The Yin and Yang of Ceftolozane-Tazobactam Resistance Against Multidrug-Resistant Pseudomonas aeruginosa

Multidrug-resistant (MDR) Pseudomonas aeruginosa is a major public health threat. Rates of hospital-onset MDR P aeruginosa infections increased 32% from 2019 to 2020.¹ P aeruginosa exhibits inherent and acquired mechanisms of resistance, including an impermeable outer membrane, repression or inactivation of the porin oprD, upregulation of efflux pumps, increased production of chromosomal AmpC β-lactamase, and the presence of other antibiotic-inactivating enzymes.^2-7 In fact, “difficult to treat” resistance (DTR) phenotypes are commonly encountered in clinical practice and are defined as nonsusceptibility to traditional treatment options, including all β-lactams and fluoroquinolones.⁸

Current guidance from the Infectious Diseases Society of America for the management of serious infections due to DTR P aeruginosa is monotherapy with either ceftolozane-tazobactam, ceftazidime-avibactam, or imipenem-relebactam, with cefiderocol as an alternative.⁹ The European Society of Clinical Microbiology and Infectious Diseases recommends monotherapy with ceftolozane-tazobactam, but not with imipenem-relebactam, ceftazidime-avibactam or cefiderocol due to a lack of clinical evidence.¹⁰

Ceftolozane demonstrates excellent in vitro activity against DTR P aeruginosa and does not require a β-lactamase inhibitor to restore activity.⁹ Ceftolozane is an oxyimino-cephalosporin that is structurally similar to ceftazidime but is more potent in vitro. Ceftolozane is unique because it is a potent PBP3 inhibitor and has greater than 2-fold higher affinities for all essential penicillin-binding proteins in P aeruginosa compared with ceftazidime.¹¹ Moreover, ceftolozane has low affinity for PBP4, which is a known trap target for β-lactams connected to AmpC induction.¹²

Ceftolozane is also stable against hydrolysis from chromosomal AmpC β-lactamases, also known as Pseudomonas-derived cephalosporinase (PDC).^11,13 This stability is the result of the substitution of a pyrazole side chain on the 3-position of the cephem ring that provides steric hindrance between ceftolozane and the gate to the PDC active-site binding pocket and increased permeability through the outer cell membrane.^14,15 The activity of ceftolozane is not affected by efflux pumps or inactivation of oprD.¹³

Combining ceftolozane with tazobactam does not extend activity against DTR P aeruginosa. Rather, tazobactam inhibits some class A extended-spectrum β-lactamases and susceptible class C β-lactamases (eg, CMY) but not class A, B, or D carbapenemases.^16-19 By comparison, avibactam and relebactam are potent inhibitors of most class A and C β-lactamases and are capable of restoring the in vitro activity of ceftazidime and imipenem, respectively, against DTR P aeruginosa.^20,21

CLINICAL EXPERIENCE TREATING MDR P AERUGINOSA INFECTIONS

Four randomized, controlled trials have assessed the efficacy of ceftolozane-tazobactam vs other antibiotics for treatment of complicated urinary tract infection, complicated intra-abdominal infection, and hospital-acquired or ventilator-associated bacterial pneumonia.^22-25 Across all 4 studies, however, few patients infected by MDR and DTR P aeruginosa have been evaluated. Thus, real-world clinical data have been essential in assessing the efficacy of ceftolozane-tazobactam compared with traditional antipseudomonal regimens used to treat MDR P aeruginosa infections.

Clinical outcomes were evaluated in a retrospective, multicenter cohort study that compared ceftolozane-tazobactam with either a polymyxin or an aminoglycoside-based regimen as definitive therapy for infections due to MDR/extensively drug-resistant P aeruginosa (52% of participants had ventilator-associated bacterial pneumonia). The receipt of ceftolozane-tazobactam was independently associated with clinical cure; the number needed to treat for a clinical cure was 5. Ceftolozane-tazobactam was also found to be protective against acute kidney injury.²⁶

Five randomized, controlled trials have assessed the efficacy of ceftazidime-avibactam vs traditional antipseudomonal agents in the treatment of complicated urinary tract infection, complicated intra-abdominal infection, and nosocomial pneumonia including ventilator-associated pneumonia.^27-31 In a pooled analysis of patients with MDR P aeruginosa infections who received ceftazidime-avibactam vs best available therapy (mostly carbapenems), clinical responses were similar, at 57% and 54%, respectively; however, only 66% of isolates were susceptible to ceftazidime-avibactam.³² There is even less clinical experience with imipenem-relebactam and cefiderocol.

