or VRE). These anti-MRSA agents are associated with adverse effects, such as nephrotoxicity and ototoxicity with vancomycin, thrombocytopenia and serotonin toxicity with linezolid, and increased creatinine phosphokinase and rhabdomyolysis with ­daptomycin.²⁰ Metronidazole, a nitroimidazole, is active against anaerobes, Clostridium species, and protozoa.²¹ ­Clindamycin has activity against MRSA, streptococci, anaerobes, and certain protozoa.²² Trimethoprim/sulfamethoxazole (TMX/SMP) has adequate MRSA coverage as well as activity against Stenotrophomonas maltophilia and Pneumocystis ­jirovecii but possesses no pseudomonal or enterococcal coverage. In addition to causing hyperkalemia, TMX/SMP can also cause an increase in serum creatinine without affecting the glomerular filtration rate by inhibiting a cationic transport in the convoluted tubules of the kidney, which is responsible for creatinine secretion.²³

Fluoroquinolones have excellent oral bioavailability and a favorable side effect profile. Due to widespread use, Gram-negative resistance to these agents has increased and can vary by geographic region. These antibiotics can be categorized as “respiratory” (ie, levofloxacin and moxifloxacin) or “nonrespiratory” (ie, ciprofloxacin). It is important to note that these categories do not refer to the penetration of the fluoroquinolones into the lungs, since these drugs are able to concentrate in tissues (such as the lungs, kidneys, and prostate) at levels that exceed serum concentrations. Respiratory fluoroquinolones are thus named because they have activity against S pneumoniae (including penicillin-resistant strains) and can be initiated empirically for community-acquired ­pneumonia.^24,25 Fluoroquinolones have otherwise poor Gram-positive coverage (with the exception of levofloxacin and moxifloxacin’s activity against S pneumoniae) but have great activity against atypical and Gram-negative organisms, including Pseudomonas species. Moxifloxacin, a newer generation fluoroquinolone, has activity against anaerobes but lacks anti-pseudomonal activity. Although moxifloxacin previously had excellent activity against Bacteroides species, resistance has become prevalent.²⁶ The most notable adverse effects with the fluoroquinolone class are QT prolongation, central nervous system (CNS) side effects (confusion, dizziness, somnolence), neuropathy, and arthralgias.²⁴

Macrolide antibiotics are commonly used in both the inpatient and the outpatient setting. Although they have broad antimicrobial coverage, including excellent atypical coverage, there is increasing resistance to these agents, especially to S pneumoniae. This class is generally well tolerated, with gastrointestinal (GI) side effects being the most prevalent. Of the available agents, erythromycin has the most GI side effects as well as the most frequent dosing, which is why it is currently limited to use as a promotility agent.²⁵ Tetracyclines, such as minocycline and doxycycline, are also broad-spectrum antibiotics with excellent atypical coverage and have activity against community-acquired MRSA. These agents have poor anaerobe and Gram-negative coverage. Tigecycline, a tetracycline-derivative, can evade many of the tetracycline resistance mechanisms and has a similar spectrum of activity to the aforementioned class. In addition, tigecycline possesses activity against enterococci (including VRE), Gram-negatives organisms (with exception of ­Pseudomonas spp, Proteus spp, and Providencia spp), and anaerobes. ­Common side effects of these agents include nausea, vomiting, and diarrhea, as well as increased photosensitivity.^27,28 The aminoglycoside and the polymyxin classes (ie, colistin and polymyxin B) are used less frequently and are generally reserved for use in patients with multidrug-resistant Gram-negative infections due to an effort to preserve their activity and limit their use, due to the potential for systemic toxicity (eg, neurotoxicity and nephrotoxicity).^29,30

Antimicrobial resistance has continued to trend steadily upward over the past few decades and has given rise to multidrug-resistant organisms, or organisms that are nonsusceptible to at least 1 agent in 3 or more antibacterial classes.^31,32 There are 4 fundamental mechanisms by which antimicrobial resistance can develop: (1) alteration in the bacterial membrane permeability to antibiotics, (2) enzymatic degradation, (3) active efflux out of the bacterial cell, and (4) alteration of bacterial proteins that act as antimicrobial targets (Table 21-2).³³

