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Pharmacology: Mechanism of Action: ZERBAXA is an antibacterial drug.
Pharmacodynamics: As with other beta-lactam antibacterial agents, the time that the plasma concentration of ceftolozane exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to be the best predictor of efficacy in animal models of infection.
For tazobactam the PD index associated with efficacy was determined to be the percentage of the dose interval during which the plasma concentration of tazobactam exceeds a threshold value (%T>threshold). The time above a threshold concentration has been determined to be the parameter that best predicts the efficacy of tazobactam in in vitro and in vivo nonclinical models.
The exposure-response analyses in efficacy and safety clinical trials for cIAI, cUTI, and nosocomial pneumonia support the recommended dose regimens of ZERBAXA.
Cardiac Electrophysiology: In a randomized, positive and placebo-controlled crossover thorough QTc study, 51 healthy subjects were administered a single therapeutic dose of ZERBAXA 1.5 gram (ceftolozane 1 g and tazobactam 0.5 g) and a supratherapeutic dose of ZERBAXA 4.5 gram (ceftolozane 3 g and tazobactam 1.5 g). No significant effects of ZERBAXA on heart rate, electrocardiogram morphology, PR, QRS, or QT interval were detected. Therefore, ZERBAXA does not affect cardiac repolarization.
CLINICAL STUDIES: Complicated Intra-abdominal Infections: A total of 979 adults hospitalized with cIAI were randomized and received study medications in a multinational, double-blind study comparing ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) intravenously every 8 hours plus metronidazole (500 mg intravenously every 8 hours) to meropenem (1 g intravenously every 8 hours) for 4 to 14 days of therapy. Complicated intra-abdominal infections included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, perforation of the intestine, and other causes of intra-abdominal abscesses and peritonitis.
The primary efficacy endpoint was clinical response, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 24 to 32 days after the first dose of study drug. The primary efficacy analysis population was the Clinically Evaluable (CE) population, which included all protocol adherent patients that received an adequate amount of study drug. The key secondary efficacy endpoint was clinical response at the TOC visit in the Intent-to-Treat (ITT) population, which included all randomized subjects regardless of whether or not the subjects went on to receive study drug.
The CE population consisted of 774 patients; the median age was 49 years and 58.7% were male. The most common diagnosis was appendiceal perforation or peri-appendiceal abscess, occurring in 47.7% of patients. Diffuse peritonitis at baseline was present in 35.9% of patients.
ZERBAXA plus metronidazole was non-inferior to meropenem with regard to clinical cure rates at the TOC visit in the CE population. Clinical cure rates at the TOC visit are displayed by patient population in Table 1. Clinical cure rates at the TOC visit by pathogen in the Microbiologically Evaluable (ME) population are presented in Table 2. The ME included all protocol adherent patients with at least 1 baseline intra-abdominal pathogen regardless of the susceptibility to study drug. (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageIn a subset of the E. coli and K. pneumoniae isolates from both arms of the cIAI Phase 3 trial that met pre-specified criteria for beta-lactam susceptibility, genotypic testing identified certain ESBL groups (e.g., TEM, SHV, CTX-M, OXA) in 53/601 (9%). Cure rates in this subset were similar to the overall trial results. In vitro susceptibility testing showed that some of these isolates were susceptible to ZERBAXA, while some others were not susceptible. Isolates of a specific genotype were seen in patients who were deemed to be either successes or failures.
Complicated Urinary Tract Infections, including Pyelonephritis: A total of 1068 adults hospitalized with complicated urinary tract infections (including pyelonephritis) were randomized and received study medications in a multinational, double-blind study comparing ZERBAXA (1.5 g IV every 8 hours) to levofloxacin (750 mg IV once daily) for 7 days of therapy. The primary efficacy endpoint was defined as microbiological eradication (all uropathogens found at baseline at ≥ 105 were reduced to <103 CFU/mL) at the test-of-cure (TOC) visit 7 (± 2) days after the last dose of study drug. The primary efficacy analysis population was the microbiologically evaluable (ME) population, which included protocol-adherent microbiologically modified intent-to-treat (mMITT) patients with a urine culture at the TOC visit. The key secondary efficacy endpoint was microbiological eradication at the TOC visit in the mMITT population, which included all patients who received study medication and had at least 1 baseline uropathogen.