Taken together, there remains an overall paucity of comparative clinical evidence for the management of carbapenem-resistant P aeruginosa.

MECHANISMS OF RESISTANCE TO CEFTOLOZANE-TAZOBACTAM AND CROSS-RESISTANCE TO OTHER β-LACTAMS

The development of resistance to each of the previously mentioned agents (like other β-lactams) was reported shortly after FDA approval.

Ceftolozane-tazobactam resistance is most commonly mediated through structural alterations in PDC, a chromosomally encoded class C β-lactamase in P aeruginosa.³³ Amino acid substitutions, insertions, and deletions in PDC have been reported and likely facilitate more efficient hydrolysis of ceftolozane.^{16, 33-40} Specific modifications typically occur in or bordering a region of PDC known as the Ω-loop. The Ω-loop functions to form the floor of the active site in PDC, which binds to the R1 group of β-lactam molecules and determines substrate specificity.⁴¹ Amino acid substitutions within the Ω-loop result in widening of the active site to better accommodate the bulky R2 group of ceftolozane, facilitating hydrolysis.^33,40

A wider binding pocket also accommodates ceftazidime better.⁴² In fact, enzyme kinetics of common PDC mutations (E247K, G183D, T96I, and ΔG229-E247) demonstrate greater catalytic efficiencies to both ceftolozane and ceftazidime compared with wild-type PDC. The same PDC mutations further showed decreased affinity for avibactam, reducing PDC’s susceptibility to inhibition by avibactam.⁴³

Other mechanisms may play a complementary role in ceftolozane-tazobactam resistance, which includes overexpression of PDC. Derepression of PDC can result from mutations in the genes involved in AmpC regulation, namely ampR, ampG, ampD, and dacB.^{33, 40} Less common mechanisms that have been reported include mutations in the DNA polymerase subunits gama and tau or ftsI (which encodes PBP3).^42,44,45 Reported rates of treatment-emergent resistance to ceftolozane-tazobactam range from 3% to 50% across observational studies.^37,42,46-48 Definitions of resistance have varied across studies.

In one study, resistance was defined as a 4-fold or greater ceftolozane-tazobactam minimum inhibitory concentration (MIC) increase against P aeruginosa isolates collected after 72 or more hours of treatment. Isolates from 14 of 28 patients met the study definition after a median of 15 days of therapy.⁴¹ Such cases were more likely to have inadequate source control and less likely to receive ceftolozane-tazobactam as an extended 3-hour infusion compared with control patients whose isolates did not evolve resistance. Common mutations were identified in ampC, ampR, DNA polymerase subunits gama and tau, and ftsI. Notably, 86% of isolates showed high-level cross-resistance to ceftazidime-avibactam without prior ceftazidime-avibactam exposure.⁴¹

In a study by Haidar et al, ceftolozane-tazobactam resistance was defined as a MIC greater than or equal to 16 μg/mL. Three of 21 patients (14%) developed ceftolozane-tazobactam resistance as early as 8 days into treatment. Whole-genome sequence analyses demonstrated mutations in the ampC-ampR region of resistant isolates.⁴⁷

In a Spanish study, ceftolozane-tazobactam resistance (MIC ≥ 32 μg/mL) developed in 8 of 58 patients (14%). In 6 of 8 cases, resistance was due to structural modifications in AmpC. Interestingly, all 6 cases were associated with baseline isolates that harbored preexisting mutations in the AmpC repressor gene, ampR. In the other 2 cases, mutations in OXA-10 were identified. Overall, 88% of cases were associated with cross-resistance to ceftazidime-avibactam.^37,45

