Antibiotic Doripenem Essay Example

Individuals with pyelonephritis and acute concomitant sickness have severe tissue infection and are in danger of bacteremia. the advantage is realized due to early admission for discussion and concentrated parenteral antimicrobial treatment (Klostranec and Kolin 2012).The infection normally begins from the lower urinary tract as a UTI. Bacteria penetrate one’s body through the urethra and start to multiply and increase up the track. From the bladder, the microorganisms propagate up through the urethras to the kidneys. Bacteria such as Escherichia coli usually acknowledged as E. coli often ground the contagion. But any severe infectivity in the bloodstream can extend to the kidneys and lead to acute pyelonephritis (Madara and Pomarico-Denino 2008).Chronic pyelonephritis is more frequent in youngsters or in individuals with urinary obstructions. When the urinary region is of abnormal shape or size, it is more probable that illness can cause acute pyelonephritis.Antibiotic Doripenem Essay Example.  Any person with persistent kidney stones or other kidney or bladder situation is also a danger. At any time there is a problem that interrupts the normal run of urine there is a bigger threat of sensitive pyelonephritis (Madara and Pomarico-Denino 2008).Ascending urinary tract infection: 75% of pyelonephritis circumstances are because of E. coli. ten to fifteen percent are caused by additional Gram-negative rods, Enterobacter, Proteus, Klebsiella. others consist of Pseudomonas, Citrobacter and Serratia (Schlossberg 2008). Gram-positive agents comprise Enterococcus faecalis and, not common, Staphylococcus aureus anaerobesThe antimicrobial fight has been influencing the discipline of communicable diseases since the detection of penicillin (Mayers 2008).

Pharmacology and mechanism of action

Beta-lactam antibiotic of the carbapenems class with broad spectrum of activity. Action on cell wall is similar to other beta-lactams, which is to bind penicillin-binding proteins (PBPs) that weaken or interfere with cell wall formation. In Escherichia coliand Pseudomonas aeruginosa, doripenem binds to PBP 2, which is involved in the maintenance of cell shape, and to PBPs 3 and 4. Carbapenems have a broad spectrum of activity and are among the most active of all antibiotics. Doripenem has similar activity as imipenem and meropenem to include gram-negative bacilli, including Enterobacteriaceaeand P. aeruginosa. It is slightly more active against P. aeruginosa. It also is active against most gram-positive bacteria, except methicillin-resistant strains of Staphylococcus.Antibiotic Doripenem Essay Example.  It is not active against

Doripenem (S-4661) is a new parenteral antibiotic from the carbapenem class; similarly to imipenem and meropenem, it has a broad-spectrum activity against Gram-positive, Gram-negative, and anaerobic bacteria. It is active against multiresistant Gram-negative bacilli such as extended-spectrum beta-lactamase-producing (ESBL) Gram-negative Enterobacteriaceae and nonfermentative Gram-negative bacilli including some strains of Pseudomonas aeruginosa that are resistant to other carbapenems. Doripenem’s chemical structure is similar to that of meropenem (substitution of one sulfamoxil-aminomethyl chain for the dimethyl-carboxyl chain), and has one 1-beta-methyl chain which provides resistance to dehydropeptidase-I enzyme. The clinical trials conducted so far have focused on the treatment of severe infections such as complicated intra-abdominal infections, complicated urinary tract infections and pyelonephritis, nosocomial pneumonia, and ventilator-associated pneumonia. Given its activity profile and the results from the clinical trials, this antibiotic may be used for empirical treatment of multibacterial infections produced by potentially multiresistant Gram-negative bacilli. In 2007, the US Food and Drug Administration approved the use of doripenem for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. The European Medicines Agency has approved the use of doripenem for the same indications in addition to nosocomial pneumonia regardless of whether it is ventilator-associated or not. Antibiotic Doripenem Essay Example.

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Keywords: doripenem, antimicrobial activity, clinical efficacy, pharmacokinetics, tolerability
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Pharmacodynamic profile
Mechanism of action
Like the other beta-lactams, doripenem inhibits bacterial cell wall biosynthesis by inactivating the penicillin-binding proteins (PBP), which results in bacterial cell death.1 Doripenem has shown a marked affinity for PBP2 and 4 in strains of Escherichia coli MC4100, for PBP2 and PBP3 in strains of Pseudomonas aeruginosa PAO1 and 27853, and for PBP 1 in Staphylococcus aureus.2,3 Because these PBP are considered a fundamental target, the profile described above justifies the broad spectrum of the carbapenem against Gram-negative microorganisms. Furthermore, its greater activity against P. aeruginosa compared to imipenem is due to its higher affinity for PBP2 and PBP3 in strains of this specie. Doripenem is resistant to most beta-lactamases produced by Gram-negative and Gram-positive microorganisms, including penicillinases and cephalosporinases. However, it is hydrolyzed by metallo-beta-lactamases (MBL) and carbapenemases. Results from an in vitro study show a greater stability of doripenem compared to imipenem after exposure to a human recombinant dehydropeptidase I.4 Although this greater stability was first attributed to the 1-beta-methyl group in its structure, this association was later ruled out, based on its lesser stability compared to other carbapenems that have this chemical group. Thus, other functional groups, the distance between them, as well as other factors, may play a role in the stability of these antibiotics in regards to dehydropeptidase I.