The ME population consisted of 693 patients with cUTI, including 567 (82%) with pyelonephritis. The median age was 50 years and 73% were female. Concomitant bacteremia was identified in 50 (7.2%) patients at baseline.
ZERBAXA was superior to levofloxacin with regard to the microbiological eradication rates at the TOC visit in both the ME and mMITT populations (Table 3).
Microbiological eradication rates at the TOC visit by pathogen in the ME population are presented in Table 4. (See Tables 3 and 4.)
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Click on icon to see table/diagram/imageIn patients with levofloxacin-resistant pathogens at baseline, ZERBAXA was superior to levofloxacin with regards to microbiological eradication rate in the ME population, 58/89 (65.2%) in the ZERBAXA treatment arm and 42/99 (42.4%) in the levofloxacin treatment arm (95% CI: 22.7 [8.47, 35.73]).
In the ME population, the microbiological eradication rate in patients with concurrent bacteremia were 21/24 (87.5%) for ZERBAXA and 20/26 (76.9%) for levofloxacin.
In a subset of the E. coli and K. pneumoniae isolates from both arms of the cUTI Phase 3 trial that met pre-specified criteria for beta-lactam susceptibility, genotypic testing identified certain ESBL groups (e.g., TEM, SHV, CTX-M, OXA) in 104/687 (15%). Cure rates in this subset were similar to the overall trial results. In vitro susceptibility testing showed that some of these isolates were susceptible to ZERBAXA, while some others were not susceptible. Isolates of a specific genotype were seen in patients who were deemed to be either successes or failures.
Nosocomial Pneumonia, including Ventilator-associated Pneumonia: A total of 726 adult patients hospitalized with ventilated nosocomial pneumonia (including hospital-acquired pneumonia and ventilator-associated pneumonia) were enrolled in a multinational, double-blind study comparing ZERBAXA 3 g (ceftolozane 2 g and tazobactam 1 g) intravenously every 8 hours to meropenem (1 g intravenously every 8 hours) for 8 to 14 days of therapy.
The primary efficacy endpoint was all-cause mortality at Day 28. Clinical response, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 7 to 14 days after the end of treatment was a pre-specified key secondary endpoint. The analysis population for both the primary and key secondary endpoints was the intent-to-treat (ITT) population, which included all randomized patients.
Of the 726 patients in the ITT population the median age was 62 years and 44% of the population was greater than or equal to 65 years of age, with 22% of the population greater than or equal to 75 years of age. The majority of patients were white (83%), male (71%) and were from Eastern Europe (64%). The median APACHE II score was 17 and 33% of subjects had a baseline APACHE II score of greater than or equal to 20. All subjects were on mechanical ventilation and 519 (71%) had VAP. At randomization, the majority of subjects had been hospitalized for greater than or equal to 5 days (77%), ventilated for greater than or equal to 5 days (49%) and in an ICU (92%). Approximately 36% of patients had renal impairment at baseline and 14% had moderate or severe impairment (CrCL less than 50 mL/min). Approximately 13% of subjects had failed prior antibiotic treatment for nosocomial pneumonia and bacteremia was present at baseline in 15% of patients. Key comorbidities included chronic obstructive pulmonary disease (COPD), diabetes mellitus, and congestive heart failure at rates of 12%, 22% and 16%, respectively.
In the ITT population, ZERBAXA was non-inferior to meropenem with regard to the primary endpoint of all-cause mortality at Day 28 and key secondary endpoint of clinical cure rates at the TOC visit (see Table 5).
