The carbapenem class of antibiotics

Through the decades, bacterial resistant are increased which need to use a new types of antibiotic with a wide range of sensitivity; one of them is the carbapenem class of antibiotics.
The discovery of Streptomyces cattleya and its antibiotic product, thienamycin, has ushered in a new era of beta-lactam agents, the carbapenems. Numerous carbapenems were subsequently discovered; however, none had the potency, broad-spectrum activity, and lack of cross-resistance exhibited by thienamycin. Chemical instability encountered with thienamycin was overcomed by the N-formimidoyl derivative, imipenem. Imipenem is distinguished from other beta-lactams by its outstanding activity against gram-positive organisms as well as against enterobacteriaceae, pseudomonas aeruginosa, and bacteroides. However, development was hindered by extensive renal metabolism of imipenem, resulting in low urinary concentrations of antibiotic. A renal dipeptidase, dehydropeptidase-I, was responsible for hydrolyzing imipenem and other carbapenems. To counter its action, a specific inhibitor, cilastatin, was developed. Co-administered with imipenem in a one-to-one ratio, cilastatin provides prolonged, reversible blockade of imipenem metabolism, dramatically improving urinary recoveries to therapeutically significant levels. Cilastatin also contributes to the safety of imipenem, since its co-administration prevents proximal tubular necrosis, which had been observed in sensitive animals receiving imipenem alone in high doses. Thus, the combination imipenem and cilastatin overcame the pharmaceutical and metabolic challenges presented by thienamycin, and allowed for the evaluation in humans of the outstanding antimicrobial activity of this new class of beta-lactam antibiotics. (1)
Imipenem (Primaxin) is an intravenous ??-lactam antibiotic discovered by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in 1980. It was the first member of the carbapenem class of antibiotics. Carbapenems are highly resistant to the ??-lactamase enzymes produced by many multiple drug-resistant gram-negative bacteria thus play a key role in the treatment of infections not readily treated with other antibiotics. Imipenem has a broad spectrum of activity against aerobic and anaerobic, gram-positive and gram-negative bacteria. It is particularly important for its activity against pseudomonas aeruginosa and the enterococcus species. However, it is not active against methicillin-resistance staphylococcus aureus (MRSA).
Drug-induced acute kidney injury (AKI) is a significant problem in critically ill patients. The kidneys receive about 25% of cardiac output and concentrate several drugs far in excess of blood levels, making the kidneys susceptible to toxicities. Almost all drugs’including antibiotics such as ??-lactams, cephalosporins, sulfonamides, quinolones, macrolides, rifampin, and isoniazid’have the potential to cause AKI by causing AIN.41 AIN has been implicated as the underlying pathology in 10 to 15% of renal biopsies in patients with unexplained renal failure. An increase in serum creatinine is seen within 2 to 44 days of drug exposure, and earlier with subsequent re-exposure to the same drug. Fever, skin rash, and arthralgias are seen in up to 30 to 40% of patients, eosinophilia and eosinophiluria in 40 to 100%. The outcome is usually favorable after withdrawal of the drug; systemic corticosteroid therapy may hasten recovery, although data from prospective, randomized trials evaluating the efficacy of this approach are lacking. Temporary hemodialysis was needed in 35% of patients. Drug-induced AIN may be associated with a rare systemic process called DRESS syndrome, or drug rash with eosinophilia and systemic symptoms, that is characterized by skin rash, fever, eosinophilia, and visceral involvement; it has a 10% mortality rate, and interstitial nephritis occurs in about 10% of these cases (2).
