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


Rates of hospital-onset multidrug-resistant P aeruginosa infections have increased significantly in recent years.

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


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.


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


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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