Click on icon to see table/diagram/imageIn the ITT population, Day 28 all-cause mortality rates in patients with renal hyperclearance at baseline (CrCL greater than or equal to 150 mL/min) were 10/67 (14.9%) for ZERBAXA and 7/64 (10.9%) for meropenem; the clinical cure rates were 40/67 (59.7%) and 39/64 (60.9%), respectively. In those patients who failed prior antibiotic therapy for nosocomial pneumonia, Day 28 all-cause mortality rates were 12/53 (22.6%) for ZERBAXA and 18/40 (45%) for meropenem; the clinical cure rates were 26/53 (49.1%) and 15/40 (37.5%), respectively. In patients with bacteremia at baseline, Day 28 all-cause mortality rates were 23/64 (35.9%) for ZERBAXA and 13/41 (31.7%) for meropenem; clinical cure rates were 30/64 (46.9%) and 15/41 (36.6%), respectively.
Per pathogen clinical and microbiologic responses were assessed in the microbiologic intention to treat population (mITT), which consisted of all randomized subjects who had a baseline lower respiratory tract (LRT) pathogen that was susceptible to at least one of the study therapies, and in the microbiologically evaluable (ME) population, which included protocol-adherent mITT patients with a baseline LRT pathogen that grew at the appropriate colony-forming unit (CFU)/mL threshold. In the mITT and ME populations, Klebsiella pneumoniae (34.6% and 38.6%, respectively) and Pseudomonas aeruginosa (25% and 28.8%, respectively) were the most prevalent pathogens isolated from baseline LRT cultures. Among all Enterobacteriaceae, 157 (30.7%) in the mITT and 84 (36.1%) in the ME were ESBL-positive; among all K. pneumoniae isolates, 105 (20.5%) in the mITT and 57 (24.5%) in the ME were ESBL-positive. AmpC-overexpression among P. aeruginosa was detected in 15 (2.9%) and 9 (3.9%) of the P. aeruginosa isolates in the mITT and ME populations, respectively. Clinical cure rates at TOC by pathogen in the mITT and ME populations are presented in Table 6. In the mITT population clinical cure rates in patients with a Gram-negative pathogen at baseline were 157/259 (60.6%) for ZERBAXA and 137/240 (57.1%) for meropenem; results were consistent in the ME population with 85/113 (75.2%) and 78/117 (66.7%) clinical cure rates, respectively. Microbiologic response rates at TOC by pathogen in the mITT and ME populations are presented in Table 7. In the mITT population microbiologic response rates in patients with a Gram-negative pathogen at baseline were 189/259 (73%) for ZERBAXA and 163/240 (67.9%) for meropenem; results were consistent in the ME population with 79/113 (69.9%) and 73/117 (62.4%) microbiologic response rates, respectively. (See Tables 6 and 7.)
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Click on icon to see table/diagram/imageIn the mITT population, per subject microbiologic cure was achieved in 193/264 (73.1%) of ZERBAXA-treated patients and in 168/247 (68.0%) of meropenem-treated patients. Similar results were achieved in the ME population in 81/115 (70.4%) and 74/118 (62.7%) patients, respectively.
In a subset of Enterobacteriaceae isolates from both arms of the trial that met pre-specified criteria for beta-lactam susceptibility, genotypic testing identified certain ESBL groups (e.g., TEM, SHV, CTX-M, OXA) in 157/511 (30.7%). Cure rates in this subset were similar to the overall trial results.
Pharmacokinetics: General Introduction: The mean pharmacokinetic parameters of ZERBAXA (ceftolozane and tazobactam) in healthy adults with normal renal function after multiple 1-hour intravenous infusions of ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) or 3 g (ceftolozane 2 g and tazobactam 1 g) administered every 8 hours are summarized in Table 8. Ceftolozane and tazobactam pharmacokinetics are similar following single- and multiple-dose administration. The Cmax and AUC of ceftolozane and tazobactam increase in proportion to dose. The elimination half-life (t½) of ceftolozane or tazobactam is independent of dose. (See Table 8.)