Antibacterial activity
In vitro studies have shown that doripenem has a spectrum of activity similar to that of imipenem against Gram-positive microorganisms, while it is similar to meropenem against Gram-negative microorganisms.5–7

Table 1 shows the doripenem-sensitive microorganisms most often involved in infections for which the carbapenem is indicated.1 Similarly to the others in the group, the activity of this carbapenem is limited against strains of methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium, and Stenotrophomonas maltophilia. Antibiotic Doripenem Essay Example.US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) definitions of doripenem’s breakpoints are shown in Table 2.8,9

Table 1
Indications for which doripenem is approved as monotherapy and the microorganisms involved

Indication Microorganism
Complicated intra-abdominal infection Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Bacteroides caccae
Bacteroides fragilis
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Streptococcus intermedius
Streptococcus constellatus
Peptostreptococcus micros
Complicated urinary tract infection, including pyelonephritis Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa
Acinetobacter baumannii
Nosocomial pneumonia, including ventilator-associated pneumonia Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Staphylococcus aureus
Streptococcus pneumoniae
Enterobacter cloacae
Acinetobacter baumannii
Haemophilus influenzae
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Table 2
Breakpoints defined by FDA and EMEA

EMEA FDA
Minimum inhibitory concentration
Microorganism S R S R
Staphylococcus spp.* ≤1 >4 – –
Enterobacteriaceae ≤1 >4 ≤0.5 –
Acinetobacter spp. ≤1 >4 – –
Acinetobacter baumannii – – ≤1 –
Pseudomonas aeruginosa – – ≤2
Pseudomonas spp. ≤1 >4 – –
Streptococcus pneumoniae ≤1 >4 – –
Haemophilus spp. ≤1 >4 – –
Anaerobes ≤1 >4 ≤1 –
Note:

*From methicillin breakpoint.
Abbreviations: EMEA, European Medicines Agency; FDA, US Food and Drug Administration; R, resistant; S, sensitive. Antibiotic Doripenem Essay Example.

Aerobic Gram-negative microorganisms
Different studies have shown a high in vitro activity of doripenem against aerobic Gram-negative microorganisms (Table 3).6,7,10–16

Table 3
In vitro activity of doripenem against various species of Gram-negative microorganisms

Microorganism Strains tested (n) MIC50 MIC90 Range
Acinetobacter spp. 155 0.5 4 0.016–>16
Acinetobacter spp. 3844 2 >8
Acinetobacter baumannii 33 0.5 16 0.03–>32
Acinetobacter baumannii 2982 2 >8
Aeromonas spp. 44 0.5 1 0.03–4
Aeromonas spp. 172 0.5 2
Bordetella pertussis 52 0.25 0.5 0.25–0.5
Burkholderia cepacia 20 2 8 0.12–>16
Burkholderia cepacia 25 8 8 4–16
Burkholderia cepaciaa 200 8 32 0.5–256
Citrobacter spp. 136 0.03 0.06 ≤0.008–2
Citrobacter freundii 22 0.032 0.063 0.032–0.125
Enterobacter spp. 601 0.06 0.12 ≤0.008–4
Enterobacter spp. AmpC 33 – 0.12 –
Enterobacter cloacae 30 0.032 0.063 0.032–0.125
Non-ESBL-producing Escherichia coli 15478 ≤0.06 ≤0.06 –
Non-ESBL-producing Escherichia coli 3023 0.03 0.03 ≤0.008–1
ESBL Escherichia coli 2363 ≤0.06 ≤0.06 –
ESBL Escherichia coli 121 0.03 0.06 0.016–1
Beta-lactamase-negative Haemophilus influenzae 1426 0.06 0.25 ≤0.008–2
Beta-lactamase-positive Haemophilus influenzae 398 0.12 0.25 ≤0.008–1
Beta-lactamase-negative Haemophilus influenzae 33 0.12 1 ≤0.015–1
Beta-lactamase-positive Haemophilus influenzae 28 0.12 0.5 0.12–1
Non-ESBL-producing Klebsiella spp. 1107 0.03 0.06 0.016–>16
ESBL Klebsiella spp. 155 0.06 0.12 0.016–8
Non-ESBL-producing Klebsiella pneumoniae 5387 ≤0.06 ≤0.06 –
Non-ESBL-producing Klebsiella pneumoniae 26 – 0.03 –
ESBL Klebsiella pneumoniae 2444 ≤0.06 1 –
ESBL Klebsiella pneumoniae 34 – 0.06 –
Klebsiella oxytoca 38 0.063 0.063 0.032–0.063
Non-ESBL-producing Klebsiella oxytoca 1013 ≤0.06 ≤0.06 –
ESBL-producing Klebsiella oxytoca 277 ≤0.06 0.12 –
Moraxella catarrhalis 108 0.016 0.03 ≤0.008–0.5
Morganella morganii 32 0.125 0.25 0.063–0.5
Proteus mirabilis 307 0.12 0.25 0.016–0.5
ESBL-producing Proteus mirabilis 11 0.12 0.25 0.06–0.25
Proteus vulgaris 30 0.25 0.5 0.063–0.5
indol-positive Proteae 148 0.12 0.5 0.03–1
Non-ESBL-producing Proteus mirabilis 1766 0.12 0.25 –
ESBL-producing Proteus mirabilis 129 0.25 0.5 –
Providencia rettgeri 21 0.125 0.25 0.063–1
Pseudomonas aeruginosa 829 0.5 8 0.03–>16
Pseudomonas aeruginosa 9256 0.5 8 –
Pseudomonas aeruginosa R carbapenems 49 – >32 –
Pseudomonas aeruginosa R carbapenems 34 8 >32 0.5–>32
MBL-producing Pseudomonas aeruginosa 15 >32 >32 4–>32
Pseudomonas aeruginosa S imipenem 83 0.25 2 0.063–8
Pseudomonas aeruginosa R imipenem 32 8 8 2–16
Pseudomonas aeruginosa R ceftazidime 39 2 8 0.063–16
Pseudomonas aeruginosa R ciprofloxacin 16 0.5 8 0.125–8
Pseudomonas aeruginosa R gentamicin 37 0.5 8 0.063–16
Pseudomonas aeruginosaa 82 0.25 2 0.25–256
Mucoid Pseudomonas aeruginosaa 200 8 32 0.25–512
Non-mucoid Pseudomonas aeruginosaa 200 8 64 0.25–512
Other Pseudomonas spp. 438 0.5 4 –
Salmonella spp. 530 0.06 0.06 0.016–0.25
Serratia spp. 187 0.12 0.25 0.03–1
Serratia marcescens 30 0.125 0.25 0.063–4
Shigella spp. 161 0.03 0.06 0.016–0.06
Stenotrophomonas maltophilia 1269 >8 >8 –
Stenotrophomonas maltophilia 80 >16 >16 1–>16
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Notes:

aStrains isolated from patients with cystic fibrosis. Data from Fritsche et al, 10 Tsuji et al,11 Jones et al,6,7,12 Traczewski et al,13 Chen et al,14 Mendes et al,15 Castanheira et al.16
Abbreviations: AmpC, ampicillinases; ESBL, extended-spectrum beta-lactamases; MBL, metallo-beta-lactamases; MIC, minimum inhibitory concentrations; R, resistant; S, sensitive.

One of the most extensive studies was conducted in 2003 as part of a global microbiological surveillance program, and included strains from more than 70 medical centers in North America, South America, and Europe.10 Strains of both Haemophilus influenzae and Moraxella catarrhalis were susceptible to doripenem (minimum inhibitory concentration required to inhibit the growth of 90% of organisms [MIC90] 0.25 mg/L and MIC50 0.06 mg/L for H. influenzae; MIC90 0.03 mg/L and MIC50 0.016 mg/L for M. catarrhalis), but the activity was lower than that observed for meropenem.10 On the other hand, ertapenem’s activity was higher than doripenem’s against beta-lactamase-producing strains of H. influenzae.6 Doripenem’s MIC50 and MIC90 against Enterobacteriaceae were 0.03–0.12 mg/L and 0.03–0.5 mg/L, respectively; these were similar to those observed for meropenem (MIC50 0.016–0.06 and MIC90 0.03–0.12 mg/L), and lower than those described for imipenem (MIC50 ≤ 0.5–2 and MIC90 0.5–4 mg/L). Similarly, doripenem’s MIC50 and MIC90 were ≤ 0.06–0.25 mg/L and ≤0.06–0.5 mg/L, respectively, in 36,614 Enterobacteriaceae isolates from more than 60 medical centers in North America, Latin America, Europe, and the Asian-Pacific area.15 These results coincide with those from other studies in which doripenem’s MIC90 in Enterobacteriaceae strains was between 0.03 and 0.5 mg/L, with the exception of strains of Proteus mirabilis, in which MIC90 was 1 mg/L.5,7,12 Doripenem’s activity against strains of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae such as E. coli and Klebsiella spp. is similar to that observed for meropenem, and four to eight times higher than ertapenem’s and imipenem’s.7 Against strains of Enterobacter spp. doripenem and meropenem showed an activity eight times higher than that observed for imipenem and ertapenem (MIC90 0.12 mg/L vs MIC90 1 mg/L, respectively).10 Similarly, the MIC of doripenem against strains of AMPc-producing Enterobacter spp. ranged between 0.06 mg/L and 0.5 mg/L, comparable to the activity of meropenem (MIC ≤0.03–0.25 mg/L), and higher than that of imipenem (MIC 0.12–2 mg/L) and ertapenem (MIC 0.06–1 mg/L).17 Other doripenem’s MIC values against imipenem-resistant Enterobacter spp. isolated from bacteremia have been reported (doripenem MIC 0.03–2 mg/L, meropenem MIC 0.06–8 mg/L, ertapenem MIC 0.015–64 mg/mL).18. Antibiotic Doripenem Essay Example.