For β-lactam antibiotics, the most common mechanism of resistance is through hydrolysis by enzymes such as β-lactamases, acylases, and esterases. β-Lactamases, encoded on bacterial chromosomes or plasmids, are the most important mechanisms of resistance. This enzyme, predominantly secreted by Gram-negative bacteria, catalyzes the β-lactam ring into an open position, which thereby removes the drug’s antibacterial properties. Extended spectrum β-lactamases (ESBLs) confer resistance to not only all penicillins and first- and second-generation cephalosporins (as seen with type I β-lactamases), but also to third-generation cephalosporins and aztreonam. Carbapenems and cephamycins (cefotetan and cefoxitin), however, are generally more resistant to degradation by most β-lactamases. In order to overcome β-lactamase–mediated resistance, certain antibiotics are coadministered with a β-lactamase inhibitor (ie, clavulanic acid, sulbactam, tazobactam)—that is, an agent that is capable of inhibiting β-lactamase activity.³⁴ Since the early 2000s, there has been a rise in the number of Klebsiella pneumoniae carbapenemase (KPC) producing bacteria, or more accurately, since other Gram-negative bacteria are capable of producing the same resistance mechanism, an increase in carbapenem-resistant Enterobacteriaceae (CRE). This resistance pattern renders all carbapenems ineffective.³⁵

β-Lactam antibiotics such as methicillin, nafcillin, and oxacillin have increased stability to Gram-positive β-lactamases; however, resistance to these agents can be mediated through alteration of the penicillin-binding proteins (PBPs). Production of an altered PBP2—such as PBP2a in Staphylococcus species or PBP2X in S pneumoniae, confers a much lower affinity for methicillin as well as most other β-lactams.^35,36 In addition to β-lactams, fluoroquinolones, macrolides, and lincosamides are other examples of antibiotics in which resistance is mediated via alteration of the target enzyme. In fluoroquinolones, the A subunit of DNA gyrase is altered so that it no longer binds to the antibiotic, while resistance to macrolides and lincosamides is due to methylation of adenine in the 23S ribosomal RNA.³³ Resistance to fluoroquinolones, as well as β-lactams and tetracyclines, can also develop via mutations in porins, which provide a path through the outer membrane of Gram-negative bacteria. Gram-negative resistance can also be mediated via production of genes that code for efflux pumps; efflux pumps can expel a wide array of molecules from both the cytoplasm and the periplasm of the bacterial cell and therefore can render an organism resistant to antibiotics.³⁷

In the 1980s, resistance to vancomycin was first identified within the Enterococcus species followed by the identification of vancomycin resistance in the Staphylococcus species. Vancomycin inhibits bacterial cell-wall formation by binding to the D-ala-D-ala portion of the cell wall precursor and therefore inhibits the synthesis of the peptidoglycan layer. Resistance to vancomycin, which is plasmid mediated and inducible, is believed to be due a transposon which alters the D-ala-D-ala to a dipeptide with a lower affinity for vancomycin, D-ala-D-lac.^38-40

Effective treatment of pneumonia requires the concentration of the antibiotic in the lung to be well above the MIC of the respective bacteria. Some systemically administered antibiotics, such as the β-lactams, polymyxins, and aminoglycosides, can have poor penetration into the lung parenchyma. An effective concentration can potentially be obtained by utilizing higher doses of the antibiotic, but this may increase the risk of systemic adverse effects. The rationale behind inhaled antibiotics is to maximize the drug delivery to the target site (ie, the lower airways) while minimizing the potential for systemic side effects.⁴¹ Clinical studies have successfully demonstrated that nebulized antibiotics are able to achieve a concentration in the epithelial lining fluid (ELF) far above the MICs for even multidrug-resistant pathogens. For example, in Badia et al, tobramycin was administered via nebulization to 6 critically ill patients who were mechanically ventilated for greater than 48 hours. The antibiotic concentration found in the patients’ bronchial specimens 1 hour after nebulization ranged from 68 mg/L to 855.7 mg/L, while serum drug concentrations were undetectable in 4 patients and were 0.4 mg/L and 0.6 mg/L in 2 of the patients.⁴²

One concern involving the use of nebulized antibiotics is the potential for development of systemic resistance. In traditional medical teaching, concentrations below the effective MIC of the invading pathogen is thought to encourage the selection of resistant mutants. However, it appears that the low systemic concentrations seen with nebulized antibiotics fall outside the mutant selection window and therefore reduce the risk of resistance.^43,44 ­Furthermore, studies involving both critically ill patients and patients with cystic fibrosis have not reported an increase in the emergence of resistance.^45-47