Click on icon to see table/diagram/imageThe mean steady-state population pharmacokinetic parameters of ZERBAXA in patients with cIAI and cUTI receiving 1 hour intravenous infusion of ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) or patients with nosocomial pneumonia receiving 1 hour intravenous infusion of ZERBAXA 3 g (ceftolozane 2 g and tazobactam 1 g) every 8 hours are summarized in Table 9. (See Table 9.)
Click on icon to see table/diagram/imageDistribution: The binding of ceftolozane and tazobactam to human plasma proteins is approximately 16% to 21% and 30%, respectively. The mean (CV%) steady-state volume of distribution of ZERBAXA in healthy adult males (n = 51) following a single intravenous dose of ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) was 13.5 L (21%) and 18.2 L (25%) for ceftolozane and tazobactam, respectively, similar to extracellular fluid volume.
Following 1 hour intravenous infusions of ZERBAXA 3 g (ceftolozane 2 g and tazobactam 1 g) or adjusted based on renal function every 8 hours in ventilated patients with confirmed or suspected pneumonia (N=22), ceftolozane and tazobactam concentrations in pulmonary epithelial lining fluid were greater than 8 mcg/mL and 1 mcg/mL, respectively, over 100% of the dosing interval. Mean pulmonary epithelial-to-free plasma AUC ratios of ceftolozane and tazobactam were approximately 50% and 62%, respectively and are similar to those in healthy subjects (approximately 61% and 63%, respectively) receiving ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g).
Metabolism: Ceftolozane is mainly eliminated in the urine as unchanged parent drug and thus does not appear to be metabolized to any appreciable extent. The beta-lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive, tazobactam metabolite M1.
Elimination: Ceftolozane, tazobactam, and the tazobactam metabolite M1 are eliminated by the kidneys. Following administration of a single 1 g / 0.5 g IV dose of ceftolozane/tazobactam to healthy male adults greater than 95% of ceftolozane was excreted in the urine as unchanged parent substance. More than 80% of tazobactam was excreted as the parent compound with the remaining amount excreted as the tazobactam M1 metabolite. After a single-dose of ZERBAXA, renal clearance of ceftolozane (3.41 - 6.69 L/h) was similar to plasma clearance (4.10 - 6.73 L/h) and similar to the glomerular filtration rate for the unbound fraction, suggesting that ceftolozane is eliminated by the kidney via glomerular filtration.
The mean terminal elimination half-life of ceftolozane and tazobactam in healthy adults with normal renal function is approximately 3 hours and 1 hour, respectively.
Special Populations: Renal Impairment: Ceftolozane, tazobactam, and the tazobactam metabolite M1 are eliminated by the kidneys.
The ceftolozane dose normalized geometric mean AUC increased up to 1.26-fold, 2.5-fold, and 5-fold in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects with normal renal function. The respective tazobactam dose normalized geometric mean AUC increased approximately up to 1.3-fold, 2-fold, and 4-fold. To maintain similar systemic exposures to those with normal renal function, dosage adjustment is required [see Renal Impairment under Dosage & Administration].
In subjects with ESRD on HD, approximately two-thirds of the administered ceftolozane/tazobactam dose is removed by HD. The recommended dose in cIAI or cUTI subjects with ESRD on HD is a single loading dose of ZERBAXA 750 mg (ceftolozane 500 mg and tazobactam 250 mg), followed by a ZERBAXA 150 mg (ceftolozane 100 mg and tazobactam 50 mg) maintenance dose administered every 8 hours for the remainder of the treatment period. The recommended dose in nosocomial pneumonia subjects with ESRD on HD is a single loading dose of ZERBAXA 2.25 g (ceftolozane 1.5 g and tazobactam 0.75 g), followed by a ZERBAXA 450 mg (ceftolozane 300 mg and tazobactam 150 mg) maintenance dose administered every 8 hours for the remainder of the treatment period. With HD, the dose should be administered immediately following completion of dialysis [see Renal Impairment under Dosage & Administration].