The recently released thienamycin antibiotic, imipenem, like the toxic cephalosporins, produces acute proximal tubular necrosis which can be prevented completely by prior administration of probenecid. The ability of imipenem to block mitochondrial substrate uptake and respiration and produce oxidative changes has not been examined. We therefore evaluated the effects of imipenem in rabbit renal cortex on the following:
(1) mitochondrial function [respiration with and uptake of succinate, and uptake of ADP];
(2) evidence of oxidative change [depletion of reduced glutathione (GSH),
production of oxidized glutathione (GSSG), and production of lipid peroxidative injury, as reflected in microsomal conjugated dienes (CDs)]. The mitochondrial effects of 300 mg/kg body wt of imipenem, given i.v. 1 and 2 hr before killing the animals, were comparable to those of the nephrotoxic cephalosporins. There was singnificant reduction of respiration with, and unidirectional uptake of, succinate at both times, while mitochondrial ADP transport was comparatively unaffected. Imipenem also depleted GSH and increased GSSG and CDs at 1 hr. These effects, however, were considerably smaller than those of a comparably nephrotoxic dose of cephaloridine, and this evidence of oxidative stress had resolved by 2 hr. We conclude that imipenem and the nephrotoxic cephalosporins have similar effects on mitochondrial substrate uptake and respiration, but differ significantly in their production of oxidative injury.(3)
Radioopaque dyes used during imaging tests of the kidneys can sometimes lead to kidney failure and nearly always result in reduced kidney function, but the results of a new study showed that popular antioxidant, N-Acetyl Cysteine (NAC), greatly reduces this risk. The dye is injected into the body, and within a few minutes, it accumulates in the kidneys. Then an X-ray picture can be taken that will show the structure of the kidneys. Many researchers think that the damage is inflicted by oxidation, which causes cell damage. NAC is used to treat several types of lung disease as well as to treat people who have overdosed on acetaminophen, the active ingredient in pain relievers like tylenol. The study included 83 people with kidney problems who were randomly assigned to receive NAC before and after injection with a dye or to receive a placebo. Based on several measures of kidney function, people taking NAC were less likely to experience kidney damage. NAC may also increase the biologic effects of nitric oxide by combining with it to form S-nitrosothiol, which is a more stable form and a potent vasodilator. This interaction may also limit the production of the damaging peroxinitrite radical, since NAC would compete with the superoxide radical for nitric oxide. NAC also increases the expression of nitric oxide synthase and may thus improve blood flow as well (4).
Contrast-induced acute kidney injury is an adverse outcome resulting from radiocontrast medium exposure during coronary angiography and percutaneous coronary intervention. A systematic search was conducted to retrieve studies that investigated the impact of statin exposure before coronary angiography or percutaneous coronary intervention on the development of contrast-induced acute kidney injury. The primary outcome was the development of contrast-induced acute kidney injury. We separately analyzed statin/placebo comparisons and high-/low-dose statin comparisons. Fifteen randomized controlled trials met inclusion criteria: 11 studies with statin-na??ve subjects, 2 studies with chronic statin users, and 2 studies with unspecified prior statin exposure. Statin exposure reduced the risk of contrast-induced acute kidney injury relative to placebo (relative risk [RR] 0.63, P = .01) with a nonsignificant reduction in the need for hemodialysis (RR 0.25, P = .08). This benefit was also observed in high-dose versus low-dose statin trials (RR 0.46, P = .004), in statin-na??ve patients (RR 0.53, P <.0001), and with all studied statins. Higher statin exposure reduced contrast-induced acute kidney injury in patients with acute coronary syndromes compared with placebo or low-dose statins (RR 0.49, P <.00001), with no significant benefit among patients undergoing elective procedures (RR 0.86, P = .50). Subgroup analyses confirmed the benefit of statins in patients with diabetes, chronic kidney disease, congestive heart failure, and those receiving >140 mL of contrast dye. Statin therapy is effective at reducing the risk of contrast-induced acute kidney injury. It should thus be considered, at least on a short-term basis, for patients at increased risk of this complication. (5)
High doses of a popular cholesterol-lowering drug significantly reduced the rate of acute kidney injury caused by dye used in imaging in acute coronary syndrome patients who underwent a coronary procedure, according to new research. This group of patients is at high risk for kidney damage related to contrast agents used in imaging tests. (6)
So our research is about the effect and the advantage of using NAC alone , statin alone and both of them with imipenem to reduce the nephrotoxicity as a acute kidney injury .
References :-
1) Jerome Birnbaum , Frederick M. Kahan , Helmut Kropp , James S. Macdonald, Carbapenems, a new class of beta-lactam antibiotics: Discovery and development of imipenem/cilastatin , The American Journal of Medicine Volume 78, Issue 6, Supplement 1, 7 June 1985, Pages 3’21.
2) Ghousia Wajida, and Richard Fatica, Drug-Induced Acute Kidney Injury in the ICU , PCCSU, the American College of Medicine , 2008.
3) Bruce M. Tune, Doris Fravert, Chieh-Yin Hsu , Thienamycin nephrotoxicity : Mitochondrial injury and oxidative effects of imipenem in the rabbit kidney, Biochemical Pharmacology Volume 38, Issue 21, 1 November 1989, Pages 3779’3783.
4) NAC Protects Kidneys From Dye-Related Failure, The New England Journal of Medicine July 20, 2000;343:180-184,210-212.
5) Gandhi S, Mosleh W, Abdel-Qadir H, Farkouh ME , Statins and contrast-induced acute kidney injury with coronary angiography. Am J Med. 2014 Oct;127(10):987-1000.
6) Drug protects against kidney injury from imaging dye in ACS patients, American College of Cardiology , Science Daily . March 11, 2013.

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