As few antibiotics have been formulated specifically for nebulized administration, intravenous preparations are usually administered utilizing a nebulizer. Ideal solutions for inhalation have a particle size in the range of 1 to 5 µm to effectively deposit in the alveoli. Although intravenous formulations are not designed to consistently deliver this ideal particle size, the use of a vibrating mesh nebulizer (which can produce particle sizes of 3 µm) can improve antibiotic delivery.⁴⁸ In addition, these formulations contain preservatives (eg, phenols) and may have suboptimal osmolarity, which can increase the risk of bronchospasm and ­coughing.⁴⁹ Antibiotics—such as colistin, tobramycin, and aztreonam—specifically formulated for nebulized administration have appeared on the market but are only approved by the US Food and Drug Administration (FDA) for patients with cystic fibrosis only.⁴¹

In the 2016 Clinical Practice Guidelines provided by the Infectious Diseases Society of America and the American Thoracic Society, the role of inhaled antibiotics was better elucidated to include patients with ventilator-associated pneumonia secondary to Gram-negative bacilli susceptible only to aminoglycosides or polymyxins. In this patient population, the concomitant use of inhaled and intravenous antibiotics was suggested, rather than the use of intravenous antibiotics alone.⁵⁰

Polyenes

The polyene agents include amphotericin B and nystatin. These agents bind to ergosterol in the fungal cell membrane, which disrupts cell permeability and results in rapid cell death. Nystatin is usually administered locally and for topical treatment due to its prohibitive toxicity when administered systemically.⁵¹ Amphotericin B’s broad spectrum of activity includes Aspergillus species (except for A terreus), ­Candida species (except C lusitaniae), Cryptococcus, ­Coccidioides ­species, Blastomyces, Histoplasma, and some activity against Mucorales and Fusarium species. In addition to the conventional formulation of amphotericin B deoxycholate (AmBd), newer lipid formulations have been developed, aiming to minimize amphotericin B’s nephrotoxicity. The lipid formulations include liposomal amphotericin B (AmBisome; L-AmB), amphotericin B lipid complex (Abelcet; ABLC), and amphotericin B colloidal dispersion (Amphotec; ABCD). Care should be taken when dosing amphotericin B, as weight-based dosing recommendations for lipid formulations (3–5 mg/kg/d) are 5 to 7 times that of the conventional amphotericin B deoxycholate (0.5–1.0 mg/kg/d). The most common adverse effects include nephrotoxicity, infusion-related reactions, and electrolyte imbalances (ie, hyperkalemia, hypokalemia, hypomagnesemia). To minimize nephrotoxicity, administering a saline load and maintaining adequate hydration has been recommended (eg, administering 500 mL of normal saline before and after each dose).^51-54 Resistance to amphotericin is infrequent; mechanisms include defects in the ERG3 gene leading to disruption in ergosterol biosynthesis and decreased ergosterol levels in the fungal membrane or increased catalase activity, which leads to decreased susceptibility to oxidative damage.⁵⁵

Azoles

Azoles exert their antifungal activity by inhibiting 14α-demethylase, a fungal cytochrome P450 (CYP)-­dependent enzyme, which impedes ergosterol synthesis and results in accumulation of methylsterols, growth arrest, and eventual fungal cell death. Agents in the azole class differ in spectrum of activity, tissue distribution, toxicities, and pharmacokinetic properties (Tables 21-3 and 21-4). Monitoring for drug-drug interactions is warranted due to collateral inhibition of human CYP enzymes. Concomitant use of medications that are CYP substrates (ie, fentanyl, methylprednisolone) and azoles may result in increased concentrations of the substrates, which may potentiate or prolong adverse effects.^51-53 As a class, azoles have been associated with QTc-interval prolongation (except for isavuconazole) and hepatotoxicity. Fluconazole is well tolerated. Itraconazole may cause gastrointestinal effects, hypokalemia, hypertension, and edema, and has negative inotropic properties. Voriconazole has been associated with rash with retinoid-like phototoxic reactions, photopsia, and visual disturbances.^51-53 Posaconazole and isavuconazole are well tolerated with reports of gastrointestinal side effects.^51-53,56 Resistance to azoles may be due to efflux pumps and/or mutations in ERG11, which encodes the target enzyme 14α-demethylase, among others.⁵⁵