Augmented renal clearance: Following a single 1 hour intravenous infusion of ZERBAXA 3 g (ceftolozane 2 g and tazobactam 1 g) to critically ill patients with CrCL greater than or equal to 180 mL/min (N=10), mean terminal half-life values of ceftolozane and tazobactam were 2.6 hours and 1.5 hours, respectively. Free plasma ceftolozane concentrations were greater than 8 mcg/mL over 70% of an 8-hour period; free tazobactam concentrations were greater than 1 mcg/mL over 60% of an 8-hour period. No dose adjustment of ZERBAXA is recommended for nosocomial pneumonia patients with augmented renal clearance [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
Hepatic impairment: As ceftolozane/tazobactam does not undergo hepatic metabolism, the systemic clearance of ceftolozane/tazobactam is not expected to be affected by hepatic impairment. No dose adjustment is recommended for ZERBAXA in subjects with hepatic impairment [see Hepatic impairment under Dosage & Administration].
Elderly: In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in AUC were observed with regard to age. No dose adjustment of ZERBAXA based on age alone is recommended. Dosage adjustment for ZERBAXA in elderly patients should be based on renal function [see Renal Impairment under Dosage & Administration].
Paediatric patients: Safety and efficacy in paediatric patients have not been established.
Gender: In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in AUC were observed for ceftolozane and tazobactam. No dose adjustment is recommended based on gender.
Race: In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in ceftolozane/tazobactam AUC were observed in Caucasians compared to other races. No dose adjustment is recommended based on race.
Drug Interaction Studies: See Interactions.
Toxicology: ANIMAL TOXICOLOGY: Carcinogenesis: Long-term carcinogenicity studies in animals have not been conducted with ZERBAXA, ceftolozane, or tazobactam.
Mutagenesis: ZERBAXA was not genotoxic in vivo. ZERBAXA was negative for genotoxicity in an in vitro mouse lymphoma assay and an in vivo rat bone marrow micronucleus assay. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, ZERBAXA was positive for structural aberrations, but only at highly toxic concentrations.
Ceftolozane was negative for genotoxicity in the in vitro microbial mutagenicity (Ames) assay, the in vitro chromosomal aberration assay in Chinese hamster lung fibroblast cells, the in vitro mouse lymphoma assay, the in vitro HPRT assay in Chinese hamster ovary cells, the in vivo mouse micronucleus assay, and the in vivo unscheduled DNA synthesis (UDS) assay.
Tazobactam was negative for genotoxicity in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosomal aberration assay in Chinese hamster lung cells, a mammalian point-mutation (Chinese hamster ovary cell HPRT) assay, an in vivo rat chromosomal aberration assay, an in vivo mouse bone marrow micronucleus assay, and a UDS assay. Tazobactam was positive for genotoxicity in an in vitro mouse lymphoma assay at ≥ 3000 mcg/mL.
Reproduction: Ceftolozane had no adverse effect on fertility in male or female rats at intravenous doses up to 1000 mg/kg/day. The mean plasma exposure (AUC) value at this dose is approximately 1.4 times the mean daily human ceftolozane exposure value at the highest recommended human dose of 2 grams every 8 hours.
In a rat fertility study with intraperitoneal tazobactam twice-daily, male and female fertility parameters were not affected at doses less than or equal to 640 mg/kg/day (approximately 2 times the highest recommended human dose of 1 gram every 8 hours based on body surface comparison).
Development: See Pregnancy under Use in Pregnancy & Lactation.
Microbiology: Mechanism of Action: Ceftolozane belongs to the cephalosporin class of antimicrobials. Ceftolozane exerts bactericidal activity through binding to important penicillin-binding proteins (PBPs), resulting in inhibition of bacterial cell wall synthesis and subsequent cell death. Ceftolozane is an inhibitor of PBPs of P. aeruginosa (e.g., PBP1b, PBP1c and PBP3) and E. coli (e.g., PBP3).