Cross-resistance between ceftolozane-tazobactam and other novel β-lactams has also been reported. Cefiderocol is a siderophore cephalosporin that demonstrates excellent in vitro activity against DTR P aeruginosa.⁴⁹ Interestingly, Streling et al described a P aeruginosa isolate that developed nonsusceptibility to cefiderocol after 14 days of ceftolozane-tazobactam treatment without cefiderocol exposure. Mutations in PDC were associated with ceftolozane-tazobactam resistance, and mutations in PiuD and PirA (TonB-dependent receptors) were associated with elevated MICs to cefiderocol.^50,51

TREATMENT OF CEFTOLOZANE-TAZOBACTAM–RESISTANT P AERUGINOSA IN CLINICAL PRACTICE

Familiarity of resistance mechanisms is essential in selecting the most appropriate treatment when ceftolozane-tazobactam resistance is identified. In some cases, metallo-β-lactamase (MBL) genes may be present, which manifest in resistance to ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-relebactam.⁵² MBLs can hydrolyze all β-lactams except aztreonam and are not inhibited by novel β-lactamase inhibitors. Additionally, MBL-producing P aeruginosa infections have been associated with more rapid onset of illness and faster progression to death compared with non–MBL-producing P aeruginosa infections.⁵³

Cefiderocol employs a “Trojan horse” strategy by exploiting the bacterial iron siderophore uptake system to allow active transport across the bacterial outer membrane and is stable against MBL-mediated hydrolysis.^54-56 A post hoc analysis of 2 randomized controlled trials (CREDIBLE-CR and APEKS-NP) highlighted the role of cefiderocol in treating infections caused by MBL-producing pathogens, with 41% (14/34) of patients infected with MBL-producing nonfermenting species like P aeruginosa.^56-58 Cefiderocol led to numerically higher clinical cure and microbiological eradication rates compared with best available therapy in patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infections. These outcomes were consistent across species and cefiderocol MIC values up to 4 μg/ mL.⁵⁷ Local epidemiology and rates of MBL should be known to assist in therapeutic decision-making.

In a patient with prior treatment of a ceftolozane-tazobactam–susceptible P aeruginosa isolate, it would be important to consider the possibility of treatment-emergent resistance and cross-resistance to ceftazidime-avibactam. Fortunately, other β-lactam antibiotics may demonstrate collateral susceptibility in these situations. In a study by Rubio et al, in vitro susceptibility of MDR P aeruginosa isolates was assessed before and after the development of resistance to ceftolozane-tazobactam (median duration of therapy = 16 days). AmpC mutations were identified in 79% of paired isolates before and after ceftolozane-tazobactam treatment. Postexposure isolates with AmpC mutations were more susceptible to imipenem-relebactam, piperacillin-tazobactam, and imipenem by 2-, 4-, and 8-fold, respectively, vs baseline isolates. Sixty-three percent of all postexposure isolates were susceptible to imipenem-relebactam, including 81% of isolates with treatment-emergent mutations in AmpC.⁵⁹

Similar findings were observed by Díaz- Cañestro et al in a study of 58 patients treated with ceftolozane-tazobactam, 8 of whom developed treatment-emergent resistance.⁴⁶ It is proposed that the widening of the substrate binding site that occurs in AmpC structural mutations allows imipenem to rotate its 6α-hydroxyethyl side chain away from the point of hydrolytic attack, translating into increased carbapenem susceptibility.^60-62 In a ceftolozane-tazobactam-resistant P aeruginosa isolate, imipenem-relebactam would be preferred vs imipenem because the addition of relebactam would also combat AmpC hyperproduction.38 Cefiderocol may be a consideration in these scenarios as well; however, cross-resistance has been described.^49,50

In general, in vitro susceptibility testing should always be performed whenever possible to guide decision-making against MDR/DTR/extensively drug-resistant P aeruginosa given the complexity of the underlying mechanisms of resistance. Comparative effectiveness studies are also notably lacking for the novel antipseudomonal agents. Thus, understanding these mechanisms and interplay of β-lactam resistance can be vital when faced with selecting treatment in these challenging clinical scenarios.

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