In contrast, against strains of P. mirabilis, Serratia spp. and Salmonella spp. doripenem’s MIC90 was higher than that observed for meropenem and ertapenem, and lower than that observed for imipenem.10 Several studies have concluded that the activity of doripenem is comparable to that of meropenem against strains of P. aeruginosa and Acinetobacter spp.10,11,19 Thus, doripenem and meropenem were the most active carbapenems against strains of these bacteria, displaying a higher activity than imipenem and ertapenem.6,10 Additionally, doripenem’s activity was similar to that of meropenem against imipenem-sensitive strains of P. aeruginosa, with a MIC90 of 2 mg/mL, and a MIC50 of 0.25 mg/L;19 its activity was higher than that of all other carbapenems against strains of P. aeruginosa that were resistant to imipenem.7 Doripenem’s MIC was ≤4 mg/L for most imipenem-resistant P. aeruginosa isolates from bacteremia included in other study.20 Similarly, doripenem showed a high activity against strains of P. aeruginosa that were resistant to ceftazidime, ciprofloxacin, imipenem or gentamicin; the activity was comparable to that of meropenem, and higher than that of the other antibiotics tested.11,21 As expected, doripenem, like the other carbapenems, had no activity against strains of carbapenemase-producing Gram-negative bacilli.17

Doripenem’s activity is superior to that of imipenem and meropenem in A. baumannii clinical isolates producing the OXA-58 carbapenemase (doripenem’s MIC50 and MIC90 of 4 and 8 mg/L, respectively, and imipenem’s and meropenem’s MIC50 and MIC90 of 16 and 64 mg/L, respectively).22

Aerobic Gram-positive microorganisms
According to various studies conducted, doripenem’s activity against Gram-positive microorganisms is comparable to imipenem’s and superior to meropenem’s and ertapenem’s (Table 4).6,10,11,23

Table 4
In vitro activity of doripenem against various species of Gram-positive microorganisms

Microorganism Strains tested (n) MIC50 MIC90 Range
Enterococcus faecalis (1206) and other non-faecium species (70) 1276 4 8 ≤ 0.008–>16
Enterococcus faecalisa 45 4 16 ≤ 0.015–>32
Enterococcus faecium 198 >16 >16 0.03–>16
Staphylococcus aureus S oxacillin 2705 0.06 0.06 ≤ 0.008–4
Coagulase-negative Staphylococcus S oxacillin 297 0.03 0.06 ≤ 0.008–8
Staphylococcus aureus S methicillin 75 0.03 0.06 0.03–0.06
Staphylococcus aureus R methicillin 75 0.5 8 0.06–32
Staphylococcus aureus I vancomycin 4 16 16 0.06–16
Streptococcus pneumoniae 885 0.016 0.5 ≤ 0.008–1
Streptococcus pneumoniae S penicillin 20 ≤ 0.015 ≤ 0.015 ≤ 0.015
Streptococcus pneumoniae I penicillin 10 0.03 0.25 ≤ 0.015–0.5
Streptococcus pneumoniae R penicillin 23 0.5 1 0.25–2
Streptococcus pneumoniae S penicillin 25 0.008 0.008 0.004–0.016
Streptococcus pneumoniae R penicillin 25 0.25 0.5 0.016–2
Streptococcus viridans group 140 0.03 0.5 ≤ 0.008–>16
Streptococcus viridans group S penicillin 23 0.03 0.06 ≤ 0.015–0.12
Streptococcus viridans group I penicillin 13 0.25 0.5 ≤ 0.015–2
Streptococcus viridans group R penicillin 13 2 4 0.25–4
Beta-hemolytic Streptococcus 397 ≤ 0.008 0.03 ≤ 0.008–0.25
Streptococcus pyogenes 42 ≤ 0.004 ≤ 0.004 ≤ 0.004
Streptococcus agalactiae 32 0.016 0.032 0.016–0.032
Open in a separate window. Antibiotic Doripenem Essay Example.
Notes:

aincludes four van A strains and two van B strains. Data from Fritsche et al,10 Tsuji et al,11 Jones et al,6,7 Brown et al.23
Abbreviations: I, intermediate sensitivity; MIC, minimum inhibitory concentrations; R, resistant; S: sensitive.