Tazobactam is a beta-lactam structurally related to penicillin. It is an inhibitor of many Molecular Class A beta-lactamases, including CTX M, SHV, and TEM enzymes [see Resistance as follows].
ZERBAXA demonstrated in vitro activity against Enterobacteriaceae in the presence of some extended-spectrum beta-lactamases (ESBLs) and other beta-lactamases of the following groups: TEM, SHV, CTX-M, and OXA. ZERBAXA also demonstrated in vitro activity against P. aeruginosa isolates tested that had chromosomal AmpC, loss of outer membrane porin (OprD), or up-regulation of efflux pumps (MexXY, MexAB).
In the 2017 PACTS (Program to Assess Ceftolozane/Tazobactam Susceptibility) surveillance study the overall ceftolozane/tazobactam susceptibility of 3937 Enterobacteriaceae isolates collected from all sources from US hospitals was 95.6% and against extended spectrum beta-lactamase (ESBL), non-carbapenem resistant Enterobacteriaceae isolates the percent ceftolozane/tazobactam susceptibility was 93.5%. The overall ceftolozane/tazobactam susceptibility of 910 P. aeruginosa isolates collected from US hospitals was 97.7%. When ceftolozane/tazobactam was tested against isolates non-susceptible to ceftazidime, meropenem or piperacillin/tazobactam, the percent susceptibility to ceftolozane/tazobactam was 87.2%, 91.3% and 89.5%, respectively.
Resistance: Mechanisms of bacterial resistance to ceftolozane and tazobactam include: Production of beta-lactamases that can hydrolyse ceftolozane and which are not inhibited by tazobactam (see as follows); Modification of PBPs.
Tazobactam does not inhibit all Class A enzymes.
In addition, tazobactam does not inhibit the following types of beta-lactamase: Serine-based carbapenemases (e.g., Klebsiella pneumoniae carbapenemases [KPCs]); Metallo-beta-lactamases (e.g., New Delhi metallo-beta-lactamase [NDM]); Ambler Class D beta-lactamases (OXA-carbapenemases).
Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.
Cross-Resistance: Isolates resistant to other cephalosporins may be susceptible to ceftolozane and tazobactam, although cross-resistance may occur.
Interaction with Other Antimicrobials: In vitro synergy studies suggest no antagonism between ceftolozane and tazobactam and other antibacterial drugs (e.g., meropenem, amikacin, aztreonam, levofloxacin, tigecycline rifampin, linezolid, daptomycin, vancomycin, and metronidazole).
List of Microorganisms: ZERBAXA has been shown to be active against the following bacteria, both in vitro and in clinical infections [see Indications/Uses].
Complicated Intra-abdominal Infections: Gram-negative bacteria: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa.
Gram-positive bacteria: Streptococcus anginosus, Streptococcus constellatus, Streptococcus salivarius.
Anaerobic bacteria: Bacteroides fragilis.
Complicated Urinary Tract Infections, Including Pyelonephritis: Gram-negative bacteria: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa.
Nosocomial Pneumonia, including Ventilator-associated Pneumonia: Gram-negative bacteria: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella (Enterobacter) aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens.
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftolozane and tazobactam against isolates of similar genus or organism group. However, the efficacy of ZERBAXA in treating clinical infections due to these bacteria has not been established in adequate and well controlled clinical trials.
Gram-negative bacteria: Citrobacter koseri, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Serratia liquefaciens.
Gram-positive bacteria: Streptococcus agalactiae, Streptococcus intermedius. (See Table 10.)
Click on icon to see table/diagram/imageA report of "Susceptible" indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard ceftolozane and tazobactam powder should provide the following range of MIC values provided in Table 11. For the diffusion technique using the 30 mcg ceftolozane / 10 mcg tazobactam disk, the criteria provided in Table 11 should be achieved. (See Table 11.)
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