Doripenem proved to be more powerful than other carbapenems against strains of oxacillin-sensitive S. aureus (OSSA), with a MIC90 and a MIC50 of 0.06 mg/L, and against oxacillin-sensitive coagulase-negative Staphylococcus spp. with at MIC90 of 0.06 mg/L and a MIC50 of 0.03 mg/L,6,10 while for oxacillin-resistant strains, the MIC90 ranged between 4 mg/L for strains of S. epidermidis, and 32 mg/L for strains coagulase-negative Staphylococcus spp. These values were comparable to those observed with imipenem, and lower than those observed with meropenem and ertapenem.5,19 Doripenem’s activity against strains of Enterococcus faecalis and Enterococcus spp. other than E. faecium was lower than imipenem’s, and higher than that observed with meropenem or ertapenem.10 Thus the MIC90 for doripenem was 8 mg/L, vs 4 mg/L for imipenem, 16 mg/L for meropenem, and >8 mg/L for ertapenem, while the MIC50 for doripenem was 4 mg/L, vs 1 mg/L for imipenem and 8 mg/L for meropenem and ertapenem. Similar results were obtained in another study with strains of E. faecalis, but a lower MIC90 was observed for imipenem, 2 mg/L.5 Like the rest of the carbapenems, doripenem showed little activity against strains of E. faecium, with values of MIC90 and MIC50 over 16 mg/L.5,6,10 These values were independent from the pattern of vancomycin-resistance showed in the strains examined. Doripenem’s activity was comparable to that of imipenem against strains of Streptococcus in the viridans group, with MIC90 of 0.5 mg/L and MIC50 of 0.03 mg/L.10 Based on the MIC50, the activity observed was twice as high as that of meropenem (MIC50 0.06 mg/L, MIC90 0.5 mg/L), and four times as high as that of ertapenem (MIC50 0.12 mg/L, MIC90 1 mg/L). Additionally, doripenem showed an excellent activity against strains of beta-hemolytic Streptococcus spp., Streptococcus pyogenes, and Streptococcus agalactiae, with MIC90 of 0.03 mg/L and MIC50 ≤ 0.008 mg/L.5,10 The activity of the various carbapenems was comparable against strains of Streptococcus pneumoniae, but differences were observed depending on the penicillin-resistance pattern.5 Thus, the MIC50 against penicillin-sensitive strains was ≤0.008 mg/L for doripenem, meropenem, and imipenem, and 0.015 mg/L for ertapenem, while in penicillin-resistant strains, it was 0.5 mg/L, except for ertapenem, whose MIC was 1 mg/L. Antibiotic Doripenem Essay Example.

Anaerobic microorganisms
Doripenem has shown a high in vitro activity against a large number of anaerobic microorganisms (Table 5), with a MIC ranging, in various studies, from ≤0.015 to 32 mg/L.6,24–28

Table 5
In vitro activity of doripenem against various species of anaerobic microorganisms

Microorganism Strains tested (n) MIC50 MIC90 Range
Anaerococcus spp.a 22 ≤ 0.015 0.06 ≤ 0.015–0.5
Bacteroides caccae 16 0.5 2 0.25–4
Bacteroides distasonis 15 0.5 2 0.125–2
Bacteroides fragilis 26 0.25 0.5 0.12–1
Bacteroides fragilis 81 0.5 1 0.25–16
Bacteroides fragilis 198 0.5 1 0.125–16
Bacteroides ovatus 20 0.5 1 0.12–2
Bacteroides ovatus 35 0.5 2 0.25–4
Bacteroides thetaiotaomicron 42 0.5 1 0.12–2
Bacteroides thetaiotaomicron 78 0.5 1 0.125–8
Bacteroides uniformis 21 0.5 1 0.125–1
Bacteroides vulgatus 31 0.5 2 0.125–2
Bilophila wadsworthia 21 0.12 0.12 0.03–0.12
Clostridium difficile 110 1 2 0.5–4
Clostridium perfringensa 10 ≤ 0.015 0.03 ≤ 0.015–0.03
Clostridium perfringens 13 0.06 0.125 0.06–0.125
Corynebacterium amycolatuma 14 0.5 2 0.06–>32
Corynebacterium spp. group I (C. aurimucosum, C. jeikeium, C. minutissimum, C. urealyticum)a 14 1 8 0.25–>32
Corynebacterium spp. group I (C. striatum, C. accolens, C. simulans, C. xerosis)a 18 0.125 0.25 ≤ 0.015–0.25
Finegoldia magnaa 30 0.06 0.125 ≤ 0.015–0.25
Fusobacterium spp. 15 0.031 1 0.03–1
Peptoniphilus asaccharolyticusa 20 ≤ 0.015 0.06 ≤ 0.015–0.125
Peptostreptococcus spp.a 17 0.06 0.25 0.03–0.25
Peptostreptococcus magnus 21 0.0625 0.125 0.0156–0.5
Porphyromonas spp. 20 0.031 0.5 0.03–4
Prevotella spp. 20 0.12 0.25 0.03–1
Prevotella bivia 28 0.25 1 0.125–4
Prevotella intermedia/nigrescens 10 0.031 0.062 0.03–0.06
Prevotella oris/buccae 10 0.12 0.5 0.03–0.5
Propionibacterium acnesa 14 0.06 0.125 0.03–0.25
Propionibacterium acnes 18 0.06 0.06 0.06–0.06
Propionibacterium spp. 13 0.06 0.06 0.06–0.06
Sutterella wadsworthensis 12 4 8 0.06–32
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Notes:

aStrains isolated from patients with infected diabetic foot wound. Data from Goldstein et al,26 Jones et al,6,7 Wexler et al,24 Hecht et al,27 Mikamo et al,28 Snydman et al.25
The highest MIC values were obtained against strains of Clostridium difficile, but they were lower than the MICs obtained with ertapanem and meropenem.24,27 Doripenem has shown a high activity against strains of Bacteroides fragilis, with MIC50 and MIC90 values of 0.25 mg/L and 0.5 mg/L, respectively.6

Mechanisms of resistance
Various resistance mechanisms to carbapenems have been identified; they include the loss of porin OprD, the expression of efflux systems, the production of carbapenemases, and the alteration of certain penicillin-binding proteins (PBPs).29

In the specific case of doripenem, treatment with the carbapenem has been associated with a reduced potential of selection of resistance in strains of P. aeruginosa, for which reason it may be a good alternative to cover infections by these microorganisms.7,30 With regard to the loss of porins, an experiment with five mutant strains selected after exposure to doripenem identified the loss of OprD in some of the strains, which produced cross-resistance only with the other carbapenems.30

Another study had the objective of determining the specific substrates of three different efflux systems, MexAB-OprM, MexCD-OprJ, and MexXY-OprM, in strains of P. aeruginosa.31 For this purpose, three isogenic mutants were constructed, each constitutively producing mostly one of the three efflux systems and neither of the other two; the isogenic mutants lacking this mechanism were then compared.Antibiotic Doripenem Essay Example.  All efflux pumps expelled different antibiotics, including quinolones, macrolides, tetracyclines, lincomycin, chloramphenicol, most penicillins and cephalosporins, meropenem, and doripenem. However, polymyxin B and imipenem were not affected. Another study included two strains of B. fragilis, WAL 108 and WAL 219;32 its objective was to determine the potential of various antimicrobials, including doripenem, to select mutant strains of multi-resistant B. fragilis by overexpression of bmeB efflux pumps. Ampicillin, doripenem, imipenem, levofloxacin, and metronidazole selected multiresistant mutants derived form both strains. All mutant strains derived from WAL 219, except those selected with doripenem, showed more than twice an overexpression of one or more of the bmeB genes compared to strains selected from WAL 108. Although the strains derived from WAL 219 after exposure to doripenem did not overexpress any bmeB efflux pump, they did show multidrug resistance, which means that there is overexpression of other genes that codify other efflux pumps.

Like the rest of the carbapenems, doripenem’s activity is decreased in the presence of carbapenemases produced by strains of certain microorganisms.17 Thus, the MIC increased from 0.25–1 μg/mL to 16–64 μg/mL in strains of metallo-beta-lactamase (MBL)- or OXA-type carbapenemase-producing Acinetobacter spp. and from 8 μg/mL to more than 64 μg/mL in strains of IMP-, KPC-, and SME-type beta-lactamase-producing Klebsiella spp. and Serratia spp. However, based on the sensitivity displayed by IMP-1 and NMC-A beta-lactamase-producing strains of E. coli by transconjugation, resistance to carbapenems might require other additional mechanisms.

Although the enzymes described above have been more often implicated in the inactivation of carbapenems, these antibiotics did not behave like inactivators of the enzyme CTX-M-14 produced by strains of E. coli TUM1121.33 However, the enzyme’s catalytic activity was very reduced, according to the values obtained for kinetic parameters at steady state.

Although doripenem has shown a high affinity for all types of PBP in strains of penicillin-sensitive S. pneumoniae, it has been reduced in resistant strains, especially when PBP2x and PBP2b are affected.34

Associating doripenem with an aminoglycoside seems to reduce the potential selection of strains that are highly resistant to carbapenem, according to the results observed after exposing six strains of P. aeruginosa from patients with bacteremia to doripenem or to the association of carbapenem and gentamicin.35

The various resistance mechanisms described above come mostly from in vitro studies with doripenem. For this reason, more studies are required in order to learn more about these mechanisms more precisely, and to understand their effects on routine clinical practice. Antibiotic Doripenem Essay Example.

Bactericidal activity
Doripenem has shown an excellent bactericidal activity against aerobic and anaerobic microorganisms, comparable to that of the other carbapenems, and better than that of ceftazidime. After 48 hours of exposure to doripenem at a concentration of twice the MIC (2XMIC), a 99.9% eradication of strains of seven anaerobic species was observed.36 In strains of P. aeruginosa, the exposure to doripenem achieved a higher elimination when the concentration of the antibiotic was 10 times the bacterium’s MIC.37 In a computerized pharmacokinetics simulation model, the exposure to doripenem, imipenem, and meropenem for two hours reduced the number of CFU/mL more than 2 log10, while ceftazidime only achieved a similar reduction with an exposure of over four hours. Experimental models have yielded similar results.28

Pharmacokinetic/pharmacodynamic parameters
The integration of pharmacokinetic/pharmacodynamic parameters (PK/PD) derived from nonclinical models with pharmacokinetic data from phase I studies may be useful for the purpose of optimizing antibiotic dosage regimens in phase II and III studies.38 In the case of doripenem, one study39 used the PK/PD parameters obtained in another study with a mouse-thigh infection model, in which the mean value of parameter T > MIC associated with 1 log10 and 2 log10 reductions in CFU/thigh were 21.1 ± 8.9% and 27.3 ± 11.9% for strains of S. pneumoniae, 32.3 ± 6.7% and 35.4 ± 5.0% for strains of S. aureus, and 36.1 ± 7.4% and 43.3 ± 7.1% for Gram-negative bacilli, respectively.40 Additionally, by using the pharmacokinetic data from phase I studies, and applying the Monte Carlo simulation, the probability of obtaining a T > MIC over 35% was determined for different dosage regimens of doripenem (doses of 250, 500, 750, 1,000, 2,000, and 3,000 mg; intervals of 6, 8, 12, and 24 hours, and duration of infusion of 1 to 6 hours, and 24 hours). According to the results, when the MIC was 1 mg/L, the probability of obtaining a T > MIC of 35% was observed with all the doses studied (250–1,000 mg) administered every eight hours, irrespective of the duration of the infusion. On the other hand, when the MIC was 2 mg/L, the probability of obtaining the objective value of the PK/PD parameter was similar with doses of 500 mg or higher administered every eight hours in one-hour infusions. A regimen of 500 mg every eight hours in one-, two-, and three-hour infusions resulted in a 0.99, 1, and 1 probability of obtaining a value of T > MIC of 35%, respectively. Antibiotic Doripenem Essay Example.Finally, when MIC was 4 or 8 mg/L, the probability of obtaining a T > MIC of 35% was higher when the same daily doses of doripenem were used, but over a longer infusion time. When MIC was 4 mg/L a regimen of 500 mg every eight hours in three-, four- or five-hour infusions resulted in a 1, 1, and 0,99 probability of obtaining a T > MIC of 35%, respectively. Similarly, a regimen of 1, 000 mg every 12 hours in four-, five- or six-hour infusions resulted in a probability of obtaining a T > MIC of 35% of 1 in all cases. Additionally, a regimen of 1,000 mg every eight hours in one-, two- or three-hour infusions resulted in a probability of obtaining a T > MIC of 35% of 0.99, 1, and 1, respectively. Finally, a regimen of 1,000 mg every 24 hours in 24-hour infusion led to a probability of 0, but 2,000 mg or 3,000 mg led to a probability of obtaining a T > MIC of 35% of 0,98 and 1, respectively. On the other hand, when MIC was 8 mg/L, a regimen of 1,000 mg every eight hours in three-, four- or five-hour infusions resulted in 1, 1, and 0.99 probability of obtaining a T > MIC of 35%, respectively. However, a regimen of 1,000, 2,000 or 3,000 mg every 24 hours in 24-hour infusion led to a 0, 0, 0,46 probability of obtaining a T > MIC of 35%, respectively.

Thus, by prolonging the infusion time, the administration of similar doses may be effective in the treatment of microorganisms with different doripenem’s MICs.

Similarly to the study above, another study with a mouse-thigh infection model with strains of P. aeruginosa used the doripenem dosages that allowed an approximation to the T > MIC simulated in human beings, based on pharmacokinetic parameters from 24 healthy individuals1 after the administration of 500 mg every eight hours, either in a one-hour or a four-hour infusion.41 By administering the antibiotic in a one-hour infusion, the achieved reduction in the bacterial load was approximately 3 log10 CFU/mL when the MIC was between 0.125 mg/L and 2 mg/L, with a T > MIC between 42.5% and 100%; the results varied widely when the MIC was 4 mg/L or 8 mg/L, with T > MIC values of 20% and 30%, respectively. Thus, bacterial growth was observed in two of the eight strains that showed these MIC values, one of 4 mg/L, and the other of 8 mg/L. Finally, bacterial growth was observed in the strains with a MIC of 16 mg/L, with a T > MIC value of 10%. On the other hand, by administering the antibiotic in a four-hour infusion, the efficacy obtained was similar to that observed with the one-hour administration, when the MIC was 2 mg/L, with a T > MIC value between 42.5% and 70%. Surprisingly, the bacterial growth observed was of approximately 1 log10 CFU/mL in two of the four strains with a MIC of 4 mg/L, with a T > MIC value of 52.5%, an unexpected result. However, the decrease in the bacterial load observed in the two remaining strains was –1.5 to –2.5 log10 CFU/mL, with a T > MIC similar to that of the other two strains, ie, 52.5%. This decrease was greater than that observed with a one-hour infusion. Finally, a global growth was observed in the bacterial density when the MIC was between 8 and 16 mg/L, but MIC was not surpassed at any time (T > MIC = 0%). Thus, exposure to T > MIC values ≥ 40% resulted in a more effective bactericidal activity, while values of this parameter between 20% and 30% led to more variable results. Antibiotic Doripenem Essay Example. Similar values for the T > MIC parameter of doripenem were reported in a study that used an in vitro PK/PD against three strains of P. aeruginosa.42 Thus, steady state was reached with values of this index of 25%, 23.9%, and 39.8% for each of the strains, a bacterial eradication of 2 log CFU/mL was obtained with values of 28.1%, 29.5%, and 49.6%, and 90% of maximum bacterial eradication was obtained with T > MIC values of 36.5%, 46.8%, and 80.7%. This study, along with a prior study that used a pharmacodynamic model for analyzing bactericidal kinetic parameters in vitro,43 did not take into account the possible role of certain factors that appear only in vivo and which may affect the antimicrobial agent’s activity, such as the immune system. With the purpose of attenuating this limitation, another study used a simulation strategy and a PK/PD model to simulate doripenem’s, imipenem’s, and meropenem’s bactericidal profile in a murine model of P. aeruginosa lung infection.44 The results showed a good estimation of the bacterial eradication curves obtained by the model when applied to animals, which may be useful in the future design of therapeutically useful dosage regimens.

The results of another study with 100 strains of P. aeruginosa showed a higher probability of reaching a T > MIC value of 25% (T > MIC 25%) and 40% (T > MIC 40%) with doripenem vs imipenem and meropenem, regardless of the dosage regimen used.45 Thus, the probability of achieving the T > MIC 25% and T > MIC 40% for doripenem with the 500 mg every eight hours in a half-hour infusion regimen was 77.2% and 54.9%, respectively, when the dilution method used to obtain the MIC was the serial twofold dilution method; these values were 80.2% and 54.7% respectively, when an integrated concentration method was used to obtain the MIC. Similarly, the probability of obtaining T > MIC 25% and T > MIC 40% for doripenem with the 250 mg every eight hours in a half-hour infusion scheme was 60.6% and 37.4%, respectively, when the dilution method used to obtain the MIC was the serial twofold dilution method, while these values were 60.4% and 36.8%, respectively, when an integrated concentration method was used. Population pharmacokinetic modeling was conducted using drug concentration data in plasma and urine from 18 patients with urinary tract infection and prostatitis.46 Based on this pharmacokinetic model, a Monte Carlo simulation predicted the probabilities of attaining T > MIC 40% in plasma and defined the PK/PD breakpoints. Antibiotic Doripenem Essay Example. The highest MIC at which the probability of target attainment in plasma was ≥90% varied with creatinine clearance (CL) and doripenem regimen. The value for 500 mg every eight hours with a creatinine CL of 80 mL/min corresponded to those for 250 mg every eight hours with a creatinine CL of 40 mL/min and 250 mg every 12 hours with a creatinine CL of 20 mL/min, all of them administered in one-hour infusion. The aim of a recent study was to analyze the urinary bactericidal titers (UBTs) and 24-hour area under the UBT-versus-time curve (AUBT) of intravenous doripenem (500 mg every eight hours) versus those of intravenous levofloxacin (250 mg every 24 hours) in patients with complicated urinary tract infections or pyelonephritis.47 For the selected clinical strains, median UBTs and median 24-hours AUBTs of doripenem ranged between 1.5 and 65,536 and between 224 and 909,312, respectively. These values were significantly higher than those of levofloxacin, with the exception of S. aureus 1134684 (median UBTs 0–128, median 24-hour AUBTs 0–2,208). Eight microbiological failures were observed, three after doripenem treatment and five after levofloxacin treatment. In the levofloxacin group, microbiological failures were observed only in patients with AUBT values of 152 or lower, whereas no correlation between treatment failure and AUBT level was found in the doripenem group.

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The clinical safety and efficacy of some of the dosing regimens have been confirmed in phase III clinical trials.48 However, phase III clinical trials of doripenem in hospital-acquired pneumonia at a dose of 1,000 mg infused over four hours every eight hours are undergoing clinical evaluation.

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Pharmacokinetic profile
Distribution
The administration of a single 500 mg dose of doripenem to 24 healthy subjects by intravenous infusion over one hour was associated with a mean maximum concentration (Cmax) of 23 ± 6.6 μg/mL and an AUC of 36.3 ± 8.8 μg·h/mL.1 In another study, the administration of a single 500 mg dose of radiolabeled doripenem to eight healthy individuals in a one-hour infusion produced a Cmax of 22.9 ± 2.37 μg/mL, which was reached in a period (Tmax) of 1.02 hours.26 Also, AUC0–∝ was 31.8 ± 4.50 μg·h/mL. Doripenem was the main plasma component, and represented 80.7% of the AUC0–∝ for total plasma radioactivity. Antibiotic Doripenem Essay Example.

The binding of doripenem to plasma proteins is estimated to be 8.1%, regardless of the plasma concentrations obtained.1 The mean distribution volume is 16.8 L (range: 8.09–55.5) in healthy individuals once steady state has been reached; this value is similar to the extracellular fluid volume (18.2 L).

The administration of doripenem to 10 abdominal surgery patients yielded an AUC0–∝ of 59.3 ± 7.2 mg·h/L in serum, and of 49.3 ± 6.5 mg·h/L in peritoneal exudate, with a ratio of AUC0–∝ exudate/AUC0–∝ serum of 0.84 ± 0.13.49 Despite these values, T > MIC yielded a slightly higher value in peritoneal exudate compared to serum, but significant differences were seen only when the MIC was 1 or 4 mg/L. Thus, T > MIC in the exudate compared to that in serum was 78.2 ± 10.6% vs 73.6 ± 12%, respectively when the MIC was 1 mg/L; 41.5 ±7.3% vs 37.0 ± 6.3% respectively, for a MIC of 4 mg/L; and 13.1 ± 4.0% vs 12.7 ± 1.7% respectively, for a MIC of 16 mg/L. This fact may be explained by the small difference (only 0.2 hours) observed in reaching the Tmax in both compartments; for this reason it has been thought that the concentration in the exudate would be higher than in serum once 0.81 hours had elapsed after administration. In addition to the peritoneal level, doripenem has also shown an ability to penetrate other tissues and/or fluids, according to studies in animal models (Table 6).50. Antibiotic Doripenem Essay Example